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What was the dosage of drug 'PREDNISONE'? | SRP-positive necrotising myopathy: takes more than just the muscles.
Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.
Background
Necrotising myopathy is a rare autoimmune disease that is thought to primarily affect muscles and commonly presents as weakness; it has been reported that there are associated effects on the heart and lungs. This case describes a middle-aged woman presenting with a chief report of shortness of breath, who was subsequently found to have muscle weakness and respiratory failure due to signal recognition particle (SRP)-positive myopathy. In this case, we evaluate her clinical course, review the literature regarding SRP-positive myopathy and strengthen the case that due to the ubiquitous nature of the SRP autoantibodies; patient presentations can extend beyond proximal muscle weakness.
Case presentation
A previously independently functioning 52-year-old obese African American woman initially presented to her primary care office with a chief report of unresolving shortness of breath, which seemed to be incited after she tripped over a broom at work. Previous medical history was significant for hyperlipidaemia treated with simvastatin 40 mg for primary prevention from 2013 to 2020, morbid obesity, congestive heart failure and coronary artery disease.
Patient’s primary care doctor sent the patient for a CT angiogram that was significant for pulmonary hypertension and hepatic inflammation. In the following weeks, she was admitted for progressive muscle weakness.
Patient was found to have a creatine kinase (CK) elevation that peaked at 25 295 U/L. MRI of the lumbar spine revealed diffuse oedema of the pelvic muscles. Left quadriceps muscle biopsy was interpreted with ‘rare’ necrotic fibres, ‘occasional’ cytochrome c oxidase-intermediate (COX)-negative fibres, without deposits of complement macrophage antigens (MAC), and major histocompatibility (MHC) class I staining. SRP and -hydroxy-3-methyl-glutaryl-coenzymereductase (HMGCR) antibodies were negative. Antinuclear antibodies (ANA), nuclear ribonucleoprotein (RNP), Sjögren’s syndrome antibody (SSA), double-stranded DNA and myeloperoxidase antibodies were positive. Her home simvastatin was held, she was treated with prednisone and intravenous immunoglobulin. Her CK gradually decreased to the 2000–4000 U/L.
She continued to experience shortness of breath and was found to have a non-ST elevation myocardial infarction treated with medical management and stent placement for left anterior descending lesion. Further evaluation with an electromyography showed a diffuse, proximal-predominant, irritable myopathy and distal axonal polyneuropathy.
Laboratory workup was consistent with elevated erythrocyte sedimentation rate (ESR) and positive ANA with a homogeneous pattern, which is typically seen in lupus, RNP as well as SSA antibodies as noted at the outside hospital. SRP 54 was now positive. CT C/A/P did not identify any malignancy. Muscle biopsy was significant for highly active and chronic necrotising myopathy with inflammation, mild mitochondrial dysfunction, preferential type 2 atrophy, increased type 2C fibres, occasional rounded atrophic fibres and mild denervation atrophy, indicative of highly active and possibly chronic necrotising myopathy.
Treatment
Patient was treated with prednisone, IVIG and mycophenolate mofetil.
Outcome and follow-up
Patient initially failed to improve. Her course was complicated by worsening heart failure, respiratory failure requiring intubation with transition to tracheostomy and dysphagia requiring nasogastric tube for nutrition. She continued to slowly decline and was evaluated for placement at a long-term care facility. After a course at a long-term acute care, the patient returned home with continued needs for assistance with activities of daily living.
Discussion
Immune-mediated necrotising myopathy (IMNM) is characterised by minimal infiltration on muscle biopsy and is one of the most severe and progressive myopathies.1 2 In our case, the patient was SRP 54 positive, a subunit of the SRP protein complex, presenting with shortness of breath, followed by weakness, then dysphagia. It is commonly thought that the type of autoantibody will predict the course of the myopathy and the associated extra muscular manifestations. SRP is a ribonuclear protein that regulates translocation of protein across the endoplasmic reticulum. It is not specific to muscle tissue but is ubiquitously found in all protein processing cells.2 Myopathies associated with SRP antibodies were thought to have a similar clinical presentation; however, the literature suggests the presentation of SRP associated myopathy can vary greatly. Anti-SRP-related myopathy is now considered a subset of IMNM, also known as necrotising autoimmune myopathy. Symptoms of anti-SRP myopathy are range from weakness, dysphagia and cardiovascular involvement, with some studies showing lower association with interstitial lung disease (ILD).3 While limb weakness is the most common manifestation of myositis, there are reports of the SRP protein antibodies leading to different presenting symptoms involving the lungs and heart.2 4Involvement of the haematologic system with neutropenia and other alterations in proliferation were also identified.2 5 The ubiquitous nature of the SRP protein leads to multiple different manifestations when attacked by the immune system, from pulmonary, cardiac and haematologic.6 7 Myocardial involvement in anti-SRP myopathy can be severe and is considered a poor prognostic factor. Extramuscular manifestations such as ILD, Raynaud’s and arthralgia have been reported, though these features are typically mild. Some authors have suggested that radiographic suggestion of ILD in these patients may in fact arise from respiratory insufficiency due to musculoskeletal weakness.8
Other autoimmune conditions may have been at play in our patient and her dramatic hospital course. It has been shown that patients positive for ANA in a homogeneous pattern, consistent with SLE, is potentially associated with an overlap syndrome of SLE and necrotising myopathy. While this may have been present in our patient, the likelihood is low as there was no history of SLE in our patient. Furthermore, the overlap between SLE and necrotising myopathy has only been described in one case report to date.9 With this knowledge, clinicians should be aware of the complications of dysphagia, respiratory and cardiac failure and initiate prompt treatment to avoid further complications in the patient’s clinical course.
In fact, involvement of muscles with a symptom of weakness may not be as prominent as other symptoms such as shortness of breath or dysphagia. This is logical given the ubiquity of SRP and the ability of the antibody to cause dysfunction in different tissues.2
Patient’s perspective
As this was during the COVID pandemic, it was extremely difficult for me to adjust to the situation and the loss of the ability to care for myself. I often felt alone and was very scared. As I was in the hospital for over 6 months, I feel that I missed out a lot with my family. We lost my son to a gunshot wound before my sickness and I was also grieving that loss.
Learning points
Necrotising myopathy is a rare but fatal aetiology in patient’s presenting with weakness and shortness of breath.
Patients can have variable presentations and may initially present with symptoms other than skeletal muscle weakness.
Treatment of the condition should not be delayed while workup is undertaken as it can result in pulmonary hypertension and serious pulmonary and cardiac manifestations.
It is imperative to know a patient’s functional baseline to set expectations for the clinical course of a myopathy pathology
Contributors: MB: served as scientific advisor. SB: wrote and researched case.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | UNKNOWN | DrugDosageText | CC BY-NC | 33608334 | 19,753,479 | 2021-02-19 |
What was the dosage of drug 'SIMVASTATIN'? | SRP-positive necrotising myopathy: takes more than just the muscles.
Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.
Background
Necrotising myopathy is a rare autoimmune disease that is thought to primarily affect muscles and commonly presents as weakness; it has been reported that there are associated effects on the heart and lungs. This case describes a middle-aged woman presenting with a chief report of shortness of breath, who was subsequently found to have muscle weakness and respiratory failure due to signal recognition particle (SRP)-positive myopathy. In this case, we evaluate her clinical course, review the literature regarding SRP-positive myopathy and strengthen the case that due to the ubiquitous nature of the SRP autoantibodies; patient presentations can extend beyond proximal muscle weakness.
Case presentation
A previously independently functioning 52-year-old obese African American woman initially presented to her primary care office with a chief report of unresolving shortness of breath, which seemed to be incited after she tripped over a broom at work. Previous medical history was significant for hyperlipidaemia treated with simvastatin 40 mg for primary prevention from 2013 to 2020, morbid obesity, congestive heart failure and coronary artery disease.
Patient’s primary care doctor sent the patient for a CT angiogram that was significant for pulmonary hypertension and hepatic inflammation. In the following weeks, she was admitted for progressive muscle weakness.
Patient was found to have a creatine kinase (CK) elevation that peaked at 25 295 U/L. MRI of the lumbar spine revealed diffuse oedema of the pelvic muscles. Left quadriceps muscle biopsy was interpreted with ‘rare’ necrotic fibres, ‘occasional’ cytochrome c oxidase-intermediate (COX)-negative fibres, without deposits of complement macrophage antigens (MAC), and major histocompatibility (MHC) class I staining. SRP and -hydroxy-3-methyl-glutaryl-coenzymereductase (HMGCR) antibodies were negative. Antinuclear antibodies (ANA), nuclear ribonucleoprotein (RNP), Sjögren’s syndrome antibody (SSA), double-stranded DNA and myeloperoxidase antibodies were positive. Her home simvastatin was held, she was treated with prednisone and intravenous immunoglobulin. Her CK gradually decreased to the 2000–4000 U/L.
She continued to experience shortness of breath and was found to have a non-ST elevation myocardial infarction treated with medical management and stent placement for left anterior descending lesion. Further evaluation with an electromyography showed a diffuse, proximal-predominant, irritable myopathy and distal axonal polyneuropathy.
Laboratory workup was consistent with elevated erythrocyte sedimentation rate (ESR) and positive ANA with a homogeneous pattern, which is typically seen in lupus, RNP as well as SSA antibodies as noted at the outside hospital. SRP 54 was now positive. CT C/A/P did not identify any malignancy. Muscle biopsy was significant for highly active and chronic necrotising myopathy with inflammation, mild mitochondrial dysfunction, preferential type 2 atrophy, increased type 2C fibres, occasional rounded atrophic fibres and mild denervation atrophy, indicative of highly active and possibly chronic necrotising myopathy.
Treatment
Patient was treated with prednisone, IVIG and mycophenolate mofetil.
Outcome and follow-up
Patient initially failed to improve. Her course was complicated by worsening heart failure, respiratory failure requiring intubation with transition to tracheostomy and dysphagia requiring nasogastric tube for nutrition. She continued to slowly decline and was evaluated for placement at a long-term care facility. After a course at a long-term acute care, the patient returned home with continued needs for assistance with activities of daily living.
Discussion
Immune-mediated necrotising myopathy (IMNM) is characterised by minimal infiltration on muscle biopsy and is one of the most severe and progressive myopathies.1 2 In our case, the patient was SRP 54 positive, a subunit of the SRP protein complex, presenting with shortness of breath, followed by weakness, then dysphagia. It is commonly thought that the type of autoantibody will predict the course of the myopathy and the associated extra muscular manifestations. SRP is a ribonuclear protein that regulates translocation of protein across the endoplasmic reticulum. It is not specific to muscle tissue but is ubiquitously found in all protein processing cells.2 Myopathies associated with SRP antibodies were thought to have a similar clinical presentation; however, the literature suggests the presentation of SRP associated myopathy can vary greatly. Anti-SRP-related myopathy is now considered a subset of IMNM, also known as necrotising autoimmune myopathy. Symptoms of anti-SRP myopathy are range from weakness, dysphagia and cardiovascular involvement, with some studies showing lower association with interstitial lung disease (ILD).3 While limb weakness is the most common manifestation of myositis, there are reports of the SRP protein antibodies leading to different presenting symptoms involving the lungs and heart.2 4Involvement of the haematologic system with neutropenia and other alterations in proliferation were also identified.2 5 The ubiquitous nature of the SRP protein leads to multiple different manifestations when attacked by the immune system, from pulmonary, cardiac and haematologic.6 7 Myocardial involvement in anti-SRP myopathy can be severe and is considered a poor prognostic factor. Extramuscular manifestations such as ILD, Raynaud’s and arthralgia have been reported, though these features are typically mild. Some authors have suggested that radiographic suggestion of ILD in these patients may in fact arise from respiratory insufficiency due to musculoskeletal weakness.8
Other autoimmune conditions may have been at play in our patient and her dramatic hospital course. It has been shown that patients positive for ANA in a homogeneous pattern, consistent with SLE, is potentially associated with an overlap syndrome of SLE and necrotising myopathy. While this may have been present in our patient, the likelihood is low as there was no history of SLE in our patient. Furthermore, the overlap between SLE and necrotising myopathy has only been described in one case report to date.9 With this knowledge, clinicians should be aware of the complications of dysphagia, respiratory and cardiac failure and initiate prompt treatment to avoid further complications in the patient’s clinical course.
In fact, involvement of muscles with a symptom of weakness may not be as prominent as other symptoms such as shortness of breath or dysphagia. This is logical given the ubiquity of SRP and the ability of the antibody to cause dysfunction in different tissues.2
Patient’s perspective
As this was during the COVID pandemic, it was extremely difficult for me to adjust to the situation and the loss of the ability to care for myself. I often felt alone and was very scared. As I was in the hospital for over 6 months, I feel that I missed out a lot with my family. We lost my son to a gunshot wound before my sickness and I was also grieving that loss.
Learning points
Necrotising myopathy is a rare but fatal aetiology in patient’s presenting with weakness and shortness of breath.
Patients can have variable presentations and may initially present with symptoms other than skeletal muscle weakness.
Treatment of the condition should not be delayed while workup is undertaken as it can result in pulmonary hypertension and serious pulmonary and cardiac manifestations.
It is imperative to know a patient’s functional baseline to set expectations for the clinical course of a myopathy pathology
Contributors: MB: served as scientific advisor. SB: wrote and researched case.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed. | 40 mg (milligrams). | DrugDosage | CC BY-NC | 33608334 | 19,753,479 | 2021-02-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adverse event'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthralgia'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac disorder'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chills'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Colitis'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal disorder'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Herpes virus infection'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Injection site cellulitis'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Injection site pain'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Injection site reaction'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastatic malignant melanoma'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oral herpes'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | TALIMOGENE LAHERPAREPVEC | DrugsGivenReaction | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
What was the administration route of drug 'TALIMOGENE LAHERPAREPVEC'? | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | Intratumor | DrugAdministrationRoute | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
What was the outcome of reaction 'Death'? | Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany.
Talimogene laherparepvec (T-VEC) is a licensed therapy for use in melanoma patients of stage IIIB-IVM1a with injectable, unresectable metastatic lesions in Europe. Approval was based on the Oncovex Pivotal Trial in Melanoma study, which also included patients with distant metastases and demonstrated an overall response rate (ORR) of 40.5% and a complete response (CR) rate of 16.6%.
The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Based on data from 10 melanoma centers in Austria, Switzerland and southern Germany, we conducted a retrospective chart review, which included 88 patients (44 male, 44 female) with a median age of 72 years (range 36-95 years) treated with T-VEC during the period from May 2016 to January 2020.
88 patients fulfilled the inclusion criteria for analysis. The ORR was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a partial response, 8 (9.1%) had stable disease and 24 (27.3%) patients had a progressive disease. The median treatment period was 19 weeks (range: 1-65), an average of 11 doses (range: 1-36) were applied. 39 (45.3%) patients developed adverse events, mostly mild, grade I (64.1%).
This real-life cohort treatment with T-VEC showed a high ORR and a large number of durable CRs.
Introduction
Talimogene laherparepvec (T-VEC) is the first approved intralesional oncolytic therapy in the European Union, the USA and Australia for the treatment of unresectable stage IIIB, IIIC or IVM1a melanoma in Europe and up to IVM1c melanoma in the USA.1 2 It is injected directly into metastatic lesions.3 T-VEC is a genetically modified oncolytic herpes simplex virus type 1 (HSV-1).4 HSV-1 is modified through (1) the deletion of a neurovirulence gene (ICP34.5) and a immunogenicity gene (ICP47) and (2) the insertion of two gene copies encoded for human granulocyte macrophage colony-stimulating factor (GM-CSF).5 6 These modifications enhance tumor-selective replication, reduce virally mediated suppression of antigen presentation, and induce tumor-specific T-cell responses. Approval, in 2015, was based on the results of the phase III study Oncovex Pivotal Trial in Melanoma (OPTiM).1 7 Intralesional treatment with T-VEC, which was compared with subcutaneous application of human GM-CSF led to durable responses over at least 6 months, the primary endpoint of the OPTIM trial, in 25,2% of patients over only 1.2% in the GM-CSF arm. While the impact of T-VEC on overall survival (OS) did not show significance in the intention to treat population it did significantly improve OS in patients with stage IIIB, IIIC and IVM1a in a descriptive post hoc analysis.6 8 9
Well-implemented systemic therapies, like checkpoint inhibitors (CTLA-4, PD-1 Inhibitors)10–12 and targeted therapies (BRAF and MEK inhibitors) dramatically improved survival of patients with metastatic melanoma.13 However, large multicenter studies of checkpoint inhibitors and BRAF and MEK inhibitors did not pre-specify the subgroup of stage IIIB–IVM1a melanoma patients during recruitment.11 This subgroup was analyzed retrospectively with limited conclusions due to the small number of patients.11 14 15 Exactly this subgroup of patients with an initial low tumor burden might benefit from a treatment with T-VEC as an alternative treatment option to checkpoint inhibitors and targeted therapies, which in case of progression would still be available. The aim of this study was to assess the outcome of melanoma patients treated with T-VEC in a real-life clinical setting.
Material and methods
We performed a multi-institutional retrospective analysis of melanoma patients treated with T-VEC within the period of May 2016 and January 2020 (1370 days) (data cut-off).
Study site selection
Data were provided by 10 melanoma centers in Austria (AT), Switzerland (CH) and Germany (DE): Medical University of Vienna AT, University Hospital St. Poelten AT, Ordensklinikum Linz AT, Medical University of Graz AT, Landeskrankenhaus Klagenfurt AT, Krankenhaus der Elisabethinen AT, Krankenanstalt Rudolfstiftung, AT, University Hospital Zürich and Service d'Oncologie, CH, Center hospitalier Universitaire Vaudois, Lausanne, CH; Technical University of Munich, DE.
Study population
All participating centers were asked to provide data on all patients treated with T-VEC during the study period to avoid selection bias. Patients treated outside the approved indication and patients treated concurrently with other drugs were also included to provide a precise picture of real-life use of T-VEC. In total, 88 patients with a median age of 72 years (range 36–95 years), 44 male, 44 female, diagnosed with metastatic melanoma stage IIIB–IVM1d, based on the American Joint Committee on Cancer (AJCC V.8.0), were included in this retrospective chart review.
Data collection
Anonymized data were collected and entered in an electronic case report form. Patient data included demographics, melanoma history (primary melanoma diagnosis, tumor characteristics, anatomical region and mutation status), clinical characteristics (Eastern Cooperative Oncology Group (ECOG) Performance Status and comorbidities), laboratory parameters (lactate dehydrogenase (LDH), differential blood count, S100), the use of other melanoma therapies (type, duration) before, during, and after therapy with T-VEC, and finally the investigator assessed response rates, safety, and survival outcomes on T-VEC (table 1). Best overall response (BOR) was classified based on Investigator’s assessment as the best response achieved during the treatment with T-VEC. Due to the retrospective nature of this cohort investigator-assessed responses could be variably based on either measurement, count of metastases, clinical photographs or radiological assessments.
Table 1 Patient data before and following the first dose of T-VEC
Patient data for characteristics before the first dose of T-VEC Patient data for events following the first dose of T-VEC
Demographics Use of T-VEC (dosage, duration)
Clinical characteristics and comorbidities Use of other anti-melanoma treatments
Tumor characteristics Adverse events
Laboratory parameters Best overall response
T-VEC, talimogene laherparepvec.
Statistical analysis
Descriptive statistics were provided for demographic, safety and efficacy analyzes. For nominally scaled variables we present absolute numbers and percentages. For metric variables mean, SD, median, minimum and maximum are provided. P values less than 0.05 are considered significant. Statistical analyzes were conducted using the statistic programs SPSS (V.26.0). Kaplan-Meier methods were used to estimate treatment persistence.
Results
Study population
Data were abstracted from 88 patients’ medical charts. The decision diagram is illustrated as a flow chart in figure 1. At the time of data abstraction, 6 patients (6.8%) had ongoing treatment and 82 patients (93.2%) had discontinued treatment. The reasons for discontinuation were as follows: (1) a complete response (CR) in 38 patients, (2) a stable disease (SD) in 8 patients, (3) a partial response (PR) in 18 patients, (4) a progressive disease (PD) in 24 patients and (3) adverse events (AEs) in 2 patients. Staging of disease was based on the AJCC criteria V.8.0: 9 patients (10.2%) were stage IIIB, 47 (53.4%) stage IIIC, 1 (1.1%) stage IIID, 18 (20.5%) stage IVM1a, 5 (5.7%) stage IVM1b, 4 (4.5%) stage IVM1c and 4 (4.5%) stage IVM1d. Demographics and baseline characteristics are presented in table 2. Similar numbers of patients were treated on an annual basis during the study period with a slight peak during 2018 (figure 2).
Figure 1 Flow chart of patients from centers in Austria, Switzerland and Germany included in the study. T-VEC, Talimogene laherparepvec.
Table 2 Demographics and baseline characteristics
Demographics and baseline characteristics
Stage IIIB-IVM1a (n=75) Stage IVM1b-IVM1d (n=13) Total (n=88)
Sex; n (%)
Female 37 (42.1) 7 (7.9) 44 (50.0)
Male 38 (43.2) 6 (6.8) 44 (50.0)
ECOG; n (%)
0 56 (63.7) 12 (13.6) 68 (77.3)
1 16 (18.2) 1 (1.1) 17 (19.3)
>2 3 (3.4) 3 (3.4)
Mutation status; n %
BRAF 25 (38.3) 6 (6.8) 31 (35.2)
c-KIT 1 (1.1) 2 (2.2) 3 (3.3)
NRAS 10 (11.4) 2 (2.2) 12 (13.6)
No detected mutation (“wild type“) 39 (44.3) 3 (3.4) 42 (47.7)
Herpes anamnesis
Positiv 27 (30.7) 5 (5.7) 32 (36.4)
Negativ 42 (47.7) 6 (6.8) 48 (54.5)
Unknown 6 (6.7) 2 (2.3) 8 (9.1)
Location of metastases
Head 9 (10.1) 3 (3.5) 12 (13.6)
Trunk 8 (9.1) 8 (9.1)
Lower extremities 51 (58) 6 (6.8) 57 (64.8)
Upper extremities 5 (5.6) 3 (3.5) 8 (9.1)
Unknown 2 (2.4) 1 (1.1) 3 (3.4)
Tumor stage based on the American Joint Committee on Cancer V.8.0.
ECOG, Eastern Cooperative Oncology Group Performance Status.
Primary tumor characteristics
The median primary tumor thickness Breslow Index within our patient cohort was 2.9 mm (range 0.35–40.00 mm). All patients underwent surgery on their primary melanoma with an adequate safety margin excision. In 74 patients (84.1%) a sentinel lymph node biopsy was performed, of which 38 (43.2%) were positive. Additionally, the mutation status information of melanoma metastases was collected (BRAF, NRAS, c-KIT). In 46 patients (52.3%) a mutation was detected: 31 patients (35.2%) had a BRAF mutation, 3 (3.4%) had a c-KIT and 12 (13.7%) had an NRAS mutation (table 2). The melanoma metastases were located as follows; trunk: 8 patients (9.1%), head: 12 (13.6%), lower extremities: 57 (64.8%), and upper extremities: 8 (9.1%) (table 2).
Clinical parameters and comorbidities
ECOG performance status (0–5) was ECOG 0 for 68 patients (77.3%), ECOG 1 for 17 patients (19.3%) and ECOG 3 for 3 patients (3.4%) (table 2). Comorbidities were as follows: arterial hypertension in 37 patients (42.0%), diabetes mellitus in 9 patients (10.2%), 15 patients (17.0%) had a history of a second malignancy, 1 patient (1.1%) had a history of organ transplantation, 3 (3.4%) had a chronic obstructive lung disease, 31 patients (36.0%) had a positive herpes simplex anamnesis.
Administration of T-VEC
T-VEC was administered into injectable metastatic melanoma lesions (cutaneous, subcutaneous and nodal tumors). The initial dose on day 1 was 106 plaque-forming units (PFU)/mL (up to 4 mL based on the lesion size). The second dose on day 21 was 108 PFU/mL (up to 4 mL based on the lesion size), the following cycles were applied every 14 days thereafter with 108 PFU/mL (up to 4 mL based on the lesion size). The median treatment period was 19.0 weeks (range: 1–65), an average of 11 doses (range: 1–36) were applied.
Efficacy outcomes
Eighty-eight patients fulfilled the criteria for analyzes. Investigator-assessed responses are shown in table 3. The overall response rate (ORR) was 63.7%. 38 patients (43.2%) showed a CR, 18 (20.5%) had a PR, 8 (9.1%) had an SD and 24 (27.3%) patients had a PD. The 45 patients (51.1%) treated with T-VEC as first line therapy showed better response rates, however differences where not statistically significant (p=0.185), compared with the remaining 43 patients (48.9%) treated with T-VEC as second line therapy (table 4). The BOR from patients treated with T-VEC as first-line therapy correlated significantly with longer progression free survival (PFS) (p=0.04), but did not correlate significantly with longer OS (p=0.199).
Table 3 Investigator assessed best overall response.
Investigator-assessed best overall response
Response rates n=88 100%
CR 38 43.2%
PR 18 20.5%
SD 8 9.1%
PD 24 27.3%
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Table 4 Talimogene laherparepvec (T-VEC) as first-line therapy correlated with best overall response rates (complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD))
Best overall response rate
Total CR SD PR PD
T-VEC secondline 43 (48.9%) 15 (17.0%) 5 (5.7%) 8 (9.1%) 15 (17.0%)
T-VEC firstline 45 (51.1%) 23 (26.1%) 3 (3.4%) 10 (11.4%) 9 (10.2%)
The median time to response was 124 days (range: 44–397) (figure 3). The median PFS was 9 months (95% CI 5.9 to 10.12) (figure 4A). The median OS was not reached (figure 5A). At the 1-year landmark 45% of all patients were without progression and 82% of patients were still alive (figures 4A, 5A). PFS (p=0.011) and OS (p=0.004) were significantly worse in patients with stage IVM1b to IVM1d melanoma (figures 4B, 5B). The 45 patients (51.1%) treated with T-VEC as first line therapy showed significant improved PFS (p=0.016) (figure 4C) and a trend toward improved OS (p=0.267) (figure 5C). However, OS differences were not statistically significant, compared with the remaining 43 patients (48.9%) treated with T-VEC as second line. The median follow-up period was 542 days (range: 14–1463 days). During the follow-up period 58 (65.9%) patients had a progression of disease: 32 (36.4%) patients progressed locoregional, 16 (18.2%) developed distant metastasis and 10 (11.4%) developed both, locoregional and distant metastases.
Figure 3 Time to response. Median time to response was 4 months=124 days (range: 44–397 days).
Figure 4 Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A). Kaplan-Maier analysis of PFS according to disease stage (B). PFS according to first and second line treatment with Talimogene laherparepvec (T-VEC) (C). T-VEC, Talimogene laherparepvec.
Figure 5 Kaplan-Maier analysis of OS. One-year OS was 82%, 2-year OS was 71%, 3-year OS was 65% and 4-year OS was 65%. Median OS was not reached (A). Kaplan-Maier analysis of OS according to disease stage (B). OS according to first and second line treatment with tlimogene laherparepvec (T-VEC) (C). Kaplan-Maier analysis of PFS. One-year PFS was 45%, 2-year PFS was 35% and 3-year PFS was 28%. Median PFS was 9 months (95% CI 5.9 to 10.1) (A).
Figure 2 Talimogene laherparepvec (T-VEC) treatment over the years 2016–2020, in 10 melanoma centers in Austria, Switzerland and Germany. CPI, checkpoint inhibitors.
Laboratory parameters
Prior to therapy with T-VEC, the following laboratory parameters were collected: Lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dl), LDH and S100 (µg/L). Elevated S100 correlated with decreased PFS (p=0.0046). There was no significant association between eosinophils, lymphocytes, leucocytes, LDH and CRP and OS and PFS. Baseline laboratory parameters grouped in upper limits of normal and lower limits of normal based on BOR, namely CR, SD, PR, PD are shown in table 5.
Table 5 Blood biomarkers: lymphocytes (G/L), leucocytes (G/L), eosinophils (G/L), C reactive protein (CRP) (mg/dL), lactate dehydrogenase (LDH) and S100 (ug/L) correlated with response rates
Baseline laboratory parameters and response rates
CR N (%) SD N (%) PR N (%) PD N (%)
LDH (U/L)
Norm 27 (37.0) 2 (2.7) 12 (16.4) 13 (17.8)
>ULN 6 (8.2) 2 (2.7) 3 (4.1) 8 (11.0)
Leucocytes (G/L)
Norm 33 (44.6) 4 (5.4) 12 (16.2) 17 (23.0)
<LLN 2 (2.7) – – –
>ULN 2 (2.7) – – 4 (5,4)
Lymphocytes (G/L)
Norm 32 (43.2) 4 (5.4) 9 (12.2) 18 (24.3)
<LLN 3 (4.1) – 2 (2.7) 3 (4.1)
>ULN 1 (1.4) – 1 (1.4) –
Eosinophils (G/L)
Norm 35 (47.9) 2 (2.7) 12 (16.4) 17 (23.3)
<LLN – 1 (1.4) – 2 (2.7)
>ULN 1 (1.4) 1 (1.4) – 2 (2.7)
S100 (ug/L)
Norm 24 (38.1) – 5 (7.9) 8 (12.7)
>ULN 10 (15.9) 2 (3.2) 5 (7.9) 9 (14.3)
CRP (mg/dL)
Norm 18 (27.7) – 3 (4.6) 7 (10.8)
>ULN 16 (24.6) 3 (4.6) 6 (9.2) 37 (18.5)
CR, complete response; LLN, lower limit of normal; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Use of other melanoma therapies before, during or after treatment with T-VEC
Tumor therapies used before, during or after T-VEC are shown in table 6. Forty-five patients (51.1%) received T-VEC as the sole melanoma therapy without prior antineoplastic treatment. Forty-three patients (48.9%) received therapy prior to treatment with T-VEC: 3 (3.4%) received radiotherapy, 12 (13.6%) PD-1 inhibitors, 10 (11.4%) Interferon, 5 (5.7%) BRAF and MEK inhibitors, 1 (1.1%) Imiquimod and 3 (3.4%) electrochemotherapy. A further nine patients (10.2%) received prior but unknown therapy.
Table 6 Tumor therapies used before, during or after therapy with talimogene laherparepvec (T-VEC)
Therapies before, during or after treatment with T-VEC
Before T-VEC
43 (48.9%) During T-VEC
11 (12.5%) After T-VEC
33 (37.5%)
PD-1 inhibitors 12 (13.6%) T-VEC +PD-1 Inhibitors 10 (11.4%) PD-1 Inhibitors 16 (18.2%)
Interferon adjuvant 10 (11.4%) T-VEC +CTLA4 Inhibitors 1 (1.1%) BRAF/MEK Inhibitors 8 (9.2%)
BRAF/MEK inhibitors 5 (5.7%) PD-1 and CTLA4 Inhibitors 4 (4.5%)
Radiation 3 (3.4%) Electrochemotherapy 2 (2.3%)
Electrochemotherapy 3 (3.4%) Chemotherapy 1 (1.1%)
Local therapy/Imiquimod 1 (1.1%) CTLA-4 Inhibitor 2 (2.3%)
Yes, therapy unknown 9 (10.2%)
In addition to T-VEC, 11 patients (12.5%) received concurrent treatment: 10 patients (11.4%) PD-1 inhibitors and 1 patient (1.1%) a CTLA-4 inhibitor. These patients had advanced tumor stages: one patient stage IIIC, two patients stage IVM1a, two patients stage IVM1b, three patients stage IVM1c and three patients stage IVM1d. Eight of these 11 patients did receive T-VEC as an add on therapy on progression on a PD-1 inhibitor (5/8) or PD-1 based combination treatment (3/8). One patient received CTLA4 +T VEC on progression on a PD1 inhibitor and two patients received first line combinations of T-VEC with a PD-1 inhibitor. PFS and OS for patients on concurrent therapy are shown in figure 6A, B.
Figure 6 PFS of patients on concurrent therapy with checkpoint inhibitors (CPI) and talimogene laherparepvec (T-VEC). One-year PFS was 68%, 2-year PFS was 34%. The median PFS was 13 months (95% CI 10.0 to 15.3) (A). OS of patients on concurrent therapy with CPI and T-VEC. One-year OS was 70% and the 2- year OS was 56%. The median OS was not reached (B).
Thirty-three patients (37.5%) required therapy during the follow-up period. A detailed outline of follow-up therapies according to BOR and first or second line therapy with T-VEC is presented in table 7.
Table 7 Follow-up therapy according to best overall response (BOR) (complete response (CR), stable disease (SD), Partial response (PR) and progressive disease (PD)) and first and second line therapy with talimogene laherparepvec (T-VEC)
Follow-up therapy according to BOR and first and second line therapy with T-VEC
Patients with follow-up therapy BRAF MEK inhibitor PD-1
Inhibitor PD-1+CTLA4 Inhibitor CTLA4
Inhibitor Chemo- therapy Electro-chemotherapy
First line therapy 14/45 (15.9%) 1 (1.1%) 10 (11.4%) 1 (1.1%) 2 (2.3%)
with T-VEC
Second line therapy 19/43 (21.6%) 7 (8.0%) 6 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
with T-VEC
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
BOR
CR 6/38 (6.8%) 1 (1.1%) 4 (4.5%) 1 (1.1%)
SD 3/8 (3.4%) 1 (1.1%) 1 (1.1%) 1 (1.1.%)
PR 6/18 (6.8%) 3 (3.4%) 2 (2.3%) 1 (1.1%)
PD 18/24 (20.4%) 3 (3.4%) 9 (10.2%) 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 (1.1%)
In total 33/88 (37.5%) 8 (9.1%) 16 (18.2%) 4 (4.5%) 2 (2.3%) 1 (1.1%) 2 (2.3%)
Tolerability and safety
AEs were classified based on the common terminology criteria for AE V.5.0 on severity from grade 1 to 5. AEs were reported in 39 (44.3%) of the patients; 26 patients (29.5%) developed grade 1 AEs, 16 (18.2%) grade 2 AEs, 2 (2.3%) grade 3 AEs, 2 (2.3%) grade 4 AEs. No grade 5 AE occurred. Most common AEs were influenza like symptoms such as fever 21.6% (n=19), shivering 6.8% (n=6) and fatigue 8.1% (n=7). Herpetic lesions appeared in only one patient (1.1%) (table 8). Among the 11 patients that received concurrent treatment with T-VEC and checkpoint inhibitors, 5 (45.5%) developed AEs. Out of the remaining 77 patients which were treated only with T-VEC, 36 (46.8%) developed AEs.
Table 8 AEs (adverse events): classified based on the CTCAE criteria V.5.0 on severity from grade 1 to 5
AEs
AEs In total; n (%) Grade 1; 25 (29%) Grade 2; 16 (18.6%) Grade 3; 1 (1.2%) Grade 4; 2 (2.4%)
Fever 19 (21.6) 10 (11.4) 9 (10.2) – –
Fatigue 7 (8.1) 6 (7.0) 1 (1.2) – –
Shivering 6 (6.8) 6 (6.8) – – –
Nausea 5 (5.7) 5 (5.7) – – –
Local reaction/pain 4 (4.6) 1 (1.1) 2 (2.3) 1 (1.2) –
Gastrointestinal AEs 4 (4.5) 2 (2.3) – 1 (1.1) 1 (1.1)
Arthralgia 2 (2.2) 1 (1.1) 1 (1.1) – –
Herpetic lesions 1 (1.1) – 1 (1.1) – –
Cardiac AEs 1 (1.1) – – – 1 (1.1)
CTCAE, common terminology criteria for AE.
Discussion
There is an increasing amount of clinical data that supports the efficacy of T-VEC in treating metastatic melanoma.16–20 In our analysis, we provide data from an international cooperation across AT, CH and DE, countries that have similar access to novel melanoma treatments and follow comparable treatment standards in the management of metastatic melanoma. We provide detailed insights of patients treated with T-VEC in routine clinical practice.
Compared with 25.7 weeks in the OPTiM trial (which led to the approval of T-VEC), the median duration of T-VEC treatment was 19.0 weeks, whereas the ORR in our patients was 63.7%, vs 26.4% in the OPTiM trial.21 Our study included a population of patients with disease stages ranging from IIIB to IVM1d. 85.3% of the patients had stage IIIB–IVM1a and only a minority, 14.7%, had stage IVM1b–IVM1d. 51.1% of the patients in our cohort received T-VEC as first-line therapy. In the OPTiM study, only 55% of the patients were in stage IIIB-IVM1a and 47% of patients received T-VEC as first line therapy. Therefore, patient selection, also in relation to the European label for T-VEC, is the most likely explanation for the observed difference in ORR.
In other published real-life data analyzes, study populations with differing tumor stages were included. In the cosmus-1 trial, only 55.3% of patients had earlier stage IIIB-IVM1a metastatic melanoma, whereas other recent publications included only stage IIIB–IVM1a metastatic melanoma. In the cosmus-1 trial, 19.7% of the patients had a CR, however, the ORR was not evaluated.17–20 22 23 A multicenter retrospective German study, which included 27 patients with unresectable early stage IIIB–IVM1a melanoma treated with T-VEC, reported that 63% of the patient cohort received T-VEC as first-line therapy. The ORR was not evaluated.19 In a multicenter US study, conducted between 2015 and 2018, in which 42.5% of patients received T-VEC as first-line therapy the ORR was 56.4%.20 A single-site study of 26 T-VEC-treated patients from the Netherlands presented a similar safety profile and an ORR of 88.5%.24
While the majority of our patients were treated within the approved European indication, a minority of our patients with stage IVM1b–d received T-VEC as well. These were mostly patients with stable systemic disease, but locoregional progression, that received T-VEC as an add-on therapy. Responses have been observed in some of these patients. In our cohort, 11 patients (12.5%) received concurrent therapy with PD-1 or CTLA-4 checkpoint inhibitors. 22 patients (25.0%) received treatment with checkpoint inhibitors following progression on T-VEC. Due to the low number of patients requiring follow-up or concurrent treatment in our cohort we cannot assess if treatment with T-VEC did alter the response to a subsequent or concurrent systemic immunotherapy. The possibility that a local induction of an anti-tumor immune response could alter the response to systemic therapy with checkpoint inhibitors like PD-1 or CTLA-4 blocking antibodies has been addressed in early clinical trials and randomized studies to evaluate this possibility are currently ongoing in metastatic melanoma patients with injectable lesions.25–29
An analysis of the type of follow-up therapy according to BOR and first or second line treatment with T-VEC shows that patients receiving T-VEC as a first line therapy more often received a PD-1 inhibitor therapy compared with patients receiving T-VEC as a second-line therapy, which is in line with current recommendations to use PD-1 inhibitors as systemic first line treatment.30 From all the laboratory values collected at baseline only elevated S100 was associated with decreased PFS (p=0.046). The tolerability of T-VEC was similar to the OPTiM trial and other real-life studies with only 2 out of 88 patients stopping treatment due to AEs.9 17–20 22 23 The most common grade 1 and 2 AEs were fever 21.6% (n=19), chills 6.8% (n=6), fatigue 8.0% (n=7) and pain on the injection site 5.8% (n=5). There were 2 grade 3 AEs, namely cellulites on the injection site and colitis. One grade 3 AE colitis, one grade 4 cardiac AE and one grade 4 gastrointestinal AE occurred in patients who received simultaneous therapy with PD-1 inhibitors. Only one patient (1.1%) reported cold sores. T-VEC was well-tolerated, even though the study cohort represents an elderly population with a median age of 72 years and multiple comorbidities, with one patient even having a history of organ transplantation.31 In our cohort, no difference in the frequency of occurrence of AEs was observed between the patients who received T-VEC in combination with immunotherapy (45.5%) and patients who received T-VEC without immunotherapy (46.8%). While the documentation of AEs is usually less stringent outside of clinical trials, the recorded AEs are more likely to represent clinically significant events.
The era of checkpoint inhibitors and targeted therapies like BRAF and MEK inhibitors has led to dramatic improvements in OS and PFS for patients with metastatic melanoma and these drugs are the current standard therapies in the adjuvant as well as in the inoperable metastatic setting. In the latter, the 5-year OS rate for PD-1 inhibitor based therapies is between 39% and 52%,10 and for BRAF and MEK inhibitors up to 34%.13 However, more than 50% of patients do not respond to these and between 10% and 42% of patients, depending on the type of therapy have to stop these treatments because of AEs.32 Furthermore, despite the great effectivity of these drugs, the number of lines of therapies with a proven impact on OS is still limited for melanoma patients. Therefore, an additional treatment option that, as shown in our data collection, can add to the number of patients that achieve control of their disease is a clear advantage. We believe that T-VEC with its low toxicity profile is an ideal treatment option for selected patients with unresectable, but still limited cutaneous or subcutaneous metastases, especially for elderly patients or patients with multiple comorbidities. Checkpoint inhibitors and BRAF and MEK inhibitors would still be available to these patients in case of a potential recurrence of disease.
The strengths of our study include the size of the study population, the insights provided by a heterogeneous group of patients with different disease stages, clear and comprehensive information about clinical parameters, medical history and laboratory parameters. The main limitation of our study is its retrospective character which naturally limits the size, the depth and the availability of the data.
Conclusion
In our real-life cohort, treatment with T-VEC showed a high ORR and CR rate. Our findings support that T-VEC is a well-tolerated therapy that can be successfully used in patients with unresectable, locoregional and injectable metastatic melanoma. Elderly patients with multiple comorbidities who may not bear the risk of AEs from other systemic therapies and patients with a low tumor burden at the beginning of the treatment, might benefit specifically from T-VEC therapy.
Contributors: Study design and supervision: CHO and JMR. Contributed in data collection: JMR, MK, LK, RS, JM, SL, VA, HK, FW, PK, CP, JK, OM, ER, CHA and CHO. Analyzed the data: JMR, RS and CHO. Wrote the paper: JMR, RS and CHO.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: JMR received project funding by Amgen, Speakers bureau of Amgen and Bristol Myers Squibb and travel support from Bristol Myers Squibb, Pierre Fabre outside of the submitted work. JMR has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers and Squibb and Pierre Fabre and has received travel support from Ultrasun, L’ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb and Pierre Fabre outside of the submitted work. PK has received honoraria for travel/congress support and consulting/advisory roles for Roche, Bristol Myers Squibb (BMS), Merck Sharp and Dome (MSD), Novartis, Amgen, Pierre Fabre and Sanofi Aventis unrelated to the submitted work. ER Honoraria, consulting or advisory role: Amgen, Bayer, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, SanofiSpeakers'bureau: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, SanofiResearch funding site PI: Amgen, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Roche Research funding steering committee: Novartistravel, accommodations, expenses: Amgen, Bristol Myers Squibb, MSD, Merck, Novartis, Pierre Fabre, Roche, Sanofi. CH is associated with consulting or advisory role for Bristol-Myers Squibb, Amgen, Merck Sharp and Dohme, Novartis, Pierre Fabre and Speaker’s bureau of Bristol-Myers Squibb, Amgen, Merck Sharp & Dohme, Pierre Fabre and received travel/accommodations/expenses from Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Pierre Fabre.C.HO. is associated with advisory role for Advisory Boards: Amgen, Astra Zeneca, BMS, Inzyte, MSD, Novartis, Pierre Fabre, Roche and Speakers bureau of Amgen, BMS, MSD, Novartis, Roche.
Patient consent for publication: Not required.
Ethics approval: This study was registered at the Medical University of Vienna with the ethics committee number 18/40 2019.
Data availability statement: All data relevant to the study are included in the article or uploaded as online supplementary information. | Fatal | ReactionOutcome | CC BY-NC | 33608376 | 18,948,777 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuroendocrine carcinoma of prostate'. | Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance.
Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as BRCA1/2, are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the BRCA2 gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency.
INTRODUCTION
Metastatic castration-sensitive prostate cancer is typically treated in the first-line setting with androgen deprivation therapy in combination with either the chemotherapeutic drug docetaxel or a newer, orally active hormonal agent, such as abiraterone or enzalutamide (Swami et al. 2020). Treatment resistance, however, is universal and associated with transdifferentiation to a small-cell neuroendocrine histology in ∼17% of cases (Aggarwal et al. 2018). Treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) has few effective therapeutic options. Platinum-based chemotherapy is typically used as first-line therapy, although median survivals are only 7 mo (Wang et al. 2014). Improvements in the treatment of t-SCNC are, therefore, urgently needed.
Germline (g) and somatic mutations in homologous recombination repair (HRR) genes—such as BRCA1/2, ATM, PALB2, RAD51D, and CHEK2—are estimated to occur in 12% and 25% of individuals with castrate-resistant prostate cancer (CRPC), respectively (Sartor and de Bono 2018). Although the superiority of platinum-based chemotherapy has not been established in this setting (Mateo et al. 2018), as it has for other types of HRR-deficient adenocarcinomas (Robson et al. 2017; Moore et al. 2018; Golan et al. 2019), the effectiveness of poly(ADP-ribose) polymerase (PARP) inhibitors has been proven (de Bono et al. 2020). In contrast, neuroendocrine prostate cancer has demonstrated sensitivity to platinum agents (Apostolidis et al. 2019; Corn et al. 2019), but there are no clinical trial reports on the use of PARP inhibitors in this setting. Given the expanding linkage between platinum sensitivity and responsiveness to PARP inhibiton in malignancies characterized by HRR deficiency, it is reasonable to study this treatment paradigm in patients with HRR-deficient t-SCNC.
Here, we report the case of a man with an aggressive t-SCNC carrying a gBRCA2 mutation who was treated with the PARP inhibitor (PARPi) olaparib following a major response to first-line platinum-based chemotherapy.
RESULTS
Clinical Presentation and Family History
Informed written consent was obtained from the patient for publication of this case report. A 65-yr-old Indian male, with a history of type 1 diabetes, presented to the Norwalk Hospital emergency department after 1 mo of progressive bilateral leg and scrotal edema as well as low back pain. Ultrasound showed an occlusive deep vein thrombosis (DVT) in the left common femoral vein with possible extension into the left external iliac vein. He underwent thrombectomy followed by treatment with enoxaparin. Computed tomography (CT) of the chest, abdomen, and pelvis showed thrombus in the left iliac veins, multiple enlarged retroperitoneal and left pelvic lymph nodes, and prostatic enlargement, measuring 5.1 × 5.3 × 5.3 cm. A bone scan showed several widely distributed osseous metastases involving the hips, spine, ribs, and sternum. The prostate-specific antigen (PSA) was 95 ng/mL. He underwent 12-quadrant prostate biopsies, which showed 50%–100% involvement in all cores with Gleason 8 (4 + 4) adenocarcinoma. The tumor was strongly positive for prostate-specific acid phosphatase (Fig. 1).
Figure 1. (A) Prostate adenocarcinoma: low-power view from left lateral mid prostate biopsy showing Gleason 4 + 4 = 8 pattern (4×). (B) Prostatic specific acid phosphatase (PSAP): low-power view from left lateral mid prostate biopsy showing positive cytoplasmic staining for PSAP by immunohistochemistry (IHC) (10×). (C) Liver small-cell carcinoma: low-power view of tumor in the liver with nests and sheets of uniform tumor cells with high nuclear to cytoplasmic ratio (10×). (D) Liver synaptophysin: IHC for synaptophysin showing membranous and cytoplasmic positive staining (20×).
The patient began leuprolide androgen deprivation therapy (ADT) and abiraterone plus prednisone, choosing to avoid chemotherapy because of the potential impact of side effects on his employment. His initial symptoms gradually improved and he was soon able to return to work and carry out all activities of daily living (ADLs). The PSA declined to 0.2 ng/mL during the first 3 mo and remained low, as shown in Figure 2. After 12 mo, a bone scan showed decreased intensity and extent of all lesions, and CT showed no visceral disease (Fig. 2). Germline genetic testing revealed a pathogenic nonsense mutation in the BRCA2 gene, predicting a truncated protein (Table 1 and next section). Family history was notable for a paternal uncle with prostate cancer and a maternal uncle with colon cancer, both in their 60s.
Figure 2. Clinical pattern of response to treatment. PSA and Chromogranin A measurement levels corresponding to the timeline showing therapy (middle panel). Top panels show corresponding axial CT images. N.B. Leuprolide continued but abiraterone was discontinued upon diagnosis of neuroendocrine carcinoma. (Pembro) Pembrolizumab.
Table 1. Germline (g) and somatic (s) mutations
Gene symbol Chromosome_position_change Clinical significance Variation type Gene region Protein variant Allele frequency (%) Impact on translation dbSNP ID
Pre-platin/PARPi Relapse during PARPi
Color panel (g) Guardant360 (g,s) MSK-IMPACT (s)
Saliva Blood (cfDNA) Tumor
BRCA2 Chr 13:32340000_C > A/C > T Pathogenic SNV Exonic p.S1882* 49.3 46.9 - Stop-gained 80358785
ATM Chr 11: 108192129_T > C VUS SNV Exonic p.I2185T 51.9 44.3 - Missense 779611511
BRCA1 Chr 17:43094766_C > T VUS SNV Exonic p.E255D ND 6.9 39.6 Missense 62625299
BRCA2 Chr 13:32339783_G>227del Reversion Indel Exonic p.V1810_C1885del ND ND 56 In-frame
ALK Chr 2_29275099_C > G Benign SNV Exonic p.V681L - NR 42 Missense
SETD2 Chr 3_47057420_G > C Likely pathogenic SNV Exonic p.R2122G - NR 39.9 Missense 1279854337
HGF Chr 7_81757271_G > A Benign SNV Exonic p.R134C - NR 60.7 Missense 1032300573
Germline origin of BRCA2 p.S1882* was determined by color hereditary cancer risk test. Guardant360 cannot distinguish germline from somatic origin.
MSK-IMPACT calls mutations against paired germline samples and does not report germline variants.
(ND) Not detected, (-) not determined, (NR) not reported (although sequenced, Guarant360 final report does not include variants of these genes), (SNV) single-nucleotide variant, (Indel) insertion deletion.
After 16 mo, the patient became acutely ill requiring hospitalization. Physical examination revealed scleral icterus, painful hepatomegaly, and profound global weakness. The aspartate transaminase was 424 U/L, alanine transaminase 241 U/L, total bilirubin 5.4 mg/dL, and lactate 5.0 mmol/L. The PSA was 0.5 ng/mL, serum chromogranin-A 7160 ng/mL (normal < 95), and neuron-specific enolase (NSE) 824 ng/mL (normal < 15). Abdominopelvic CT showed the liver was 27 cm in transverse dimension with innumerable new 2–3 cm hypodense lesions (Fig. 2). CT-guided liver biopsy showed poorly differentiated neuroendocrine carcinoma most consistent with small-cell carcinoma (Fig. 1). Immunohistochemical stains showed the tumor positive for CK20 (dot-like accentuation), synaptophysin, and chromogranin and negative for CK7, PSA, TTF-1, GATA-3, CDX-2, NKX3.1, and Merkel cell polyoma virus. There was loss of RB and the Ki-67 labeling index was >50%. There was insufficient tumor sample for genomic profiling prechemotherapy but this was performed subsequently (see below).
The patient began chemotherapy with etoposide and carboplatin every 3 wk and gradually improved with normalization of liver enzymes. After two cycles of treatment, the NSE declined to 18 ng/mL, chromogranin-A declined to 408 ng/mL, and CT scan showed markedly diminished hepatic metastases. After six cycles of chemotherapy, the chromogranin-A was 115 ng/mL, and CT showed near-complete resolution of hepatic metastases (Fig. 2). The patient was then placed on maintenance therapy with the PARPi olaparib (300 mg po bid). Olaparib was well-tolerated without significant side effects, but within 6 mo of treatment, CT scan showed recurrent hepatic metastases (Fig. 2). Upon the development of PARP inhibitor resistance, cell-free (cf) DNA analysis revealed only the pathogenic germline BRCA2 mutant. Genomic profiling from a growing hepatic metastasis, however, revealed a 228-bp deletion in BRCA2 that restored the open reading frame. This mutation results in near full-length BRCA2 protein and would be considered a reversion mutation (see the next section).
Because of the lack of known effective therapies for refractory t-SCNC, the patient was next treated with pembolizumab (200 mg every 3 wk) while olaparib was continued, given the preliminary efficacy of anti-PD1 immunotherapy drugs in patients with CRPC and an HRR gene mutation (Antonarakis et al. 2020). After three cycles of therapy, continued progression of disease was found by imaging and tumor markers (Fig. 2), and the patient began to lose weight and experience hepatic pain. He was again treated with platinum-based chemotherapy, but after three cycles developed global progression of disease including innumerable brain metastases. Hospice care was chosen and he died 18 mo after the diagnosis of t-SCNC and 34 mo from diagnosis of metastatic prostate cancer.
Germline and Somatic Genomic Alterations
Germline genetic testing was performed prior to initiation of chemotherapy by the 30-gene Color Hereditary Cancer Risk Test (Color Genomics). This revealed the presence of a pathogenic BRCA2 nonsense mutation (p.Ser1882*) at a mutation allele frequency (MAF) of 49.3%, which predicts truncation and loss of full-length functional protein. A variant of uncertain significance (VUS) in the ATM gene (p.I2185T) was also found (Table 1).
Later during the course of treatment and in the setting of resistance to PARP inhibitor therapy, blood for cfDNA was analyzed on the Guardant360 platform consisting of 74 cancer-associated genes (Guardant Health), revealing the same germline BRCA2 mutation with a MAF of 46.9% and a somatic BRCA1 (p.E255D) VUS with a MAF of 6.9% (Table 1). Liver biopsy confirmed SCNC and genomic profiling was performed on the MSK-IMPACT platform consisting of 468 genes (Memorial Hospital For Cancer & Allied Diseases) (Zehir et al. 2017). This revealed the following alterations; a somatic BRCA2 mutation (p.V1810_C1885del) with a MAF of 56%, a VUS in BRCA1, benign ALK, HGF, and likely pathogenic SETD2 mutations (Table 1). Copy-number alterations (CNAa): PTEN, TNRFSF14, HNF1A, PIK3CD, PDCD1, and SETD8. CNA from these genes are suggestive of multiple chromosomal level losses and deletion of the entire gene PTEN (Table 2). Structural variants: MAP2K1, KMT2C2, and TMPRSS2-ERG fusion (Table 2), supporting the transdifferentiation of the small-cell neuroendocrine cancer from the original prostate adenocarcinoma, as this translocation is present in approximately half of prostate cancers (Mosquera et al. 2009), Additional findings included a tumor mutation burden (TMB) of 4.4 mutations per megabase and microsatellite instability (MSI) status stable.
Table 2. Somatic alterations—copy-number alterations (CNAs) and structural variants (SVs)
Gene symbol Type Alteration Location Fold change Panel
PTEN Whole gene Deletion 10q23.31 −3.2 MSK-IMPACT
TNFRSF14 Whole gene Loss 1p36.32 −1.8
HNF1A Whole gene Loss 12q24.31 −1.7
PIK3CD Whole gene Loss 1p36.22 −1.8
PDCD1 Whole gene Loss 2q37.3 −1.7
SETD8 Whole gene Loss 12q23.31 −1.7
MAP2K1 Translocation t(14;15)(q31.2;q22.31) (Chr 14:g.84540589::Chr 15:g.66679738) exon 1
TMPRSS2-ERG Deletion c.56-537:TMPRSS2_c.18 + 8757:ERGdel TMPRSS2 exon 1 to ERG exon 2
KMT2C Deletion c.9453 + 378_c.11536del Exons 41–44
Amplification is considered when there is a greater than twofold change detected and deletion when <−2 of fold change is detected.
The patient's somatic BRCA2 (V1810_C1885del) mutation is a 228-bp deletion that includes the germline deleterious point mutation (S1882*) at the third to the last position, restoring the open reading frame, albeit a truncated predicted protein (Fig. 3A). This novel mutation could be considered a reversion mutation, if occurring in cis with the germline mutation. It has not been reported in the IRC Database of Reversion Mutations (https://reversions.icr.ac.uk/), one of the largest of such databases (Pettitt et al. 2020). Because BRCA2 allelic loss was not reported by MSK-IMPACT, we attempted to determine this by performing qualitative polymerase chain reaction (qPCR) and Sanger sequencing on microdissected tumor tissue (Fig. 3B,C). Gel electrophoresis of the PCR products from BRCA2 mutation–specific primers revealed the presence of two distinct bands migrating at 230 and 450 bp. Sanger sequencing of each gel-isolated and -purified band confirmed the secondary deletion mutation but also revealed two electropherogram peaks for the wild-type and germline mutant alleles. TaqMan qPCR genotyping assay was performed to target the germline point mutation but showed the same heterogeneity of wild-type and mutant alleles; this was in part due to the inability to eliminate all normal cells from the biopsy samples. Although we could not confirm that the somatic BRCA2 deletion was cis to the germline mutation, the concurrent emergence of resistance to platinum and PARPi therapies as well as several lines of evidence support this as a reversion mutation: (1) The affected region is frequently deleted in reversions; (2) the deletion includes the germline mutation and restores the open reading frame (ORF), an event unlikely to occur at the same location on the normal allele; and (3) the deletion is flanked by microhomology (CAA), a characteristic of many reversion mutations (Pettitt et al. 2020).
Figure 3. Detection of case patient BRCA2 germline and somatic mutations in different tissue compartments. (A) BRCA2 domains showing location of patient's germline and somatic mutations. The patient has a germline mutation S1882*, which is a pathogenic nonsense mutation. During PARPi (olaparib) treatment, a somatic deletion mutation (V1810_C1885del) of 76 aa was detected. To confirm reversion status of the deletion mutant, Sanger and qPCR (B) were performed. As shown in B, gel electrophoresis (left) from the PCR performed on the primers designed outside the deleted region showed two clear bands of 230 bp and 458 bp and Sanger sequencing (right) on each of these bands confirmed the somatic deletion mutation but also showed two peaks, for the wild-type and germline point mutation. To further confirm these findings, we designed a TaqMan genotyping assay for the point mutation and performed qPCR (C). qPCR on gDNA showed the wild-type and point mutation alleles at 30 and 32 cycles, respectively. qPCR performed on PARPi resistant tumor tissue also detected both alleles.
Although the Guardant360 assay did not detect our patient's deletion (cfDNA fragments in the assay are in general ∼150 bp in length), by using deletion targeted primers on ctDNA taken at a later time, we were able to detect the deletion mutation from a blood sample (see Supplemental Fig. 1).
DISCUSSION
The optimal management of individuals with incurable malignancies characterized by HRR deficiency is still evolving. Although germline mutations in BRCA1/2 and PALB2 predict response to both platinum-based chemotherapy and PARP inhibition, because of the requirement to repair double-strand DNA breaks through the error-prone, nonhomologous end joining pathway, the application of these therapies appears to be tumor-specific (Tutt et al. 2005). For example, platinum induction followed by PARP inhibitor maintenance has become a standard of care in the treatment of ovarian and pancreatic cancers with gBRCA1/2 or PALB2 mutations (Robson et al. 2017; Golan et al. 2019). In gBRCA1/2-mutated metastatic breast cancer, however, whereas platinum chemotherapy is being utilized in the first-line setting, PARP inhibitors are reserved for relapsed disease (Moore et al. 2018). The use of these genome-directed therapies is inherently more complicated in prostate cancer, which encompasses both castration-sensitive and castration-resistant adenocarcinomas as well as treatment-emergent and de novo neuroendocrine carcinomas.
Prostate adenocarcinoma with a gBRCA1/2 mutation is associated with an aggressive clinical course and poor prognosis compared to nonmutated disease (Castro et al. 2013). Platinum-based chemotherapy has not been prospectively studied in HRR-deficient prostate cancer and there is no general consensus on whether it is more useful than standard therapies (Pomerantz et al. 2017; Mateo et al. 2018). On the other hand, the PARP inhibitors olaparib and rucaparib have both recently been approved by the U.S. Food and Drug Administration for use in recurrent CRPC with germline or somatic HRR gene mutations.
Neuroendocrine prostate cancer (NEPC) has traditionally been considered a rare, lethal subtype of prostate cancer (Akamatsu et al. 2018). Yet, the widespread use of and subsequent resistance to newer, potent anti-androgen drugs is increasing the incidence of NEPC, specifically t-SCNC (Aggarwal et al. 2018). This observation, coupled with an expansion in germline genetic testing of individuals with prostate cancer, will likely result in more oncologists encountering t-SCNC with HRR gene mutations. Although platinum-based chemotherapy has demonstrated efficacy as first-line therapy, there are no clinical trial results on the use of PARP inhibitors for relapsed disease or as maintenance therapy. Therefore, case reports and series are important in informing practice decisions until mature clinical trial data are reported.
To our knowledge, this is the first case report of germline BRCA2-mutated t-SCNC of the prostate. Our patient developed explosive t-SCNC after 16 mo of ADT plus abiraterone for Gleason 8 metastatic prostate cancer. He achieved a complete response with first-line platinum-based chemotherapy but a <6-mo remission duration, despite the use of a PARP inhibitor as maintenance therapy. Given this brief remission, which includes a recognized continued benefit of chemotherapy for ∼2 mo after its completion, the benefit of olaparib was considered brief at best. The mechanism of PARP inhibitor resistance in our patient was revealed by tumor genomic profiling, which found a somatic BRCA2 mutation. This BRCA2 (V1810_C1885del) deletion mutant encodes for nearly full-length BRCA2 protein except for a deletion of the BRC repeat 6. This would most likely restore at least partial wild-type function as the other intact BRC repeats would allow for the necessary stabilization of RAD51–ssDNA interactions (Chatterjee et al. 2016; A. Monteiro pers. commun.). In support of this, the IRC Database of Reversion Mutations documents a case of platinum-resistant ovarian cancer with a BRCA2 germline 5946delT reverting to a functional allele by deleting c.5954–6090 (aa 1977–2002), which is part of the BRC repeat 7 (Edwards et al. 2008).
The case presented also has clinical relevance regarding the uses of cfDNA analysis vs tumor profiling to detect BRCA2 reversion mutations in patients with prostate cancer. The lack of detection of our reversion mutation by Guardant360 may relate to its large size (228 bp) relative to the typical reversion mutation, which is <100 bp (Pettitt et al. 2020). Although some groups recommend cfDNA analysis over tumor biopsy for detection of the full spectrum of tumor heterogeneity (Carneiro et al. 2018), others have found that the assay has limitations in detecting clinically relevant alterations (including large somatic deletions) in a significant percentage of patients (Taavitsainen et al. 2019).
Both epigenetic and genetic changes have been linked to the lineage plasticity of prostate cancer (Ge et al. 2020). Altered transcriptional regulation by DNA methylation, histone modification, and chromatin remodeling plays a prominent role in the clonal evolution from hormone-sensitive adenocarcinoma to castration-resistant neuroendocrine cancer (Beltran et al. 2016). In our patient, we observed somatically acquired alterations in three histone lysine N-methyltransferase genes, including a missense mutation of SETD2, whole-gene loss of SETD8 (KMT5A), and deletion in KMT2C. It has recently been shown that SETD2-mediated H3K36me3 down-regulates EZH2-catalyzed H3K27me3 chromatin repression and that SETD2 deficiency promotes the development of metastatic prostate cancer (Yuan et al. 2020). Similarly, SETD8 reduces EZH2-mediated cell proliferation, and reduction in SETD8 activity promotes oncogenesis (LeFave et al. 2015).
Our patient's genomic profile revealed a mutation in the PTEN gene and a TMPRSS2-ERG fusion, which are present in ∼50% of prostate cancers (Akamatsu et al. 2018). Yet, we did not detect loss of RB1 and TP53 nor gene amplification of MYCN or AURKA, common alterations in NEPC (Beltran et al. 2011; Ge et al. 2020). We did not test for MYCN and AURKA overexpression by immunohistochemistry, however, and therefore cannot rule out their involvement in this case of t-SCNC.
Another case of BRCA2-alterered t-SCNC was recently reported by Turina et al. (2019). In contrast to our patient, their patient did not have a gBRCA2 mutation but rather somatic complete copy-number loss of BRCA2 found on tumor genomic profiling. The patient developed t-SCNC after 4 mo of ADT plus enzalutamide, had a complete response to etoposide/carboplatinum, and was in continued remission after 9 mo of olaparib; no further clinical detail was provided. Considering both cases, inactivation of BRCA2, whether through germline or somatic alteration, appears to render t-SCNC highly sensitive to platinum-based chemotherapy, although resistance to platinum/PARPi occurred within 6 mo in our patient as a result of the emergence of a BRCA2 reversion mutation. Clearly, more reports of HRR-deficient t-SCNC are needed for a clearer understanding of the role of PARP inhibitors and the emergence of BRCA2 reversion mutations in response to platinum and/or PARPi therapy in this histologically and genetically defined subtype of prostate cancer.
In summary, the case presented provides evidence for initial platinum sensitivity of gBRCA2-mutated t-SCNC and emergence of a BRCA2 somatic reversion mutation during PARPi maintenance therapy. The candidate reversion mutation was detectable through tumor genomic profiling but not routine cfDNA analysis. PARP inhibition following effective platinum-based chemotherapy may be a less promising strategy in BRCA2-mutated t-SCNC than in other HRR-deficient malignancies (Robson et al. 2017; Moore et al. 2018; Golan et al. 2019). Clinical trials testing different sequencing of platinum-chemotherapy and PARPi along with both serial cfDNA and tumor sampling next-generation sequencing (NGS) analyses are needed for a more informed treatment paradigm to emerge for the treatment of t-SCNC characterized by mutations in HRR genes.
METHODS
DNA Isolation and PCR Assay Design
Total genomic DNA isolation was performed from formalin-fixed paraffin-embedded (FFPE) tumor tissue sample (collected after PARPi treatment) by GeneRead DNA FFPE Kit (QIAGEN 180134) and from peripheral blood monocytes by Gentra Puregene Blood Kit (QIAGEN 158422). Double-strand DNA concentrations were determined by Qubit 2.0 Fluorometer (Invitrogen by Life Technologies). A primer pair (forward: CTTGATTCTGGTATTGAGCCAGT, reverse: ACCTTATGTGAATGCGTGCT) was designed to the BRCA2 gene exon 11 to sequence somatic mutation as well as point mutation. PCR product DNAs were isolated from the agarose gel by QIAquick Gel Extraction Kit (QIAGEN 28704) and sent for Sanger sequencing (Genewiz). For the mutation analysis by qPCR, TaqMan SNP Genotyping Assay (ThermoFisher Scientific) was designed for point mutation (S1882*) and qPCR was performed on QuantStudio 7 Flex (ThermoFisher Scientific).
ADDITIONAL INFORMATION
Data Deposition and Access
Two BRCA2 variants (S1882*, V1810_C1885del) focused on in this report have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and can be found under accession numbers SCV001451935 and SCV001451938, for S1882* and V1810_C1 885del, respectively.
Ethics Statement
Informed written consent was obtained for the patient for the study, Genomic Profiling in Cancer Patients (Memorial Sloan Kettering Cancer Center IRB, ClinicalTrials.gov ID: NCT01775072).
Acknowledgments
We thank Dr. Alvaro N. Monteiro (H. Lee Moffitt Cancer Center & Research Institute) and Dr. Stephen J. Pettit and Dr. Christopher J. Lord (Institute of Cancer Research), for their expertise and generous advice. We also thank Dr. Joanna Weber for assistance with histopathology, Dr. Sabina Swierczek for assistance with Sanger and qPCR experiments, and Dr. Sandra Lobo for support and encouragement.
Competing Interest Statement
The authors have declared no competing interest.
Referees
Michael Fraser
Anonymous
Supplementary Material
Supplemental Material
[Supplemental material is available for this article.] | ABIRATERONE ACETATE, LEUPROLIDE ACETATE, PREDNISONE | DrugsGivenReaction | CC BY-NC | 33608381 | 18,972,244 | 2021-02 |
What was the administration route of drug 'ABIRATERONE ACETATE'? | Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance.
Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as BRCA1/2, are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the BRCA2 gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency.
INTRODUCTION
Metastatic castration-sensitive prostate cancer is typically treated in the first-line setting with androgen deprivation therapy in combination with either the chemotherapeutic drug docetaxel or a newer, orally active hormonal agent, such as abiraterone or enzalutamide (Swami et al. 2020). Treatment resistance, however, is universal and associated with transdifferentiation to a small-cell neuroendocrine histology in ∼17% of cases (Aggarwal et al. 2018). Treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) has few effective therapeutic options. Platinum-based chemotherapy is typically used as first-line therapy, although median survivals are only 7 mo (Wang et al. 2014). Improvements in the treatment of t-SCNC are, therefore, urgently needed.
Germline (g) and somatic mutations in homologous recombination repair (HRR) genes—such as BRCA1/2, ATM, PALB2, RAD51D, and CHEK2—are estimated to occur in 12% and 25% of individuals with castrate-resistant prostate cancer (CRPC), respectively (Sartor and de Bono 2018). Although the superiority of platinum-based chemotherapy has not been established in this setting (Mateo et al. 2018), as it has for other types of HRR-deficient adenocarcinomas (Robson et al. 2017; Moore et al. 2018; Golan et al. 2019), the effectiveness of poly(ADP-ribose) polymerase (PARP) inhibitors has been proven (de Bono et al. 2020). In contrast, neuroendocrine prostate cancer has demonstrated sensitivity to platinum agents (Apostolidis et al. 2019; Corn et al. 2019), but there are no clinical trial reports on the use of PARP inhibitors in this setting. Given the expanding linkage between platinum sensitivity and responsiveness to PARP inhibiton in malignancies characterized by HRR deficiency, it is reasonable to study this treatment paradigm in patients with HRR-deficient t-SCNC.
Here, we report the case of a man with an aggressive t-SCNC carrying a gBRCA2 mutation who was treated with the PARP inhibitor (PARPi) olaparib following a major response to first-line platinum-based chemotherapy.
RESULTS
Clinical Presentation and Family History
Informed written consent was obtained from the patient for publication of this case report. A 65-yr-old Indian male, with a history of type 1 diabetes, presented to the Norwalk Hospital emergency department after 1 mo of progressive bilateral leg and scrotal edema as well as low back pain. Ultrasound showed an occlusive deep vein thrombosis (DVT) in the left common femoral vein with possible extension into the left external iliac vein. He underwent thrombectomy followed by treatment with enoxaparin. Computed tomography (CT) of the chest, abdomen, and pelvis showed thrombus in the left iliac veins, multiple enlarged retroperitoneal and left pelvic lymph nodes, and prostatic enlargement, measuring 5.1 × 5.3 × 5.3 cm. A bone scan showed several widely distributed osseous metastases involving the hips, spine, ribs, and sternum. The prostate-specific antigen (PSA) was 95 ng/mL. He underwent 12-quadrant prostate biopsies, which showed 50%–100% involvement in all cores with Gleason 8 (4 + 4) adenocarcinoma. The tumor was strongly positive for prostate-specific acid phosphatase (Fig. 1).
Figure 1. (A) Prostate adenocarcinoma: low-power view from left lateral mid prostate biopsy showing Gleason 4 + 4 = 8 pattern (4×). (B) Prostatic specific acid phosphatase (PSAP): low-power view from left lateral mid prostate biopsy showing positive cytoplasmic staining for PSAP by immunohistochemistry (IHC) (10×). (C) Liver small-cell carcinoma: low-power view of tumor in the liver with nests and sheets of uniform tumor cells with high nuclear to cytoplasmic ratio (10×). (D) Liver synaptophysin: IHC for synaptophysin showing membranous and cytoplasmic positive staining (20×).
The patient began leuprolide androgen deprivation therapy (ADT) and abiraterone plus prednisone, choosing to avoid chemotherapy because of the potential impact of side effects on his employment. His initial symptoms gradually improved and he was soon able to return to work and carry out all activities of daily living (ADLs). The PSA declined to 0.2 ng/mL during the first 3 mo and remained low, as shown in Figure 2. After 12 mo, a bone scan showed decreased intensity and extent of all lesions, and CT showed no visceral disease (Fig. 2). Germline genetic testing revealed a pathogenic nonsense mutation in the BRCA2 gene, predicting a truncated protein (Table 1 and next section). Family history was notable for a paternal uncle with prostate cancer and a maternal uncle with colon cancer, both in their 60s.
Figure 2. Clinical pattern of response to treatment. PSA and Chromogranin A measurement levels corresponding to the timeline showing therapy (middle panel). Top panels show corresponding axial CT images. N.B. Leuprolide continued but abiraterone was discontinued upon diagnosis of neuroendocrine carcinoma. (Pembro) Pembrolizumab.
Table 1. Germline (g) and somatic (s) mutations
Gene symbol Chromosome_position_change Clinical significance Variation type Gene region Protein variant Allele frequency (%) Impact on translation dbSNP ID
Pre-platin/PARPi Relapse during PARPi
Color panel (g) Guardant360 (g,s) MSK-IMPACT (s)
Saliva Blood (cfDNA) Tumor
BRCA2 Chr 13:32340000_C > A/C > T Pathogenic SNV Exonic p.S1882* 49.3 46.9 - Stop-gained 80358785
ATM Chr 11: 108192129_T > C VUS SNV Exonic p.I2185T 51.9 44.3 - Missense 779611511
BRCA1 Chr 17:43094766_C > T VUS SNV Exonic p.E255D ND 6.9 39.6 Missense 62625299
BRCA2 Chr 13:32339783_G>227del Reversion Indel Exonic p.V1810_C1885del ND ND 56 In-frame
ALK Chr 2_29275099_C > G Benign SNV Exonic p.V681L - NR 42 Missense
SETD2 Chr 3_47057420_G > C Likely pathogenic SNV Exonic p.R2122G - NR 39.9 Missense 1279854337
HGF Chr 7_81757271_G > A Benign SNV Exonic p.R134C - NR 60.7 Missense 1032300573
Germline origin of BRCA2 p.S1882* was determined by color hereditary cancer risk test. Guardant360 cannot distinguish germline from somatic origin.
MSK-IMPACT calls mutations against paired germline samples and does not report germline variants.
(ND) Not detected, (-) not determined, (NR) not reported (although sequenced, Guarant360 final report does not include variants of these genes), (SNV) single-nucleotide variant, (Indel) insertion deletion.
After 16 mo, the patient became acutely ill requiring hospitalization. Physical examination revealed scleral icterus, painful hepatomegaly, and profound global weakness. The aspartate transaminase was 424 U/L, alanine transaminase 241 U/L, total bilirubin 5.4 mg/dL, and lactate 5.0 mmol/L. The PSA was 0.5 ng/mL, serum chromogranin-A 7160 ng/mL (normal < 95), and neuron-specific enolase (NSE) 824 ng/mL (normal < 15). Abdominopelvic CT showed the liver was 27 cm in transverse dimension with innumerable new 2–3 cm hypodense lesions (Fig. 2). CT-guided liver biopsy showed poorly differentiated neuroendocrine carcinoma most consistent with small-cell carcinoma (Fig. 1). Immunohistochemical stains showed the tumor positive for CK20 (dot-like accentuation), synaptophysin, and chromogranin and negative for CK7, PSA, TTF-1, GATA-3, CDX-2, NKX3.1, and Merkel cell polyoma virus. There was loss of RB and the Ki-67 labeling index was >50%. There was insufficient tumor sample for genomic profiling prechemotherapy but this was performed subsequently (see below).
The patient began chemotherapy with etoposide and carboplatin every 3 wk and gradually improved with normalization of liver enzymes. After two cycles of treatment, the NSE declined to 18 ng/mL, chromogranin-A declined to 408 ng/mL, and CT scan showed markedly diminished hepatic metastases. After six cycles of chemotherapy, the chromogranin-A was 115 ng/mL, and CT showed near-complete resolution of hepatic metastases (Fig. 2). The patient was then placed on maintenance therapy with the PARPi olaparib (300 mg po bid). Olaparib was well-tolerated without significant side effects, but within 6 mo of treatment, CT scan showed recurrent hepatic metastases (Fig. 2). Upon the development of PARP inhibitor resistance, cell-free (cf) DNA analysis revealed only the pathogenic germline BRCA2 mutant. Genomic profiling from a growing hepatic metastasis, however, revealed a 228-bp deletion in BRCA2 that restored the open reading frame. This mutation results in near full-length BRCA2 protein and would be considered a reversion mutation (see the next section).
Because of the lack of known effective therapies for refractory t-SCNC, the patient was next treated with pembolizumab (200 mg every 3 wk) while olaparib was continued, given the preliminary efficacy of anti-PD1 immunotherapy drugs in patients with CRPC and an HRR gene mutation (Antonarakis et al. 2020). After three cycles of therapy, continued progression of disease was found by imaging and tumor markers (Fig. 2), and the patient began to lose weight and experience hepatic pain. He was again treated with platinum-based chemotherapy, but after three cycles developed global progression of disease including innumerable brain metastases. Hospice care was chosen and he died 18 mo after the diagnosis of t-SCNC and 34 mo from diagnosis of metastatic prostate cancer.
Germline and Somatic Genomic Alterations
Germline genetic testing was performed prior to initiation of chemotherapy by the 30-gene Color Hereditary Cancer Risk Test (Color Genomics). This revealed the presence of a pathogenic BRCA2 nonsense mutation (p.Ser1882*) at a mutation allele frequency (MAF) of 49.3%, which predicts truncation and loss of full-length functional protein. A variant of uncertain significance (VUS) in the ATM gene (p.I2185T) was also found (Table 1).
Later during the course of treatment and in the setting of resistance to PARP inhibitor therapy, blood for cfDNA was analyzed on the Guardant360 platform consisting of 74 cancer-associated genes (Guardant Health), revealing the same germline BRCA2 mutation with a MAF of 46.9% and a somatic BRCA1 (p.E255D) VUS with a MAF of 6.9% (Table 1). Liver biopsy confirmed SCNC and genomic profiling was performed on the MSK-IMPACT platform consisting of 468 genes (Memorial Hospital For Cancer & Allied Diseases) (Zehir et al. 2017). This revealed the following alterations; a somatic BRCA2 mutation (p.V1810_C1885del) with a MAF of 56%, a VUS in BRCA1, benign ALK, HGF, and likely pathogenic SETD2 mutations (Table 1). Copy-number alterations (CNAa): PTEN, TNRFSF14, HNF1A, PIK3CD, PDCD1, and SETD8. CNA from these genes are suggestive of multiple chromosomal level losses and deletion of the entire gene PTEN (Table 2). Structural variants: MAP2K1, KMT2C2, and TMPRSS2-ERG fusion (Table 2), supporting the transdifferentiation of the small-cell neuroendocrine cancer from the original prostate adenocarcinoma, as this translocation is present in approximately half of prostate cancers (Mosquera et al. 2009), Additional findings included a tumor mutation burden (TMB) of 4.4 mutations per megabase and microsatellite instability (MSI) status stable.
Table 2. Somatic alterations—copy-number alterations (CNAs) and structural variants (SVs)
Gene symbol Type Alteration Location Fold change Panel
PTEN Whole gene Deletion 10q23.31 −3.2 MSK-IMPACT
TNFRSF14 Whole gene Loss 1p36.32 −1.8
HNF1A Whole gene Loss 12q24.31 −1.7
PIK3CD Whole gene Loss 1p36.22 −1.8
PDCD1 Whole gene Loss 2q37.3 −1.7
SETD8 Whole gene Loss 12q23.31 −1.7
MAP2K1 Translocation t(14;15)(q31.2;q22.31) (Chr 14:g.84540589::Chr 15:g.66679738) exon 1
TMPRSS2-ERG Deletion c.56-537:TMPRSS2_c.18 + 8757:ERGdel TMPRSS2 exon 1 to ERG exon 2
KMT2C Deletion c.9453 + 378_c.11536del Exons 41–44
Amplification is considered when there is a greater than twofold change detected and deletion when <−2 of fold change is detected.
The patient's somatic BRCA2 (V1810_C1885del) mutation is a 228-bp deletion that includes the germline deleterious point mutation (S1882*) at the third to the last position, restoring the open reading frame, albeit a truncated predicted protein (Fig. 3A). This novel mutation could be considered a reversion mutation, if occurring in cis with the germline mutation. It has not been reported in the IRC Database of Reversion Mutations (https://reversions.icr.ac.uk/), one of the largest of such databases (Pettitt et al. 2020). Because BRCA2 allelic loss was not reported by MSK-IMPACT, we attempted to determine this by performing qualitative polymerase chain reaction (qPCR) and Sanger sequencing on microdissected tumor tissue (Fig. 3B,C). Gel electrophoresis of the PCR products from BRCA2 mutation–specific primers revealed the presence of two distinct bands migrating at 230 and 450 bp. Sanger sequencing of each gel-isolated and -purified band confirmed the secondary deletion mutation but also revealed two electropherogram peaks for the wild-type and germline mutant alleles. TaqMan qPCR genotyping assay was performed to target the germline point mutation but showed the same heterogeneity of wild-type and mutant alleles; this was in part due to the inability to eliminate all normal cells from the biopsy samples. Although we could not confirm that the somatic BRCA2 deletion was cis to the germline mutation, the concurrent emergence of resistance to platinum and PARPi therapies as well as several lines of evidence support this as a reversion mutation: (1) The affected region is frequently deleted in reversions; (2) the deletion includes the germline mutation and restores the open reading frame (ORF), an event unlikely to occur at the same location on the normal allele; and (3) the deletion is flanked by microhomology (CAA), a characteristic of many reversion mutations (Pettitt et al. 2020).
Figure 3. Detection of case patient BRCA2 germline and somatic mutations in different tissue compartments. (A) BRCA2 domains showing location of patient's germline and somatic mutations. The patient has a germline mutation S1882*, which is a pathogenic nonsense mutation. During PARPi (olaparib) treatment, a somatic deletion mutation (V1810_C1885del) of 76 aa was detected. To confirm reversion status of the deletion mutant, Sanger and qPCR (B) were performed. As shown in B, gel electrophoresis (left) from the PCR performed on the primers designed outside the deleted region showed two clear bands of 230 bp and 458 bp and Sanger sequencing (right) on each of these bands confirmed the somatic deletion mutation but also showed two peaks, for the wild-type and germline point mutation. To further confirm these findings, we designed a TaqMan genotyping assay for the point mutation and performed qPCR (C). qPCR on gDNA showed the wild-type and point mutation alleles at 30 and 32 cycles, respectively. qPCR performed on PARPi resistant tumor tissue also detected both alleles.
Although the Guardant360 assay did not detect our patient's deletion (cfDNA fragments in the assay are in general ∼150 bp in length), by using deletion targeted primers on ctDNA taken at a later time, we were able to detect the deletion mutation from a blood sample (see Supplemental Fig. 1).
DISCUSSION
The optimal management of individuals with incurable malignancies characterized by HRR deficiency is still evolving. Although germline mutations in BRCA1/2 and PALB2 predict response to both platinum-based chemotherapy and PARP inhibition, because of the requirement to repair double-strand DNA breaks through the error-prone, nonhomologous end joining pathway, the application of these therapies appears to be tumor-specific (Tutt et al. 2005). For example, platinum induction followed by PARP inhibitor maintenance has become a standard of care in the treatment of ovarian and pancreatic cancers with gBRCA1/2 or PALB2 mutations (Robson et al. 2017; Golan et al. 2019). In gBRCA1/2-mutated metastatic breast cancer, however, whereas platinum chemotherapy is being utilized in the first-line setting, PARP inhibitors are reserved for relapsed disease (Moore et al. 2018). The use of these genome-directed therapies is inherently more complicated in prostate cancer, which encompasses both castration-sensitive and castration-resistant adenocarcinomas as well as treatment-emergent and de novo neuroendocrine carcinomas.
Prostate adenocarcinoma with a gBRCA1/2 mutation is associated with an aggressive clinical course and poor prognosis compared to nonmutated disease (Castro et al. 2013). Platinum-based chemotherapy has not been prospectively studied in HRR-deficient prostate cancer and there is no general consensus on whether it is more useful than standard therapies (Pomerantz et al. 2017; Mateo et al. 2018). On the other hand, the PARP inhibitors olaparib and rucaparib have both recently been approved by the U.S. Food and Drug Administration for use in recurrent CRPC with germline or somatic HRR gene mutations.
Neuroendocrine prostate cancer (NEPC) has traditionally been considered a rare, lethal subtype of prostate cancer (Akamatsu et al. 2018). Yet, the widespread use of and subsequent resistance to newer, potent anti-androgen drugs is increasing the incidence of NEPC, specifically t-SCNC (Aggarwal et al. 2018). This observation, coupled with an expansion in germline genetic testing of individuals with prostate cancer, will likely result in more oncologists encountering t-SCNC with HRR gene mutations. Although platinum-based chemotherapy has demonstrated efficacy as first-line therapy, there are no clinical trial results on the use of PARP inhibitors for relapsed disease or as maintenance therapy. Therefore, case reports and series are important in informing practice decisions until mature clinical trial data are reported.
To our knowledge, this is the first case report of germline BRCA2-mutated t-SCNC of the prostate. Our patient developed explosive t-SCNC after 16 mo of ADT plus abiraterone for Gleason 8 metastatic prostate cancer. He achieved a complete response with first-line platinum-based chemotherapy but a <6-mo remission duration, despite the use of a PARP inhibitor as maintenance therapy. Given this brief remission, which includes a recognized continued benefit of chemotherapy for ∼2 mo after its completion, the benefit of olaparib was considered brief at best. The mechanism of PARP inhibitor resistance in our patient was revealed by tumor genomic profiling, which found a somatic BRCA2 mutation. This BRCA2 (V1810_C1885del) deletion mutant encodes for nearly full-length BRCA2 protein except for a deletion of the BRC repeat 6. This would most likely restore at least partial wild-type function as the other intact BRC repeats would allow for the necessary stabilization of RAD51–ssDNA interactions (Chatterjee et al. 2016; A. Monteiro pers. commun.). In support of this, the IRC Database of Reversion Mutations documents a case of platinum-resistant ovarian cancer with a BRCA2 germline 5946delT reverting to a functional allele by deleting c.5954–6090 (aa 1977–2002), which is part of the BRC repeat 7 (Edwards et al. 2008).
The case presented also has clinical relevance regarding the uses of cfDNA analysis vs tumor profiling to detect BRCA2 reversion mutations in patients with prostate cancer. The lack of detection of our reversion mutation by Guardant360 may relate to its large size (228 bp) relative to the typical reversion mutation, which is <100 bp (Pettitt et al. 2020). Although some groups recommend cfDNA analysis over tumor biopsy for detection of the full spectrum of tumor heterogeneity (Carneiro et al. 2018), others have found that the assay has limitations in detecting clinically relevant alterations (including large somatic deletions) in a significant percentage of patients (Taavitsainen et al. 2019).
Both epigenetic and genetic changes have been linked to the lineage plasticity of prostate cancer (Ge et al. 2020). Altered transcriptional regulation by DNA methylation, histone modification, and chromatin remodeling plays a prominent role in the clonal evolution from hormone-sensitive adenocarcinoma to castration-resistant neuroendocrine cancer (Beltran et al. 2016). In our patient, we observed somatically acquired alterations in three histone lysine N-methyltransferase genes, including a missense mutation of SETD2, whole-gene loss of SETD8 (KMT5A), and deletion in KMT2C. It has recently been shown that SETD2-mediated H3K36me3 down-regulates EZH2-catalyzed H3K27me3 chromatin repression and that SETD2 deficiency promotes the development of metastatic prostate cancer (Yuan et al. 2020). Similarly, SETD8 reduces EZH2-mediated cell proliferation, and reduction in SETD8 activity promotes oncogenesis (LeFave et al. 2015).
Our patient's genomic profile revealed a mutation in the PTEN gene and a TMPRSS2-ERG fusion, which are present in ∼50% of prostate cancers (Akamatsu et al. 2018). Yet, we did not detect loss of RB1 and TP53 nor gene amplification of MYCN or AURKA, common alterations in NEPC (Beltran et al. 2011; Ge et al. 2020). We did not test for MYCN and AURKA overexpression by immunohistochemistry, however, and therefore cannot rule out their involvement in this case of t-SCNC.
Another case of BRCA2-alterered t-SCNC was recently reported by Turina et al. (2019). In contrast to our patient, their patient did not have a gBRCA2 mutation but rather somatic complete copy-number loss of BRCA2 found on tumor genomic profiling. The patient developed t-SCNC after 4 mo of ADT plus enzalutamide, had a complete response to etoposide/carboplatinum, and was in continued remission after 9 mo of olaparib; no further clinical detail was provided. Considering both cases, inactivation of BRCA2, whether through germline or somatic alteration, appears to render t-SCNC highly sensitive to platinum-based chemotherapy, although resistance to platinum/PARPi occurred within 6 mo in our patient as a result of the emergence of a BRCA2 reversion mutation. Clearly, more reports of HRR-deficient t-SCNC are needed for a clearer understanding of the role of PARP inhibitors and the emergence of BRCA2 reversion mutations in response to platinum and/or PARPi therapy in this histologically and genetically defined subtype of prostate cancer.
In summary, the case presented provides evidence for initial platinum sensitivity of gBRCA2-mutated t-SCNC and emergence of a BRCA2 somatic reversion mutation during PARPi maintenance therapy. The candidate reversion mutation was detectable through tumor genomic profiling but not routine cfDNA analysis. PARP inhibition following effective platinum-based chemotherapy may be a less promising strategy in BRCA2-mutated t-SCNC than in other HRR-deficient malignancies (Robson et al. 2017; Moore et al. 2018; Golan et al. 2019). Clinical trials testing different sequencing of platinum-chemotherapy and PARPi along with both serial cfDNA and tumor sampling next-generation sequencing (NGS) analyses are needed for a more informed treatment paradigm to emerge for the treatment of t-SCNC characterized by mutations in HRR genes.
METHODS
DNA Isolation and PCR Assay Design
Total genomic DNA isolation was performed from formalin-fixed paraffin-embedded (FFPE) tumor tissue sample (collected after PARPi treatment) by GeneRead DNA FFPE Kit (QIAGEN 180134) and from peripheral blood monocytes by Gentra Puregene Blood Kit (QIAGEN 158422). Double-strand DNA concentrations were determined by Qubit 2.0 Fluorometer (Invitrogen by Life Technologies). A primer pair (forward: CTTGATTCTGGTATTGAGCCAGT, reverse: ACCTTATGTGAATGCGTGCT) was designed to the BRCA2 gene exon 11 to sequence somatic mutation as well as point mutation. PCR product DNAs were isolated from the agarose gel by QIAquick Gel Extraction Kit (QIAGEN 28704) and sent for Sanger sequencing (Genewiz). For the mutation analysis by qPCR, TaqMan SNP Genotyping Assay (ThermoFisher Scientific) was designed for point mutation (S1882*) and qPCR was performed on QuantStudio 7 Flex (ThermoFisher Scientific).
ADDITIONAL INFORMATION
Data Deposition and Access
Two BRCA2 variants (S1882*, V1810_C1885del) focused on in this report have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and can be found under accession numbers SCV001451935 and SCV001451938, for S1882* and V1810_C1 885del, respectively.
Ethics Statement
Informed written consent was obtained for the patient for the study, Genomic Profiling in Cancer Patients (Memorial Sloan Kettering Cancer Center IRB, ClinicalTrials.gov ID: NCT01775072).
Acknowledgments
We thank Dr. Alvaro N. Monteiro (H. Lee Moffitt Cancer Center & Research Institute) and Dr. Stephen J. Pettit and Dr. Christopher J. Lord (Institute of Cancer Research), for their expertise and generous advice. We also thank Dr. Joanna Weber for assistance with histopathology, Dr. Sabina Swierczek for assistance with Sanger and qPCR experiments, and Dr. Sandra Lobo for support and encouragement.
Competing Interest Statement
The authors have declared no competing interest.
Referees
Michael Fraser
Anonymous
Supplementary Material
Supplemental Material
[Supplemental material is available for this article.] | Oral | DrugAdministrationRoute | CC BY-NC | 33608381 | 18,972,244 | 2021-02 |
What was the outcome of reaction 'Neuroendocrine carcinoma of prostate'? | Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance.
Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as BRCA1/2, are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the BRCA2 gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency.
INTRODUCTION
Metastatic castration-sensitive prostate cancer is typically treated in the first-line setting with androgen deprivation therapy in combination with either the chemotherapeutic drug docetaxel or a newer, orally active hormonal agent, such as abiraterone or enzalutamide (Swami et al. 2020). Treatment resistance, however, is universal and associated with transdifferentiation to a small-cell neuroendocrine histology in ∼17% of cases (Aggarwal et al. 2018). Treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) has few effective therapeutic options. Platinum-based chemotherapy is typically used as first-line therapy, although median survivals are only 7 mo (Wang et al. 2014). Improvements in the treatment of t-SCNC are, therefore, urgently needed.
Germline (g) and somatic mutations in homologous recombination repair (HRR) genes—such as BRCA1/2, ATM, PALB2, RAD51D, and CHEK2—are estimated to occur in 12% and 25% of individuals with castrate-resistant prostate cancer (CRPC), respectively (Sartor and de Bono 2018). Although the superiority of platinum-based chemotherapy has not been established in this setting (Mateo et al. 2018), as it has for other types of HRR-deficient adenocarcinomas (Robson et al. 2017; Moore et al. 2018; Golan et al. 2019), the effectiveness of poly(ADP-ribose) polymerase (PARP) inhibitors has been proven (de Bono et al. 2020). In contrast, neuroendocrine prostate cancer has demonstrated sensitivity to platinum agents (Apostolidis et al. 2019; Corn et al. 2019), but there are no clinical trial reports on the use of PARP inhibitors in this setting. Given the expanding linkage between platinum sensitivity and responsiveness to PARP inhibiton in malignancies characterized by HRR deficiency, it is reasonable to study this treatment paradigm in patients with HRR-deficient t-SCNC.
Here, we report the case of a man with an aggressive t-SCNC carrying a gBRCA2 mutation who was treated with the PARP inhibitor (PARPi) olaparib following a major response to first-line platinum-based chemotherapy.
RESULTS
Clinical Presentation and Family History
Informed written consent was obtained from the patient for publication of this case report. A 65-yr-old Indian male, with a history of type 1 diabetes, presented to the Norwalk Hospital emergency department after 1 mo of progressive bilateral leg and scrotal edema as well as low back pain. Ultrasound showed an occlusive deep vein thrombosis (DVT) in the left common femoral vein with possible extension into the left external iliac vein. He underwent thrombectomy followed by treatment with enoxaparin. Computed tomography (CT) of the chest, abdomen, and pelvis showed thrombus in the left iliac veins, multiple enlarged retroperitoneal and left pelvic lymph nodes, and prostatic enlargement, measuring 5.1 × 5.3 × 5.3 cm. A bone scan showed several widely distributed osseous metastases involving the hips, spine, ribs, and sternum. The prostate-specific antigen (PSA) was 95 ng/mL. He underwent 12-quadrant prostate biopsies, which showed 50%–100% involvement in all cores with Gleason 8 (4 + 4) adenocarcinoma. The tumor was strongly positive for prostate-specific acid phosphatase (Fig. 1).
Figure 1. (A) Prostate adenocarcinoma: low-power view from left lateral mid prostate biopsy showing Gleason 4 + 4 = 8 pattern (4×). (B) Prostatic specific acid phosphatase (PSAP): low-power view from left lateral mid prostate biopsy showing positive cytoplasmic staining for PSAP by immunohistochemistry (IHC) (10×). (C) Liver small-cell carcinoma: low-power view of tumor in the liver with nests and sheets of uniform tumor cells with high nuclear to cytoplasmic ratio (10×). (D) Liver synaptophysin: IHC for synaptophysin showing membranous and cytoplasmic positive staining (20×).
The patient began leuprolide androgen deprivation therapy (ADT) and abiraterone plus prednisone, choosing to avoid chemotherapy because of the potential impact of side effects on his employment. His initial symptoms gradually improved and he was soon able to return to work and carry out all activities of daily living (ADLs). The PSA declined to 0.2 ng/mL during the first 3 mo and remained low, as shown in Figure 2. After 12 mo, a bone scan showed decreased intensity and extent of all lesions, and CT showed no visceral disease (Fig. 2). Germline genetic testing revealed a pathogenic nonsense mutation in the BRCA2 gene, predicting a truncated protein (Table 1 and next section). Family history was notable for a paternal uncle with prostate cancer and a maternal uncle with colon cancer, both in their 60s.
Figure 2. Clinical pattern of response to treatment. PSA and Chromogranin A measurement levels corresponding to the timeline showing therapy (middle panel). Top panels show corresponding axial CT images. N.B. Leuprolide continued but abiraterone was discontinued upon diagnosis of neuroendocrine carcinoma. (Pembro) Pembrolizumab.
Table 1. Germline (g) and somatic (s) mutations
Gene symbol Chromosome_position_change Clinical significance Variation type Gene region Protein variant Allele frequency (%) Impact on translation dbSNP ID
Pre-platin/PARPi Relapse during PARPi
Color panel (g) Guardant360 (g,s) MSK-IMPACT (s)
Saliva Blood (cfDNA) Tumor
BRCA2 Chr 13:32340000_C > A/C > T Pathogenic SNV Exonic p.S1882* 49.3 46.9 - Stop-gained 80358785
ATM Chr 11: 108192129_T > C VUS SNV Exonic p.I2185T 51.9 44.3 - Missense 779611511
BRCA1 Chr 17:43094766_C > T VUS SNV Exonic p.E255D ND 6.9 39.6 Missense 62625299
BRCA2 Chr 13:32339783_G>227del Reversion Indel Exonic p.V1810_C1885del ND ND 56 In-frame
ALK Chr 2_29275099_C > G Benign SNV Exonic p.V681L - NR 42 Missense
SETD2 Chr 3_47057420_G > C Likely pathogenic SNV Exonic p.R2122G - NR 39.9 Missense 1279854337
HGF Chr 7_81757271_G > A Benign SNV Exonic p.R134C - NR 60.7 Missense 1032300573
Germline origin of BRCA2 p.S1882* was determined by color hereditary cancer risk test. Guardant360 cannot distinguish germline from somatic origin.
MSK-IMPACT calls mutations against paired germline samples and does not report germline variants.
(ND) Not detected, (-) not determined, (NR) not reported (although sequenced, Guarant360 final report does not include variants of these genes), (SNV) single-nucleotide variant, (Indel) insertion deletion.
After 16 mo, the patient became acutely ill requiring hospitalization. Physical examination revealed scleral icterus, painful hepatomegaly, and profound global weakness. The aspartate transaminase was 424 U/L, alanine transaminase 241 U/L, total bilirubin 5.4 mg/dL, and lactate 5.0 mmol/L. The PSA was 0.5 ng/mL, serum chromogranin-A 7160 ng/mL (normal < 95), and neuron-specific enolase (NSE) 824 ng/mL (normal < 15). Abdominopelvic CT showed the liver was 27 cm in transverse dimension with innumerable new 2–3 cm hypodense lesions (Fig. 2). CT-guided liver biopsy showed poorly differentiated neuroendocrine carcinoma most consistent with small-cell carcinoma (Fig. 1). Immunohistochemical stains showed the tumor positive for CK20 (dot-like accentuation), synaptophysin, and chromogranin and negative for CK7, PSA, TTF-1, GATA-3, CDX-2, NKX3.1, and Merkel cell polyoma virus. There was loss of RB and the Ki-67 labeling index was >50%. There was insufficient tumor sample for genomic profiling prechemotherapy but this was performed subsequently (see below).
The patient began chemotherapy with etoposide and carboplatin every 3 wk and gradually improved with normalization of liver enzymes. After two cycles of treatment, the NSE declined to 18 ng/mL, chromogranin-A declined to 408 ng/mL, and CT scan showed markedly diminished hepatic metastases. After six cycles of chemotherapy, the chromogranin-A was 115 ng/mL, and CT showed near-complete resolution of hepatic metastases (Fig. 2). The patient was then placed on maintenance therapy with the PARPi olaparib (300 mg po bid). Olaparib was well-tolerated without significant side effects, but within 6 mo of treatment, CT scan showed recurrent hepatic metastases (Fig. 2). Upon the development of PARP inhibitor resistance, cell-free (cf) DNA analysis revealed only the pathogenic germline BRCA2 mutant. Genomic profiling from a growing hepatic metastasis, however, revealed a 228-bp deletion in BRCA2 that restored the open reading frame. This mutation results in near full-length BRCA2 protein and would be considered a reversion mutation (see the next section).
Because of the lack of known effective therapies for refractory t-SCNC, the patient was next treated with pembolizumab (200 mg every 3 wk) while olaparib was continued, given the preliminary efficacy of anti-PD1 immunotherapy drugs in patients with CRPC and an HRR gene mutation (Antonarakis et al. 2020). After three cycles of therapy, continued progression of disease was found by imaging and tumor markers (Fig. 2), and the patient began to lose weight and experience hepatic pain. He was again treated with platinum-based chemotherapy, but after three cycles developed global progression of disease including innumerable brain metastases. Hospice care was chosen and he died 18 mo after the diagnosis of t-SCNC and 34 mo from diagnosis of metastatic prostate cancer.
Germline and Somatic Genomic Alterations
Germline genetic testing was performed prior to initiation of chemotherapy by the 30-gene Color Hereditary Cancer Risk Test (Color Genomics). This revealed the presence of a pathogenic BRCA2 nonsense mutation (p.Ser1882*) at a mutation allele frequency (MAF) of 49.3%, which predicts truncation and loss of full-length functional protein. A variant of uncertain significance (VUS) in the ATM gene (p.I2185T) was also found (Table 1).
Later during the course of treatment and in the setting of resistance to PARP inhibitor therapy, blood for cfDNA was analyzed on the Guardant360 platform consisting of 74 cancer-associated genes (Guardant Health), revealing the same germline BRCA2 mutation with a MAF of 46.9% and a somatic BRCA1 (p.E255D) VUS with a MAF of 6.9% (Table 1). Liver biopsy confirmed SCNC and genomic profiling was performed on the MSK-IMPACT platform consisting of 468 genes (Memorial Hospital For Cancer & Allied Diseases) (Zehir et al. 2017). This revealed the following alterations; a somatic BRCA2 mutation (p.V1810_C1885del) with a MAF of 56%, a VUS in BRCA1, benign ALK, HGF, and likely pathogenic SETD2 mutations (Table 1). Copy-number alterations (CNAa): PTEN, TNRFSF14, HNF1A, PIK3CD, PDCD1, and SETD8. CNA from these genes are suggestive of multiple chromosomal level losses and deletion of the entire gene PTEN (Table 2). Structural variants: MAP2K1, KMT2C2, and TMPRSS2-ERG fusion (Table 2), supporting the transdifferentiation of the small-cell neuroendocrine cancer from the original prostate adenocarcinoma, as this translocation is present in approximately half of prostate cancers (Mosquera et al. 2009), Additional findings included a tumor mutation burden (TMB) of 4.4 mutations per megabase and microsatellite instability (MSI) status stable.
Table 2. Somatic alterations—copy-number alterations (CNAs) and structural variants (SVs)
Gene symbol Type Alteration Location Fold change Panel
PTEN Whole gene Deletion 10q23.31 −3.2 MSK-IMPACT
TNFRSF14 Whole gene Loss 1p36.32 −1.8
HNF1A Whole gene Loss 12q24.31 −1.7
PIK3CD Whole gene Loss 1p36.22 −1.8
PDCD1 Whole gene Loss 2q37.3 −1.7
SETD8 Whole gene Loss 12q23.31 −1.7
MAP2K1 Translocation t(14;15)(q31.2;q22.31) (Chr 14:g.84540589::Chr 15:g.66679738) exon 1
TMPRSS2-ERG Deletion c.56-537:TMPRSS2_c.18 + 8757:ERGdel TMPRSS2 exon 1 to ERG exon 2
KMT2C Deletion c.9453 + 378_c.11536del Exons 41–44
Amplification is considered when there is a greater than twofold change detected and deletion when <−2 of fold change is detected.
The patient's somatic BRCA2 (V1810_C1885del) mutation is a 228-bp deletion that includes the germline deleterious point mutation (S1882*) at the third to the last position, restoring the open reading frame, albeit a truncated predicted protein (Fig. 3A). This novel mutation could be considered a reversion mutation, if occurring in cis with the germline mutation. It has not been reported in the IRC Database of Reversion Mutations (https://reversions.icr.ac.uk/), one of the largest of such databases (Pettitt et al. 2020). Because BRCA2 allelic loss was not reported by MSK-IMPACT, we attempted to determine this by performing qualitative polymerase chain reaction (qPCR) and Sanger sequencing on microdissected tumor tissue (Fig. 3B,C). Gel electrophoresis of the PCR products from BRCA2 mutation–specific primers revealed the presence of two distinct bands migrating at 230 and 450 bp. Sanger sequencing of each gel-isolated and -purified band confirmed the secondary deletion mutation but also revealed two electropherogram peaks for the wild-type and germline mutant alleles. TaqMan qPCR genotyping assay was performed to target the germline point mutation but showed the same heterogeneity of wild-type and mutant alleles; this was in part due to the inability to eliminate all normal cells from the biopsy samples. Although we could not confirm that the somatic BRCA2 deletion was cis to the germline mutation, the concurrent emergence of resistance to platinum and PARPi therapies as well as several lines of evidence support this as a reversion mutation: (1) The affected region is frequently deleted in reversions; (2) the deletion includes the germline mutation and restores the open reading frame (ORF), an event unlikely to occur at the same location on the normal allele; and (3) the deletion is flanked by microhomology (CAA), a characteristic of many reversion mutations (Pettitt et al. 2020).
Figure 3. Detection of case patient BRCA2 germline and somatic mutations in different tissue compartments. (A) BRCA2 domains showing location of patient's germline and somatic mutations. The patient has a germline mutation S1882*, which is a pathogenic nonsense mutation. During PARPi (olaparib) treatment, a somatic deletion mutation (V1810_C1885del) of 76 aa was detected. To confirm reversion status of the deletion mutant, Sanger and qPCR (B) were performed. As shown in B, gel electrophoresis (left) from the PCR performed on the primers designed outside the deleted region showed two clear bands of 230 bp and 458 bp and Sanger sequencing (right) on each of these bands confirmed the somatic deletion mutation but also showed two peaks, for the wild-type and germline point mutation. To further confirm these findings, we designed a TaqMan genotyping assay for the point mutation and performed qPCR (C). qPCR on gDNA showed the wild-type and point mutation alleles at 30 and 32 cycles, respectively. qPCR performed on PARPi resistant tumor tissue also detected both alleles.
Although the Guardant360 assay did not detect our patient's deletion (cfDNA fragments in the assay are in general ∼150 bp in length), by using deletion targeted primers on ctDNA taken at a later time, we were able to detect the deletion mutation from a blood sample (see Supplemental Fig. 1).
DISCUSSION
The optimal management of individuals with incurable malignancies characterized by HRR deficiency is still evolving. Although germline mutations in BRCA1/2 and PALB2 predict response to both platinum-based chemotherapy and PARP inhibition, because of the requirement to repair double-strand DNA breaks through the error-prone, nonhomologous end joining pathway, the application of these therapies appears to be tumor-specific (Tutt et al. 2005). For example, platinum induction followed by PARP inhibitor maintenance has become a standard of care in the treatment of ovarian and pancreatic cancers with gBRCA1/2 or PALB2 mutations (Robson et al. 2017; Golan et al. 2019). In gBRCA1/2-mutated metastatic breast cancer, however, whereas platinum chemotherapy is being utilized in the first-line setting, PARP inhibitors are reserved for relapsed disease (Moore et al. 2018). The use of these genome-directed therapies is inherently more complicated in prostate cancer, which encompasses both castration-sensitive and castration-resistant adenocarcinomas as well as treatment-emergent and de novo neuroendocrine carcinomas.
Prostate adenocarcinoma with a gBRCA1/2 mutation is associated with an aggressive clinical course and poor prognosis compared to nonmutated disease (Castro et al. 2013). Platinum-based chemotherapy has not been prospectively studied in HRR-deficient prostate cancer and there is no general consensus on whether it is more useful than standard therapies (Pomerantz et al. 2017; Mateo et al. 2018). On the other hand, the PARP inhibitors olaparib and rucaparib have both recently been approved by the U.S. Food and Drug Administration for use in recurrent CRPC with germline or somatic HRR gene mutations.
Neuroendocrine prostate cancer (NEPC) has traditionally been considered a rare, lethal subtype of prostate cancer (Akamatsu et al. 2018). Yet, the widespread use of and subsequent resistance to newer, potent anti-androgen drugs is increasing the incidence of NEPC, specifically t-SCNC (Aggarwal et al. 2018). This observation, coupled with an expansion in germline genetic testing of individuals with prostate cancer, will likely result in more oncologists encountering t-SCNC with HRR gene mutations. Although platinum-based chemotherapy has demonstrated efficacy as first-line therapy, there are no clinical trial results on the use of PARP inhibitors for relapsed disease or as maintenance therapy. Therefore, case reports and series are important in informing practice decisions until mature clinical trial data are reported.
To our knowledge, this is the first case report of germline BRCA2-mutated t-SCNC of the prostate. Our patient developed explosive t-SCNC after 16 mo of ADT plus abiraterone for Gleason 8 metastatic prostate cancer. He achieved a complete response with first-line platinum-based chemotherapy but a <6-mo remission duration, despite the use of a PARP inhibitor as maintenance therapy. Given this brief remission, which includes a recognized continued benefit of chemotherapy for ∼2 mo after its completion, the benefit of olaparib was considered brief at best. The mechanism of PARP inhibitor resistance in our patient was revealed by tumor genomic profiling, which found a somatic BRCA2 mutation. This BRCA2 (V1810_C1885del) deletion mutant encodes for nearly full-length BRCA2 protein except for a deletion of the BRC repeat 6. This would most likely restore at least partial wild-type function as the other intact BRC repeats would allow for the necessary stabilization of RAD51–ssDNA interactions (Chatterjee et al. 2016; A. Monteiro pers. commun.). In support of this, the IRC Database of Reversion Mutations documents a case of platinum-resistant ovarian cancer with a BRCA2 germline 5946delT reverting to a functional allele by deleting c.5954–6090 (aa 1977–2002), which is part of the BRC repeat 7 (Edwards et al. 2008).
The case presented also has clinical relevance regarding the uses of cfDNA analysis vs tumor profiling to detect BRCA2 reversion mutations in patients with prostate cancer. The lack of detection of our reversion mutation by Guardant360 may relate to its large size (228 bp) relative to the typical reversion mutation, which is <100 bp (Pettitt et al. 2020). Although some groups recommend cfDNA analysis over tumor biopsy for detection of the full spectrum of tumor heterogeneity (Carneiro et al. 2018), others have found that the assay has limitations in detecting clinically relevant alterations (including large somatic deletions) in a significant percentage of patients (Taavitsainen et al. 2019).
Both epigenetic and genetic changes have been linked to the lineage plasticity of prostate cancer (Ge et al. 2020). Altered transcriptional regulation by DNA methylation, histone modification, and chromatin remodeling plays a prominent role in the clonal evolution from hormone-sensitive adenocarcinoma to castration-resistant neuroendocrine cancer (Beltran et al. 2016). In our patient, we observed somatically acquired alterations in three histone lysine N-methyltransferase genes, including a missense mutation of SETD2, whole-gene loss of SETD8 (KMT5A), and deletion in KMT2C. It has recently been shown that SETD2-mediated H3K36me3 down-regulates EZH2-catalyzed H3K27me3 chromatin repression and that SETD2 deficiency promotes the development of metastatic prostate cancer (Yuan et al. 2020). Similarly, SETD8 reduces EZH2-mediated cell proliferation, and reduction in SETD8 activity promotes oncogenesis (LeFave et al. 2015).
Our patient's genomic profile revealed a mutation in the PTEN gene and a TMPRSS2-ERG fusion, which are present in ∼50% of prostate cancers (Akamatsu et al. 2018). Yet, we did not detect loss of RB1 and TP53 nor gene amplification of MYCN or AURKA, common alterations in NEPC (Beltran et al. 2011; Ge et al. 2020). We did not test for MYCN and AURKA overexpression by immunohistochemistry, however, and therefore cannot rule out their involvement in this case of t-SCNC.
Another case of BRCA2-alterered t-SCNC was recently reported by Turina et al. (2019). In contrast to our patient, their patient did not have a gBRCA2 mutation but rather somatic complete copy-number loss of BRCA2 found on tumor genomic profiling. The patient developed t-SCNC after 4 mo of ADT plus enzalutamide, had a complete response to etoposide/carboplatinum, and was in continued remission after 9 mo of olaparib; no further clinical detail was provided. Considering both cases, inactivation of BRCA2, whether through germline or somatic alteration, appears to render t-SCNC highly sensitive to platinum-based chemotherapy, although resistance to platinum/PARPi occurred within 6 mo in our patient as a result of the emergence of a BRCA2 reversion mutation. Clearly, more reports of HRR-deficient t-SCNC are needed for a clearer understanding of the role of PARP inhibitors and the emergence of BRCA2 reversion mutations in response to platinum and/or PARPi therapy in this histologically and genetically defined subtype of prostate cancer.
In summary, the case presented provides evidence for initial platinum sensitivity of gBRCA2-mutated t-SCNC and emergence of a BRCA2 somatic reversion mutation during PARPi maintenance therapy. The candidate reversion mutation was detectable through tumor genomic profiling but not routine cfDNA analysis. PARP inhibition following effective platinum-based chemotherapy may be a less promising strategy in BRCA2-mutated t-SCNC than in other HRR-deficient malignancies (Robson et al. 2017; Moore et al. 2018; Golan et al. 2019). Clinical trials testing different sequencing of platinum-chemotherapy and PARPi along with both serial cfDNA and tumor sampling next-generation sequencing (NGS) analyses are needed for a more informed treatment paradigm to emerge for the treatment of t-SCNC characterized by mutations in HRR genes.
METHODS
DNA Isolation and PCR Assay Design
Total genomic DNA isolation was performed from formalin-fixed paraffin-embedded (FFPE) tumor tissue sample (collected after PARPi treatment) by GeneRead DNA FFPE Kit (QIAGEN 180134) and from peripheral blood monocytes by Gentra Puregene Blood Kit (QIAGEN 158422). Double-strand DNA concentrations were determined by Qubit 2.0 Fluorometer (Invitrogen by Life Technologies). A primer pair (forward: CTTGATTCTGGTATTGAGCCAGT, reverse: ACCTTATGTGAATGCGTGCT) was designed to the BRCA2 gene exon 11 to sequence somatic mutation as well as point mutation. PCR product DNAs were isolated from the agarose gel by QIAquick Gel Extraction Kit (QIAGEN 28704) and sent for Sanger sequencing (Genewiz). For the mutation analysis by qPCR, TaqMan SNP Genotyping Assay (ThermoFisher Scientific) was designed for point mutation (S1882*) and qPCR was performed on QuantStudio 7 Flex (ThermoFisher Scientific).
ADDITIONAL INFORMATION
Data Deposition and Access
Two BRCA2 variants (S1882*, V1810_C1885del) focused on in this report have been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and can be found under accession numbers SCV001451935 and SCV001451938, for S1882* and V1810_C1 885del, respectively.
Ethics Statement
Informed written consent was obtained for the patient for the study, Genomic Profiling in Cancer Patients (Memorial Sloan Kettering Cancer Center IRB, ClinicalTrials.gov ID: NCT01775072).
Acknowledgments
We thank Dr. Alvaro N. Monteiro (H. Lee Moffitt Cancer Center & Research Institute) and Dr. Stephen J. Pettit and Dr. Christopher J. Lord (Institute of Cancer Research), for their expertise and generous advice. We also thank Dr. Joanna Weber for assistance with histopathology, Dr. Sabina Swierczek for assistance with Sanger and qPCR experiments, and Dr. Sandra Lobo for support and encouragement.
Competing Interest Statement
The authors have declared no competing interest.
Referees
Michael Fraser
Anonymous
Supplementary Material
Supplemental Material
[Supplemental material is available for this article.] | Fatal | ReactionOutcome | CC BY-NC | 33608381 | 18,972,244 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mucosal inflammation'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neurotoxicity'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin toxicity'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombocytopenia'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vasospasm'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | The prevalence and clinical relevance of 2R/2R TYMS genotype in patients with gastrointestinal malignancies treated with fluoropyrimidine-based chemotherapy regimens.
The prevalence of 2R/2R TYMS genotype is variable but estimated to be around 20-30% in Caucasians. The clinical relevance of TYMS 2R/2R genotype in predicting severe fluoropyrimidine-related adverse events (FrAE) is controversial. Here, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype.
Between 2011 and 2018, 126 patients were genotyped for TYMS. FrAEs were graded according to CTCAE version 5.0. Fisher's exact test was used for statistical analysis.
The prevalence of TYMS 2R/2R genotype was 24.6%. Among patients with TYMS genotypes (N = 71) that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female (57%) and African American (60%) patients. Among patients with genotypes that predict increased TS expression (N = 55), 12 patients had grade 3-4 FrAEs (22%), while among patients with genotypes that predict decreased TS expression (N = 71), 30 patients had grade 3-4 FrAEs (42%) (p = 0.0219). Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with TYMS 2R/2R genotype had grade 3-4 FrAEs (p = 0.0039) and 15 out 40 patients (38%) with TYMS 2R/3RC and TYMS 3RC/3RC genotype had grade 3-4 FrAEs (p = 0.1108).
The prevalence of TYMS 2R/2R genotype was 24.6%, and it had a unique sex and ethnic distribution. Polymorphism in the promoter region of TYMS gene that predicts decreased TS expression due to 2R/2R variant was associated with grade 3-4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
Introduction
Fluoropyrimidines are antimetabolite chemotherapy drugs that are widely used in the treatment of cancer. There are three fluoropyrimidine drugs in clinical use: intravenous 5-fluorouracil (5-FU), oral capecitabine, and oral tegafur. Capecitabine and tegafur are precursors of 5-FU [1, 2]. Fluoropyrimidines are considered the backbone of most chemotherapeutic regimens approved for the treatment of gastrointestinal (GI) malignancies [3]. They also represent treatment options in other malignancies such as breast and head and neck cancer [4, 5].
Among patients treated with 5-FU or capecitabine, approximately 20–25% of patients experience severe (grade 3–4) fluoropyrimidine-related adverse events (FrAEs) [6]. Severe FrAEs lead to patients’ hospitalization and treatment interruption or discontinuation. The inter-individual variation in the occurrence and severity of FrAEs is partly due to genetic factors [7, 8].
Dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by DPYD gene, is the rate-limiting enzyme for 5-FU catabolism, eliminating approximately 80% of administered or formed 5-FU [9]. Any variation in DPD activity can result in a cytotoxic accumulation of free 5-FU. The prevalence of DPD deficiency in Caucasians is approximately 3–5% [10, 11]. African Americans, especially women, seem to have a higher prevalence of approximately 4–12% [12]. Genomic analysis of patients with DPD deficiency has identified over 128 mutations and polymorphisms in the DPYD gene, but only four high-risk variants (DPYD*2A, DPYD*13, DPYD*9B, and HapB3) have been consistently associated with DPD deficiency and FrAEs. Genotyping for DPYD helps in identifying patients with DPD deficiency and guide the dosing of fluoropyrimidines. However, genotyping is limited to high-risk variants, and most patients who experience FrAEs are not DPD deficient [13–15].
In addition to DPYD, polymorphism in the TYMS gene that encodes thymidylate synthase (TS) may be associated with increased risk of FrAEs. TS is potently inhibited by 5-FU. Cells convert 5-FU to the metabolite fluorodeoxyuridine monophosphate, which binds to TS and inhibits the production of deoxythymidine monophosphate (dTMP). dTMP is essential for DNA replication and repair, so the lack of it leads to cell death [16, 17]. Fig. 1 shows the cascade of metabolic reactions where fluoropyrimidines inhibit TS and eventually lead to DNA damage.Fig. 1 Schematic representation of fluoropyrimidine-based drug metabolic pathway.
The capecitabine and tegafur are the oral pre-pro and pro-drug, respectively, which in turn converted into 5-FU, while 5-FU is directly administered as IV. In normal condition of DPD and TS activity, maximum drug is eliminated from body while minimal amount is functionally active and inhibits the DNA and RNA synthesis leading to cell death during cancer treatment. Patients possessing the DPD deficiency show grade 3–4 toxicity as maximum drug is accumulated in the body that inhibit the TYMS. The TYMS 2R/2R genotype has low TS level and correlated with severe fluoropyrimidines-related adverse events. DPD dihydropyrimidine dehydrogenase, UP uridine phosphorylase, UK uridine kinase, TK thymidine kinase, TP thymidine phosphorylase, TS thymidylate synthetase, OPRT orotate phosphoribosyltransferase, RNR ribonucleotide reductase, NME1-NME2 nucleoside diphosphate kinase.
TYMS gene expression is regulated by transcription factors that bind to the promoter region. The 5′ untranslated region contains a 28-base-pair variable number of tandem repeats (VNTRs), which act to enhance the promoter and transcriptional activity (Fig. 2). Most patients have either 2 (2R) or 3 (3R) repeats. Homozygous TYMS 3R/3R genotype has a higher level of TS, while homozygous TYMS 2R/2R genotype has low TS level and may be at greater risk of FrAEs [18, 19]. A single-nucleotide polymorphism of the second repeat of the 3R allele (3RC) abolishes a binding site in the 3R second repeat allele and reduces TS activity compared to wild-type 3R allele (3RG) [20].Fig. 2 Regulation of TYMS gene expression by 5′ and 3′ untranslated regions (UTRs).
Upstream or 5′UTR of the thymidylate synthase gene (TYMS) contains either two tandem repeats (2R) or three tandem repeats (3R) of 28-bp sequences. These tandem repeats regulate the transcription and translation of TYMS gene with the impaired enzyme activity. Moreover, other functional variants of the TYMS gene have been also identified such as single-nucleotide polymorphism (SNP) G>C within the second repeat of the 3R allele. Thymidylate synthase promoter 3RC/3RC genotype causes lower transcriptional activity of TYMS, comparable with the TS 2R/2R genotype. The six nucleotide insertion or deletion also identified to affect the RNA stability of TYMS gene.
The prevalence of 2R/2R TYMS genotype in different ethnic background is variable but estimated to be around 20–30% in Caucasians [21]. The clinical relevance of TYMS 2R/2R genotype in predicting severe FrAEs is controversial [7, 19, 22–26]. Here, in a cohort of patients with GI malignancies treated with fluoropyrimidine-based chemotherapy regimens, we explored the prevalence and clinical relevance of 2R/2R TYMS genotype. Moreover, given the different racial and sex background in our cohort, ethnic and sex differences were explored.
Materials and methods
Patient population
This is a retrospective study conducted at the University of South Alabama Mitchell Cancer Institute in Mobile, Alabama, USA in collaboration with ARUP Laboratories, The University of Utah, Salt Lake City, Utah, USA. Cohort was identified through searching our cancer center tumor registry for patients with GI malignancies genotyped for TYMS gene between 2011 and 2018. The University of South Alabama Institutional Review Board (IRB) approved this study and the IRB-approved database provided a waiver of the requirement for informed consent and allowed for the publication of de-identified data.
Fluoropyrimidine-based chemotherapy
The fluoropyrimidine-based chemotherapy regimens that the patients in this cohort received include FOLFIRINOX, FOLFOX with or without bevacizumab, cetuximab or panitumumab, XELOX, FOLFIRI with or without bevacizumab, cetuximab or panitumumab, XELIRI with or without bevacizumab, cetuximab or panitumumab, FLOT, 5-FU and mitomycin, 5-FU and liposomal irinotecan, capecitabine and gemcitabine, single agent 5-FU with or without concurrent radiotherapy, and capecitabine with or without concurrent radiotherapy. FOLFIRINOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2 every 2 weeks. FOLFOX consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and oxaliplatin 85 mg/m2 every 2 weeks. XELOX consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and oxaliplatin 130 mg/m2 every 3 weeks. FOLFIRI consists of 5-FU bolus of 400 mg/m2, 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and irinotecan 180 mg/m2. XELIRI consists of capecitabine 1000 mg/m2 twice daily for 2 weeks and irinotecan 250 mg/m2 every 3 weeks. FLOT consists of 5-FU continuous infusion 2600 mg/m2 for 24 h, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2. 5-FU and mitomycin consist of 5-FU 4000 mg/m2 and mitomycin 10 mg/m2. 5-FU and nanoliposomal irinotecan consists of 5-FU continuous infusion 2400 mg/m2 for 46 h, leucovorin 400 mg/m2, and nanoliposomal irinotecan 70 mg/m2. Capecitabine and gemcitabine consist of capecitabine 1660 mg/m2 for 21 days and gemcitabine 1000 mg/m2 day 1, 8, and 15 every 4 weeks.
Genotyping strategy
Genotyping strategies were quite variable. The most common genotyping strategy was to genotype patients prior to initiating treatment with fluoropyrimidines-based chemotherapy. Between 2016 and 2018, genotyping was conducted almost universally on all patients with GI malignancies treated with fluoropyrimidines-based chemotherapy. Prior to 2016, only 24 patients were genotyped and genotyping was conducted at the discretion of the treating medical oncologist. Those patients were genotyped either because they experienced toxicities or because they had significant comorbidities and their medical oncologist decided to do upfront genotyping.
TYMS genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped TYMS gene in ARUP laboratories (Salt Lake City, UT, USA). The VNTRs of the 5’UTR flank of TYMS (rs45445694) and their additional single-nucleotide variant (SNV) G>C in the first repeat of the 2R allele (rs183205964, named 2RG or 2RC), the SNV G>C in the second repeat of the 3R allele (rs2863542, named 3RG or 3RC), and the 6 bp insertion in the second repeat of the 3R allele (rs538469385) (all located into the rs45445694 variant) were performed by polymerase chain reaction-restriction fragment length polymorphism. A 6-bp deletion variant at the 3′UTR region of TYMS (rs151264360) was genotyped as well.
DPYD genotyping
Germline DNA was obtained from peripheral blood specimens and genotyped for high-risk DPYD variants (IVS14+1G>A [DPYD*2A], DPYD c.1679T>G [DPYD*13A] and DPYD c.2846A>T [DPYD*9B]) in ARUP laboratories (Salt Lake City, UT, USA). Only patients with no mutant high-risk DPYD variants were included in this cohort. Patients with mutant DPYD*9A (c.85T>C) were included in our cohort since the 2017 updated Clinical Pharmacogenetics Implementation Consortium guidelines for DPD genotype and fluoropyrimidine dosing and other studies stated that the DPYD*9A (c.85T>C) does not affect DPD activity in a clinically relevant manner [14, 15].
Toxicity grading and statistical analysis
Demographic and clinical data were extracted from the patients’ charts. FrAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Association between dichotomous fluoropyrimidine-related toxicities and TYMS genotype was performed using Fisher’s exact test. Analyses with p values ≤ 0.05 were considered significant. Tests were performed using GraphPad software QuickCalcs (GraphPad software 2016, San Diego, CA).
Results
Patient characteristics
Between 2011 and 2018, a total of 126 patients with GI malignancies were genotyped for TYMS and had no identifiable high-risk DPYD variants. The baseline characteristics of the patients are summarized in Table 1. Median age is 59 years. Males represented 55% of the patients, while females represented 45%. In our cohort, 63% were Caucasian, 35% were African Americans, and 2% were other ethnicities (Hispanics, Asians, and Indian Americans). Colon adenocarcinoma represented the most common malignancy in our cohort. Other patients had anal squamous cell carcinoma, appendix adenocarcinoma, cholangiocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, neuroendocrine tumor, pancreatic adenocarcinoma, and rectal adenocarcinoma. A fluorouracil-based chemotherapy regimen was administered in 74% of the patients, while 26% of the patients received a capecitabine-based chemotherapy regimen.Table 1 Patient baseline characteristics.
Patient characteristics Number subject, N [%]
Age (years)
Median (range) 59 (21–90)
Sex
Female 57 [45%]
Male 69 [55%]
Ethnicity
African American 44 [35%]
Other ethnicitiesa 3 [2%]
Caucasians 79 [63%]
Diagnosis
Anal SCC 6 [5%]
Appendix 3 [2%]
Cholangiocarcinoma 4 [3%]
Colon adenocarcinoma 50 [40%]
Esophageal adenocarcinoma 2 [2%]
Gastric adenocarcinoma 8 [6%]
Neuroendocrine tumor (SB) 3 [3%]
Pancreatic adenocarcinoma 13 [10%]
Rectal adenocarcinoma 37 [29%]
Chemotherapy regimen
Fluorouracil-based 93 [74%]
Capecitabine-based 33 [26%]
SCC squamous cell carcinoma, SB small bowel.
aHispanics, Asians, and Indian Americans
TYMS genotyping
TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) were identified in 55 patients (44%). TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) were seen in 71 patients (56%). In our cohort, patients with 2R/2R TYMS genotype represented 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. TYMS genotyping in patients with genotypes that predict increased and decreased TS expression is summarized in Table 2.Table 2 TYMS genotyping in patients with GI malignancies with different racial and sex backgrounds.
TYMS genotyping (N = 126) Number of subjects N [%] Sex N [%] Ethnicity N [%]
Male Female Caucasians AA Others
Genotypes predictive of increased TS expression 55 [44%] 33 [26.2%] 22 [17.5%] 30 [23.8%] 23 [18.3%] 2 [1.6%]
3RG/3RG 12 [9.5%] 11 [8.7%] 1 [0.8%] 6 [4.8%] 5 [4.0%] 1a [0.8%]
3RG/3RC 22 [17.5%] 10 [7.9%] 12 [9.5%] 19 [15.1%] 3 [2.4%] 0 [0.0%]
2R/3RG 18 [14.3%] 9 [7.1%] 9 [7.1%] 5 [4.0%] 12 [9.5%] 1b [0.8%]
2R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
3R/4R 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
4R/3RG 1 [0.8%] 1 [0.8%] 0 [0.0%] 0 [0.0%] 1 [0.8%] 0 [0.0%]
Genotypes predictive of decreased TS expression 71 [56%] 36 [28.6%] 35 [27.8%] 50 [39.7%] 20 [15.9%] 1 [0.8%]
2R/2R 31 [24.6%] 11 [8.7%] 20 [15.9%] 19 [15.1%] 12 [9.5%] 0 [0.0%]
2R/3RC 31 [24.6%] 19 [15.1%] 12 [9.5%] 24 [19.0%] 7 [5.6%] 0 [0.0%]
3RC/3RC 9 [7.1%] 6 [4.8%] 3 [2.4%] 7 [5.6%] 1 [0.8%] 1c [0.8%]
AA African American.
aNative American.
bAsian.
cHispanic.
Sex differences
In our cohort, the distribution of 2R/3RG TYMS genotype was similar between males and females. The distribution of all other genotypes apart from 2R/2R and 3RG/3RC TYMS genotypes was more frequent in males than females. The 2R/2R TYMS genotype had a very unique sex distribution where 20 out of 31 patients (65%) were females. This is the only TYMS genotype where females were twice as common as males. In fact, among all the female patients in our cohort (N = 57), the 2R/2R TYMS genotype was present in 20 female patients (35%). Moreover, among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all males. TYMS genotyping in patients with GI malignancies with different sex background is summarized in Table 2.
Ethnic differences
Caucasians were the majority in both genotypes that predict decreased TS expression and in genotypes (3RG/3RG and 3RG/3RC) that predict increased TS expression. Among patients with TYMS genotypes that predict decreased TS expression, 2R/2R TYMS genotype was the most common TYMS genotype seen in African American patients (60%). Of note, the three patients with 4R containing TYMS genotypes (2R/4R, 3R/4R, and 4R/3RG) were all African Americans. There was minimal representation of other ethnic backgrounds in our cohort. TYMS genotyping in patients with GI malignancies with mixed racial background is summarized in Table 2.
Adverse events
The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict increased TS expression (3RG/3RG, 3RG/3RC, 2R/3RG, 2R/4R, 3R/4R, 4R/3RG) and TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 3. None of the patients have died as a consequence of fluoropyrimidine-induced toxicities. The most commonly experienced adverse event in both group of patients with grade 3–4 FrAEs was diarrhea. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), the frequency of grade 1–2 and grade 3–4 FrAEs was further explored. Diarrhea was the most experienced grade 3–4 FrAE in patients with 2R/2R TYMS genotype, while skin toxicity was the most experienced grade 3–4 FrAE in patients with TYMS 2R/3RC. Of note, grade 3–4 neutropenia and vasospasm were more experienced in patients with TYMS 3RC/3RC compared to 2R/2R and 2R/3RC TYMS genotypes. The frequency of grade 1–2 and grade 3–4 FrAEs in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) is summarized in Table 4.Table 3 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict increased and decreased TS expression.
Adverse events TYMS genotypes that predict increased TS expression (N = 55) TYMS genotypes that predict decreased TS expression (N = 71)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Hematological N (%) N (%) N (%) N (%)
Neutropenia 16 (29) 3 (5) 21 (30) 4 (6)
Anemia 10 (18) 0 (0) 16 (23) 0 (0)
Thrombocytopenia 4 (7) 0 (0) 6 (8) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%)
Mucositis 4 (7) 3 (5) 4 (6) 3 (4)
Nausea 17 (31) 2 (4) 23 (32) 2 (3)
Vomiting 3 (5) 2 (4) 5 (7) 1 (1)
Diarrhea 4 (7) 9 (16) 7 (13) 11 (15)
Neurotoxicity 3 (5) 0 (0) 3 (4) 4 (6)
Skin toxicity 3 (5) 3 (5) 1 (1) 8 (11)
Fatigue 30 (55) 2 (4) 27 (38) 5 (7)
Vasospasm 0 (0) 1 (2) 0 (0) 4 (6)
Table 4 The frequency of grade 1–2 and grade 3–4 fluoropyrimidines-related adverse events in patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, and 3RC/3RC genotypes).
Adverse events TYMS genotypes that predict decreased TS expression (N = 71)
2R/2R (N = 31) 2R/3RC (N = 31) 3RC/3RC (N = 9)
G 1–2 G 3–4 G 1–2 G 3–4 G 1–2 G 3–4
Hematological N (%) N (%) N (%) N (%) N (%) N (%)
Neutropenia 11 (35) 1 (3) 9 (29) 1 (3) 1 (11) 2 (22)
Anemia 8 (26) 0 (0) 6 (19) 0 (0) 2 (22) 0 (0)
Thrombocytopenia 3 (10) 0 (0) 3 (10) 0 (0) 0 (0) 0 (0)
Neutropenic fever 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Non-hematological N (%) N (%) N (%) N (%) N (%) N (%)
Mucositis 2 (6) 3 (10) 1 (3) 0 (0) 1 (11) 0 (0)
Nausea 13 (42) 2 (6) 9 (29) 0 (0) 1 (11) 0 (0)
Vomiting 2 (6) 1 (3) 2 (6) 0 (0) 1 (11) 0 (0)
Diarrhea 4 (13) 6 (19) 2 (6) 3 (10) 1 (11) 2 (22)
Neurotoxicity 0 (0) 2 (6) 3 (10) 2 (6) 0 (0) 0 (0)
Skin toxicity 1 (3) 3 (10) 0 (0) 4 (13) 0 (0) 1 (11)
Fatigue 17 (54) 2 (6) 8 (26) 3 (10) 2 (22) 0 (0)
Vasospasm 0 (0) 1 (3) 0 (0) 1 (3) 0 (0) 2 (22)
Statistical analysis
Among patients with TYMS genotypes that predict increased TS expression (N = 55), 12 patients (22%) had grade 3–4 FrAEs, while among patients with TYMS genotypes that predict decreased TS expression, 30 patients (42%) had grade 3–4 FrAEs (p = 0.0219). Given the observed statistically significant difference, we explored the impact of the different TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC) on the observed results. Compared to patients with genotypes predicting increased TS expression, 17 out of 31 patients (55%) with 2R/2R TYMS genotype had grade 3–4 FrAEs (p = 0.0039), while only 15 out 40 patients (38%) with 2R/3RC or 3RC/3RC TYMS genotypes had grade 3–4 FrAEs (p = 0.1108). The association between grade 3–4 FrAEs and TYMS genotypes is shown in Table 5. Statistical analysis was performed using Fisher’s exact test.Table 5 The association between grade 3–4 fluoropyrimidines-related adverse events (FrAEs) and TYMS genotypes.
Patients Grade 3–4 FrAEs, N [%] p
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0219
Patients with genotypes that predict decreased TS expression (N = 71) 30 [42%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.0039
Patients with 2R/2R genotype that predict decreased TS expression (N = 31) 17 [55%]
Patients with genotypes that predict increased TS expression (N = 55) 12 [22%] p = 0.1108
Patients with 2R/3RC and 3RC/3RC TYMS genotypes that predict decreased TS expression (N = 40) 15 [38%]
Statistical analysis was performed using Fisher’s exact test.
Discussion
The prevalence of 2R/2R TYMS genotype in different ethnic background is quite variable. In Caucasian Americans, the prevalence of 2R/2R TYMS genotype in infants with conotruncal heart defects and control group was 21% and 26%, respectively. In the same study, the prevalence of 2R/2R TYMS genotype in American Hispanics was 17% and 18%, respectively [27]. In children with acute lymphoblastic leukemia (ALL) and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 21% and 24% in the Netherlands, 21% and 21% in Germany, 25% and 24% in United kingdom, and 25% and 30% in Slovenia [28–31]. In patients with colorectal cancer, the prevalence of 2R/2R TYMS genotype was 18% in Hungary and 28% in Denmark [17, 32].
Many studies have explored the prevalence of 2R/2R TYMS genotype in Hispanic population as well. In healthy volunteers from Argentina, the reported prevalence is 26% [33]. In Brazil, the prevalence of 2R/2R TYMS genotype in children with ALL and matched control was 26% and 18%, respectively, in one study and 21% and 24%, respectively, in another study [34, 35]. In Mexico, the prevalence of 2R/2R TYMS genotype in patients with colorectal cancer and healthy subjects is 22% and 19%, respectively.
The prevalence of 2R/2R TYMS genotype in other ethnicities (Asians and Indians) showed lower reported prevalence compared to Caucasians and Hispanics. In children with ALL and matched control, the prevalence of 2R/2R TYMS genotype, respectively, was 16% and 0% in one study and 1% and 0% in another study from Indonesia. The prevalence was 2% and 2% in Singapore and 19% and 10% in India [36–39]. Table 6 summarizes several studies that explored the prevalence of 2R/2R TYMS genotype.Table 6 Summary of several studies that explored the prevalence of 2R/2R TYMS genotype.
Author Population N Prevalence N (%)
Zhu Case and control infants (American Caucasians) 78 and 132 16 (21) and 34 (26)
Zhu Case and control infants (American Hispanics) 144 and 396 25 (17) and 70 (18)
De Jonge Children with ALL and matched control (Netherlands) 244 and 491 51 (21) and 116 (24)
Gast Children with ALL and matched control (Germany) 457 and 541 95 (21) and 111 (21)
Lightfoot Children with ALL and matched control (UK) 759 and 754 193 (25) and 181(24)
Petra Children with ALL and matched control (Slovenia) 68 and 252 17 (25) and 76 (30)
Adleff Colorectal (Hungary) 102 18 (17.6)
Kristensen Colorectal (Denmark) 122 34 (28)
Vazquez Healthy volunteers (Argentina) 199 43 (26.1)
Canalle Children with ALL and matched control (Brazil) 126 and 300 33 (26) and 53 (18)
Silva Children with ALL and matched control (Brazil) 140 and 390 25 (18) and 66 (17)
Gallegos-Arreola Colorectal and healthy subjects (Mexico) 347 and 456 77 (22) and 85 (19)
Chan Children with ALL and matched control (Indonesia) 184 and 177 30 (16) and 0 (0)
Giovannetti Children with ALL and matched control (Indonesia) 71 and 44 1 (1) and 0 (0)
Yeoh Children with ALL and matched control (Singapore) 518 and 652 12 (2) and 15 (2)
Nazki Children with ALL and matched control (India) 43 and 144 8 (19) and 14 (10)
In our cohort of 126 patients, the prevalence of 2R/2R TYMS genotype was 24.6% of the total cohort and 44% of the patients with genotypes that predict decreased expression of TS. Among Caucasians (N = 80), 19 patients (24%) had 2R/2R TYMS genotype, which is not very different from the reported prevalence of 2R/2R TYMS genotype in Caucasians in America or Europe. Among African Americans (N = 43), 12 patients (28%) had 2R/2R TYMS genotype, which is slightly higher than the prevalence of 2R/2R TYMS genotype in Caucasians. The prevalence of 2R/2R TYMS genotype in African Americans is not well established. In one study that explored pharmacogenomics in patients with colorectal cancer, 36 patients were African Americans, and among this group, 25 patients (69%) had either 2R/2R or 2R/3R TYMS genotypes [40].
Among male patients (N = 69), 11 patients (16%) had 2R/2R TYMS genotype. Among female patients (N = 57), 20 patients (35%) had 2R/2R TYMS genotype. It is important to emphasize that 60% (12 patients) of the female patients in our cohort with 2R/2R TYMS genotype are African Americans. Several studies showed that women, especially African Americans, experienced more grade 3–4 fluoropyrimidine-associated toxicities compared to men. An underlying explanation is yet to be identified. The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation. Certainly, this should be considered hypothesis-generating observation.
The role of 2R/2R TYMS genotype in predicting severe FrAEs is controversial. The association between 2R/2R TYMS genotype and FrAEs has been demonstrated in many but not all studies. In the positive studies, the sensitivity and positive predictive value were of limited clinical benefit. Among unselected 200 patients treated with 5-FU, grade 3–4 FrAEs were experienced in 44 patients (22%). In this group of patients (N = 44), 13 patients had 2R/2R TYMS genotype (sensitivity 30%). Among all the patients with 2R/2R TYMS genotype (N = 25), 13 patients experienced grade 3–4 FrAEs (positive predictive value 52%) [7, 19, 22, 23].
On the other hand, several other studies failed to show a positive association between 2R/2R TYMS genotype and FrAEs [23–26]. In one prospective study where TYMS genotyping was used to select the chemotherapy of choice in patients with rectal cancer, the rate of grade 3–4 FrAEs was less in patients with 2R/2R, 2R/3R, or 2R/4R TYMS genotypes compared to patients with 3R/3R or 3R/4R TYMS genotypes (30% vs 54%). Moreover, the hospitalization rate was lower at 16% vs 34% [26].
Our patients with 2R/2R TYMS genotype experienced different grade 3–4 hematological and non-hematological FrAEs. Diarrhea was the most common experienced grade 3–4 FrAEs. Other adverse events include neutropenia, mucositis, nausea, vomiting, neurotoxicity, skin toxicity, fatigue, and vasospasm. In our cohort, the association between 2R/2R TYMS genotype and FrAEs was noticeable. Compared to patients with genotypes predicting increased TS expression, 2R/2R TYMS genotype was the only genotype among genotypes predicting decreased TS expression that had statistically significant association with grade 3–4 FrAEs (p = 0.0039). The association between the other genotypes (2R/3RC and 3RC/3RC TYMS genotypes) and grade 3–4 FrAEs did not reach statistical significance (p = 0.1108).
Our study has several limitations. This study represents a single-institution experience with limited cohort of ethnic diversity. Our cohort was made of Caucasians and African Americans for the most part, and only three patients were from other ethnic backgrounds (Asian, Hispanic, and Indian American). Our cohort is also quite heterogenous regarding the primary site of the tumor and stage. It is also important to recognize that this study is a retrospective study and there are inherent limitations with a retrospective analysis, particularly regarding selection bias. TYMS genotyping strategies were quite variable as TYMS genotyping was at the discretion of the treating medical oncologist, and the selected treatment included several different fluoropyrimidine-based regimens. The medical oncologists followed the recommended dose management guidelines per package insert when they managed FrAEs. However, they still had a degree of variation in their practice. The process of attributing an experienced toxicity to 5-FU or capecitabine when they were part of fluoropyrimidine-based chemotherapy regimens was quite challenging sometimes. Every effort was made to make that attribution as accurate as possible. The aforementioned limitations should be kept in mind prior to drawing any conclusions.
Conclusion
The prevalence of TYMS 2R/2R genotype in our cohort was 24.6%. Among Caucasians and African Americans, it was 24% and 28%, respectively. Polymorphism in the promoter region of TYMS gene that predict decreased TS expression due to 2R/2R variant was associated with grade 3–4 FrAEs. These data suggest that genotyping patients who are not DPD deficient for TYMS might identify patients at risk of severe FrAEs.
The 2R/2R TYMS genotype had a very unique sex and ethnic distribution. Among patients with TYMS genotypes that predict decreased TS expression (2R/2R, 2R/3RC, 3RC/3RC), 2R/2R TYMS genotype was the most common TYMS genotype seen in female patients (57%) and in African American patients (60%). The reported higher prevalence of 2R/2R TYMS genotype in female African American patients in our study might represent one possible explanation for why women, especially African Americans, experience more grade 3–4 FrAEs.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PANITUMUMAB | DrugsGivenReaction | CC BY | 33608662 | 20,129,181 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cell death'. | Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma.
High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.
Introduction
CNS relapse is a serious event in patient with aggressive non-Hodgkin lymphoma (NHL) and associated with poor outcomes. CNS relapses in DLBCL occurs in 1 to 31% depending on the series and risk factors studied [1, 2]. In peripheral T cell lymphoma, the risk of CNS relapse has not been extensively studied and was estimated between 2.1 and 6.4% in two large retrospective series [3, 4].
The incidence of CNS relapses in both brain parenchyma and meninges is usually observed during the first 2 years of follow-up in DLBCL [5, 6]. The best strategy for preventing CNS relapse is still a matter of debate [7], in all subtypes of non-Hodgkin’s lymphoma, in particular in DLBCL. The value of prophylactic intrathecal chemotherapy is controversial since CNS relapses occur more frequently in brain parenchyma than in meninges and may be observed in patients who have received intrathecal chemotherapy [1, 8]. More aggressive CNS prophylaxis such as systemic high-dose methotrexate (HD-MTX) at > 3 g/m2 seems to be the best alternative in this context [9]. This strategy has been developed in the LYSA group since 1989, after an induction regimen including 4 cycles of intensified CHOP for patients with aggressive DLBCL [10]. The validation of the CNS-IPI score by Schmitz et al. [11] in 2016 rendered possible a better identification of patients with a high risk of CNS relapses.
An exhaustive review of available data about CNS prophylaxis highlights the efficiency of HD-MTX as CNS prophylaxis at a dose superior or equal to 3 g/m2 [12, 13]. HD-MTX administration (usually between 3 and 8 g/m2) is used for a variety of pediatric and adult cancers including osteosarcoma, acute lymphoblastic leukemia, and primary or secondary CNS lymphoma.
MTX is an antimetabolite-targeting folate metabolism and penetrates through cell membranes, particularly at doses where it crosses the blood-brain barrier. MTX is mainly bound (50 to 80%) to albumin in the plasma circulation and its essentially renal clearance explains the possible occurrence of severe toxicity after high-dose administration (> 500 mg/m2). When patients experience delayed MTX elimination, the prolonged exposure to toxic MTX concentrations can lead to significant morbidity. All of these toxicities may lead to non-reversible adverse events and mortality [14]. Regarding renal toxicities, HD-MTX can induce an acute tubular necrosis and precipitate with its metabolite in 2–4% of cases. This is a major complication of HD-MTX that may be reduced by using an antidote, the glucarpidase or carboxypeptidase G2. An increase of more than 50% in serum creatinine 36–48 h after administration of HD-MTX is considered to be predictive of a delay in the elimination of methotrexate [15]. Non-renal toxicities include hepatic, hematological, gastrointestinal, and neurological toxicities. Although severe hepatic cytolysis is rare, a simple increase of liver enzymes is frequently observed, which is usually transient and spontaneously reversible. Superficial ulcers and mucositis can affect the entire digestive tract. Neurological complications may arise because MTX interferes with transmethylation reactions which are crucial for the production of myelin. They may be either acute, immediately after treatment (3.8 to 7.8% in pediatric ALL patients) [16, 17] (mainly leukoencephalopathy) and most of the time reversible, or delayed with neurological and progressive cognitive impairment (necrotic leukoencephalopathy). MTX may also induce hematological toxicity. A study of an elderly population treated with HD-MTX for PCNSL reported 39% grade III/IV neutropenia, 16% grade III/IV anemia, and 6% grade III/IV thrombopenia [18]. Immunoallergic pneumonia leading to pulmonary fibrosis can be observed in very rare cases [19].
Selection of patients on clinical and biological features, clinical monitoring, hydratation urine alkalinization, and leucovorin rescue are associated with an improvement of morbidity and mortality related to HD-MTX [19]. An adapted patient selection and management of systemic HD-MTX administration is required [19]. Because of the risks associated with HD-MTX, most institutions in the world still require a minimum 72-h inpatient stay for administration and monitoring of serum concentrations of MTX. These hospitalizations reduce life quality of patients, and are associated with a significant cost. Several studies, especially in pediatric populations [20–22], have provided evidence that outpatient administration of HD-MTX represents a safe modality, on the condition that home intravenous hydration is administered. Few data are available for adult lymphoma populations with the indication of CNS prophylaxis. Recently, Pampin et al. reported an outpatient administration of HD-MTX with daily hospital visits to monitor creatinine value, pH level, and methotrexate levels at 24 h, 48 h, and 72 h [23].
This urged us to report our experience of an outpatient administration of HD-MTX as CNS prophylaxis without MTX clearance monitoring, but based on a careful monitoring of renal and hepatic functions and a strict selection of patients.
The aim of this study was to retrospectively analyze the procedure of an ambulatory administration of HD-MTX for CNS prophylaxis in first-line treatment, based on the renal and hepatic monitoring in a highly selected population of patients with aggressive lymphoma.
Patients and methods
Population
We performed a retrospective analysis of HD-MTX administration in the outpatient clinic among patients with aggressive B cell (n = 98) or T cell (n = 5) non-Hodgkin’s lymphoma (NHL) between January 2013 and December 2016 at Saint-Louis Hospital, Paris, France. All these patients were treated as first-line treatment with CHOP or ACBVP, in association with anti-CD20 for B cell lymphoma and were eligible for HD-MTX to benefit of CNS relapses prophylaxis [11]. CNS relapse prophylaxis was administrated to all patients with aaIPI ≥ 1 in (R)-ACBVP arm of treatment and as assessed by the practitioner for patients receiving (R)-CHOP based on known risk factors.
In the (R)-CHOP group (8 patients), HD-MTX was administered 21 days after the 4th (5 patients), or 6th cycle (3 patients) of R-CHOP − 375 mg/m2 rituximab, 50 mg/m2 doxorubicin, 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine (up to a maximum dose of 2 mg) on day 1, and 60 mg/m2 prednisone on days 1–5. In the (R)-ACVBP group (95 patients), the 4 cycles consisted of an induction part, each cycle containing 375 mg/m2 rituximab if B cell NHL, 75 mg/m2 doxorubicin, and 1200 mg/m2 cyclophosphamide on day 1; 2 mg/m2 vindesine and 10 mg bleomycin on days 1 and 5; and 60 mg/m2 prednisone on days 1–5. CNS prophylaxis was included in the sequential consolidation part, starting 4 weeks after completion of the fourth cycle of R-ACVBP, consisting of 2 cycles of MTX (3 g/m2), with four subsequent cycles of rituximab (375 mg/m2) combined with etoposide (300 mg/m2) and ifosfamide (1500 mg/m2).
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Selection criteria for a HD-MTX infusion in outpatient clinic
Our strategy for ambulatory HD-MTX administration was to monitor renal and hepatic functions only and not MTX clearance, as this MTX clearance is not available in the outpatient setting. We then carefully selected the patients based on 6 criteria. These 6 mandatory criteria were (1) patient younger than 60 years; (2) performance status of 0 or 1 at the HD-MTX time infusion; (3) normal renal ≥ 60 ml/min and hepatic functions in the 7 days prior to HD-MTX; (4) albumin level strictly greater than 34 g/l; (5) an absence of significant weight loss (less than10% compared to baseline); and (6) a good understanding of practical medical guidance such as oral hydratation at 2 l of alkaline water per day for 3 days, discontinuation of all drugs with potential for interaction with MTX [24], and guidelines for oral calcium folinate administration after infusion. The selection criteria for patients, in this population with a prophylactic indication, were based on the existing literature on the subject with the aim of a minimal toxicity risk [19, 25, 26].
Treatment administration
The HD-MTX infusion was managed with 3 well-defined periods: the period before infusion, the period during infusion, and the period after the infusion of the MTX. On the day before the HD-MTX infusion, patients were asked to initiate at home the urine alkalinization by drinking 2 l of alkaline water per day, as Vichy St Yorre, as well as during the 24 h following infusion. Cotrimoxazole was discontinued 2 days before HD-MTX until the end of calcium folinate administration. On the day of infusion, a 14% sodium bicarbonate solution was administered to obtain a urine pH > 7.5 within 1 h after administration. If necessary (pH > 7.5 not obtained after 1 h), we pursued alkalinization by increasing the infusion rate. Ondansetron was administered immediately before the infusion. Then, the HD-MTX was infused over a period of 2 h and followed by 1 l of 14% sodium bicarbonate over 1.5 h. After the HD-MTX infusion, the patient started the first dose of oral calcium folinate at the dose of 50 mg at H24 and pursued this treatment every 6 h during 3 days (until day 4) for a total of 12 administrations. An alkaline hyperhydratation with 2 l of alkaline water per day was also maintained during 24 h after administration. Biological analysis of creatinine clearance, ALT, AST was performed 48 h after the administration of HD-MTX and additional tests including a blood count; complete hepatic biology including ALT, AST, gamma GT, and phosphatase alkaline; and creatinine clearance was programmed once a week until the next cycle of chemotherapy. In case of increase in renal function greater than 50%, hepatotoxicity grade ≥ II, or clinical grade ≥ 2 reported toxicity (such as nausea, mucositis), the patient was contacted by the unit for inpatient hospitalization. In this procedure, MTX plasma levels were not monitored as renal and hepatic functions were precisely controlled after HD-MTX infusion (Fig. 1).Fig. 1 Measures associated with the administration of high-dose methotrexate on an outpatient basis
Data collection and statistical analysis
The characteristics of the patients collected included the comorbidities and the clinical and biological characteristics at lymphoma diagnosis (sex, age, histology according to the 2016 WHO classification [27], ECOG performance status (PS), Ann Arbor stage, LDH level, extranodal sites, age-adjusted International Prognostic Index (aaIPI), CNS-IPI, induction treatment). The type of toxicities per organ (renal, hepatic, hematological, skin and mucosa, digestive) and grades of toxicities were collected according to the according to Common Terminology Criteria for Adverse Events (CTCAE 5.0), after each infusion, the first and the second infusion, of HD-MTX.
The objective of the study was to evaluate the toxicities with a HD-MTX administration in the outpatient clinic, in terms of incidence and grade per organ. All analyses were performed using Excel software.
Results
Characteristics of the patients
Characteristics of the 103 patients treated with HD-MTX in outpatient clinic are summarized in Table 1. The median age was 41 years old (range = 17; 60). The sex ratio was 1.4 with a larger proportion of males.Table 1 Demographic and baseline characteristics of the outclinic population treated with intravenous high-dose methotrexate
N = 103 Percentage
Sex M/F 60/43 58/42
Age (median) 41 (17–60)
Histology
- DLBCL 73 71
- PMBL 19 18
- T cell lymphoma 3 3
- Transformed follicular lymphoma 6 6
- Anaplastic lymphoma 2 2
PS
- 0 or 1 92 89
- > 2 11 11
Ann Arbor stage
- Stages I–II 18 17
- Stages III–IV 85 83
LDH level
- Normal 38 37
- Upper normal 65 63
Extranodal sites
- 0 or 1 66 64
- > 1 37 36
aaIPI
- 0 or 1 49 48
- > 2 54 52
CNS-IPI score
- Low risk 0 or 1 40 39
- Intermediate risk 2–3 53 51
- High risk 4–6 10 10
Induction treatment
- R-ACBVP 89 86
- ACBVP 3 3
- Obinutuzumab-ACBVP 3 3
- R-CHOP 6 6
- CHOP 2 2
PS, performance status; LDH, lactate dehydrogenase; aaIPI, age-adjusted International Prognosis Index; CNS-IPI, central nervous system IPI
Before the initiation of HD-MTX, comorbidities and usual treatments of patients were reviewed in order to determine a potential predisposition to known toxicities. At diagnosis, 31 patients (30.1%) presented comorbidities. These included 7 arterial hypertension, 3 prior history of solid tumors (1 thyroid adenocarcinoma and 2 basal cell carcinoma), 3 type 2 diabetes (1 insulino-requiring—2 non insulino-requiring), 2 psychiatric disorders (1 anorexia and 1 depression), 2 pulmonary diseases (1 asthma and 1 sleep apnea syndrome), 3 non-active chronic viral infections (2 chronic hepatitis B, 1 chronic hepatitis C), and 11 other diseases (3 patients with glaucoma, 3 patients with hypothyroidism, 2 patients with psoriasis, 1 patient with thromboembolic disease, and 1 patient with endometriosis). Three patients presented 2 comorbidities. All the patients had normal hepatic and renal function at time of HD-MTX infusion.
A majority of patients (n = 80, 78% patients) did not receive any concomitant treatment. Two patients received an antidiabetic treatment, 5 an antihypertensive drug, 1 an antiviral treatment, 3 a psychiatric treatment, and 7 others (painkillers, hormonal treatments, iron, thyroid substitution). Five female patients received oral contraception.
Histological subtypes were DLBCL or transformed follicular lymphoma for 79 patients (77%), PMBL for 19 patients (18%), T cell lymphoma (NOS or ALK anaplastic lymphoma) for 5 patients (5%). At presentation most of the patients had a good performance status (n = 92, 89%), a disseminated stage (n = 85, 82.5%), and elevated LDH levels (n = 65, 63%). The age-adjusted IPI (aaIPI) was 2–3 for 54 patients (52%). The CNS-IPI score was retrospectively calculated. A low risk (score 0–1) was found in 40 (39%) patients, an intermediate risk (score 2–3) in 53 (51%), and a high risk (score ≥ 4) in 10 (10%) patients.
Regarding the chemotherapy induction regimen, 95 (92%) patients received an ACVBP associated with anti-CD20 for 92 patients (89%) (rituximab, n = 89 or obinutuzumab, n = 3), and 8 (8%) a CHOP associated with anti-CD20 for 6 patients. Based on Cheson criteria 2014 [28], the response assessment at the end of the standard chemotherapy induction was a complete response for 91 (88%) patients and a partial response for 12 (12%). During induction, all the patients received prophylactic antibiotics (cotrimoxazole-atovaquone in all cases, except 1 who received atovaquone alone) and antiviral treatment (valaciclovir).
Incidence of toxicities
Among the 103 patients, 110 toxicities of any grade were reported during the 2 courses of HD-MTX chemotherapy for a total of 195 cycles. Among these toxicities, 92 (84) were grade I/II and 18 (16%) grade III/IV. Thirty-three (32%) patients presented no toxicity.
Most of the toxicities occurred after cycle 1 (n = 78 toxicities, 71%), including 67 toxicities grade I/II, and 11 grade III/IV, and 32 after cycle 2 including 25 grade I/II and 7 grade III/IV (Fig. 2).Fig. 2 Distribution of toxicities by organs and grades among the population of 103 patients
Toxicities per organs
Hepatic toxicity was the most frequent, occurring in 36 patients (35%); this toxicity was mainly an increase in blood liver enzymes. Among them, 14 toxicities were grade I, 14 grade II, and 8 grade III. There were no grade IV hepatic toxicities. Hepatic toxicity occurred mainly after the 1st cycle (32/36, 89%). Four patients presented hepatic toxicity after both 2 cycles, including 1 that presented grade III hepatic toxicities after both. All hepatic toxicities were reversible in less than 15 days.
Skin and mucosal toxicities including mucositis and conjunctivitis (n = 4) occurred in 11 patients (11%) with 8 grade I toxicities, 3 grade II toxicities, and no grade III/IV toxicities, mainly after the first cycle (9/11).
Digestive toxicities mainly included nausea, vomiting, diarrhea, and constipation. Fifteen (15%) patients presented a digestive toxicity with a total of 18 events. Digestive toxicity concerned 16 grade I, 1 grade II, and 1 grade III toxicities (reflex ileus). This occurred either after cycle 1 (9/18, 50%), or after cycle 2 (9/18, 50%). Three patients presented digestive toxicities after cycle 1 and 2.
Twenty-three patients (22%) presented a hematological toxicity with a total of 26 events, either after cycle 1 (14 events) or after cycle 2 (12 events). Seventeen toxicities were grade I/II (7 neutropenia grade I/II, 8 anemia grade I/II, and 2 thrombopenia grade I/II) and 9 were grade III/IV (8 neutropenia with only 1 grade IV and 1 patient with grade III anemia). Three patients presented a cytopenia after both cycles 1 and 2 and 1 patient presented a bicytopenia after cycle 1.
Transient grade I paresthesia occurred in 9 patients (9%) mainly after cycle 1 (7/9, 78%) patients. There was no grade III/IV neurological toxicities reported.
Renal toxicity occurred in 4 patients (3.9%) and was grade I in 2 patients and grade II in 2 patients and after the first cycle for 3 of the 4 patients. There was no grade III/IV renal toxicity.
The other toxicities included arthralgia grade I (1 patient), edema grade I (1 patient), and dyspnea grade II (1 patient).
Overall, only 2 patients (2%) were hospitalized after systemic HD-MTX. The reasons were a grade III reflex ileus (3-day hospitalization) for one patient, and one because of hepatic cytolysis (24-h hospitalization).
CNS relapses in the population
Among the 103 pts. of our study, 78 pts. remained in CR after 2 years of follow-up (76%). Five pts. in CR at the end of treatment were lost, with no follow-up. Twenty patients presented a relapse with 5 CNS relapses (4.9%) (1 was parenchymal, 1 ocular relapse, 3 leptomeningeal relapses) and 15 others relapses (15%). Three CNS relapses occur less than 6 months after the end of treatment, 1 at 1 year of follow-up, and 1 after 3 years.
Ambulatory HD-MTX administration
All patients except for 11 (89%) received the 2 cycles of systemic HD-MTX as an ambulatory administration. Among these 11 patients, 7 received only 1 cycle of HD-MTX because of toxicities and 4 because of lymphoma progression (3 patients) and viral infection (1 patient). The toxicities that induced an arrest of treatment was a grade I/II renal toxicity in 2 patients, a cytolysis in 2 patients (grade III cytolysis for 1, grade II for 1), a grade III neutropenia in 1 patient, and a grade III digestive toxicity in 1 patient.
Discussion
Results of our study highlighted the safety of outpatient HD-MTX administration associated with renal and hepatic monitoring only, in a highly selected population of patients aged less than 60. Overall, 89% of the patients completed the 2 cycles of HD-MTX, and 80% of the patients presented no toxicity or grade I/II toxicities. These results can be compared to other studies with patients with primary CNS lymphoma [26], or CNS prophylaxis with conventional hospitalization [29] in DLBCL patients. Other studies in pediatric osteosarcoma cohort with outpatient MTX administration showed higher level of grade III/IV toxicity, especially neutropenia (18% vs 8% in our cohort) and hepatic cytolysis (39% vs 8% in our cohort). However, the dose of HD-MTX administered in osteosarcoma is much higher, at 12 g/m2 in these series [30]. Only one other recent study [23] reported results on 49 de novo DLBCL outpatients receiving HD-MTX with a similar profile of toxicities. Authors reported no grade III/IV renal failure, in keeping with our observations. Also, 8% of neutropenia was reported which is in exact accordance with our study. Methotrexate serum concentrations were monitored daily starting 24 h after administration until clearance (level ≤ 0.1 μmol/l). Pampin et al. reported no MTX accumulation and no need for intensification of the rescue regimen. Our study, with a larger population (n = 103), supports a safe outpatient administration of HD-MTX in a highly selected population of patients, without MTX clearance monitoring, but with a very strict and careful monitoring of the renal and hepatic functions. Kidney function is a good indicator to monitor proper elimination of methotrexate [31] and should be monitored at 48 h and on day 7.
A key aspect of our work was to identify the selected population of patients eligible for an outpatient administration of H-MTX with no MTX clearance monitoring. This type of surveillance based on renal and hepatic monitoring is a novelty and requires a careful selection of the patient population. Young age less than 60, an albumin level ≥ 35 g/L, a good performance status (0–1), and a stable weight (< loss of 10% compared to baseline) are key parameters to avoid MTX clearance abnormalities [19, 32]. As usually required, a normal renal function, with a clearance ≥ 60 ml/min, is needed for a MTX clearance with no accumulation and subsequent complications. Finally, it is necessary to ensure the patient’s good understanding of practical medical guidance and compliance with the associated rules to allow the safety of outpatient treatment.
The number of any grade toxicity has been observed to be more frequent after cycle 1 than after cycle 2 of HD-MTX. This can be explained by the cumulative toxicity of prior cycles of immunochemotherapy during the induction period. A majority of patients received 4 cycles of R-ACBVP or 4 to 6 cycles of R-CHOP before the HD-MTX administration. Toxicity may be cumulative during this first cycle, especially for hematological and mucositis toxicities [10, 33]. To support this idea of cumulative toxicities after-ACVBP, Fitoussi et al. reported the toxicities after 4 cycles of R-ACVBP and highlighted the hematological (95% vs 43% grade III/IV neutropenia, 59% vs 14% anemia grade III/IV) and mucosal (30% vs 3% grade III/IV) toxicities of R-ACVBP regimen compared to R-CHOP [34, 35]. Only 11 patients did not receive the second cycle of HD-MTX. As this treatment is prophylactic, we recommended declining the second administration in case of any grade III–IV toxicity after the first infusion to avoid any cumulative toxicity.
DLBCL is a very aggressive lymphoma and most patients had a poor quality of life during the treatment, often related to repeated hospitalizations. Thanks to outpatient administration of HD-MTX, patients spent more time at home with a lower impact on their social functioning. Younger patients with DLBCL presented worse quality of life scores than more elderly patients, mainly because of social functioning alterations [36, 37]. Shorter hospitalizations are expected to be a significant factor to improve patient quality of life during the period of therapy.
In conclusion, we demonstrated that HD-MTX outpatient administration based on renal and hepatic monitoring only was feasible and safe in a selected population of patients. The selection is based on very practical and simple criteria. The organization necessary for this treatment can be easily adapted to different hospital settings.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | METHOTREXATE | DrugsGivenReaction | CC BY | 33608849 | 18,968,535 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal toxicity'. | Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma.
High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.
Introduction
CNS relapse is a serious event in patient with aggressive non-Hodgkin lymphoma (NHL) and associated with poor outcomes. CNS relapses in DLBCL occurs in 1 to 31% depending on the series and risk factors studied [1, 2]. In peripheral T cell lymphoma, the risk of CNS relapse has not been extensively studied and was estimated between 2.1 and 6.4% in two large retrospective series [3, 4].
The incidence of CNS relapses in both brain parenchyma and meninges is usually observed during the first 2 years of follow-up in DLBCL [5, 6]. The best strategy for preventing CNS relapse is still a matter of debate [7], in all subtypes of non-Hodgkin’s lymphoma, in particular in DLBCL. The value of prophylactic intrathecal chemotherapy is controversial since CNS relapses occur more frequently in brain parenchyma than in meninges and may be observed in patients who have received intrathecal chemotherapy [1, 8]. More aggressive CNS prophylaxis such as systemic high-dose methotrexate (HD-MTX) at > 3 g/m2 seems to be the best alternative in this context [9]. This strategy has been developed in the LYSA group since 1989, after an induction regimen including 4 cycles of intensified CHOP for patients with aggressive DLBCL [10]. The validation of the CNS-IPI score by Schmitz et al. [11] in 2016 rendered possible a better identification of patients with a high risk of CNS relapses.
An exhaustive review of available data about CNS prophylaxis highlights the efficiency of HD-MTX as CNS prophylaxis at a dose superior or equal to 3 g/m2 [12, 13]. HD-MTX administration (usually between 3 and 8 g/m2) is used for a variety of pediatric and adult cancers including osteosarcoma, acute lymphoblastic leukemia, and primary or secondary CNS lymphoma.
MTX is an antimetabolite-targeting folate metabolism and penetrates through cell membranes, particularly at doses where it crosses the blood-brain barrier. MTX is mainly bound (50 to 80%) to albumin in the plasma circulation and its essentially renal clearance explains the possible occurrence of severe toxicity after high-dose administration (> 500 mg/m2). When patients experience delayed MTX elimination, the prolonged exposure to toxic MTX concentrations can lead to significant morbidity. All of these toxicities may lead to non-reversible adverse events and mortality [14]. Regarding renal toxicities, HD-MTX can induce an acute tubular necrosis and precipitate with its metabolite in 2–4% of cases. This is a major complication of HD-MTX that may be reduced by using an antidote, the glucarpidase or carboxypeptidase G2. An increase of more than 50% in serum creatinine 36–48 h after administration of HD-MTX is considered to be predictive of a delay in the elimination of methotrexate [15]. Non-renal toxicities include hepatic, hematological, gastrointestinal, and neurological toxicities. Although severe hepatic cytolysis is rare, a simple increase of liver enzymes is frequently observed, which is usually transient and spontaneously reversible. Superficial ulcers and mucositis can affect the entire digestive tract. Neurological complications may arise because MTX interferes with transmethylation reactions which are crucial for the production of myelin. They may be either acute, immediately after treatment (3.8 to 7.8% in pediatric ALL patients) [16, 17] (mainly leukoencephalopathy) and most of the time reversible, or delayed with neurological and progressive cognitive impairment (necrotic leukoencephalopathy). MTX may also induce hematological toxicity. A study of an elderly population treated with HD-MTX for PCNSL reported 39% grade III/IV neutropenia, 16% grade III/IV anemia, and 6% grade III/IV thrombopenia [18]. Immunoallergic pneumonia leading to pulmonary fibrosis can be observed in very rare cases [19].
Selection of patients on clinical and biological features, clinical monitoring, hydratation urine alkalinization, and leucovorin rescue are associated with an improvement of morbidity and mortality related to HD-MTX [19]. An adapted patient selection and management of systemic HD-MTX administration is required [19]. Because of the risks associated with HD-MTX, most institutions in the world still require a minimum 72-h inpatient stay for administration and monitoring of serum concentrations of MTX. These hospitalizations reduce life quality of patients, and are associated with a significant cost. Several studies, especially in pediatric populations [20–22], have provided evidence that outpatient administration of HD-MTX represents a safe modality, on the condition that home intravenous hydration is administered. Few data are available for adult lymphoma populations with the indication of CNS prophylaxis. Recently, Pampin et al. reported an outpatient administration of HD-MTX with daily hospital visits to monitor creatinine value, pH level, and methotrexate levels at 24 h, 48 h, and 72 h [23].
This urged us to report our experience of an outpatient administration of HD-MTX as CNS prophylaxis without MTX clearance monitoring, but based on a careful monitoring of renal and hepatic functions and a strict selection of patients.
The aim of this study was to retrospectively analyze the procedure of an ambulatory administration of HD-MTX for CNS prophylaxis in first-line treatment, based on the renal and hepatic monitoring in a highly selected population of patients with aggressive lymphoma.
Patients and methods
Population
We performed a retrospective analysis of HD-MTX administration in the outpatient clinic among patients with aggressive B cell (n = 98) or T cell (n = 5) non-Hodgkin’s lymphoma (NHL) between January 2013 and December 2016 at Saint-Louis Hospital, Paris, France. All these patients were treated as first-line treatment with CHOP or ACBVP, in association with anti-CD20 for B cell lymphoma and were eligible for HD-MTX to benefit of CNS relapses prophylaxis [11]. CNS relapse prophylaxis was administrated to all patients with aaIPI ≥ 1 in (R)-ACBVP arm of treatment and as assessed by the practitioner for patients receiving (R)-CHOP based on known risk factors.
In the (R)-CHOP group (8 patients), HD-MTX was administered 21 days after the 4th (5 patients), or 6th cycle (3 patients) of R-CHOP − 375 mg/m2 rituximab, 50 mg/m2 doxorubicin, 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine (up to a maximum dose of 2 mg) on day 1, and 60 mg/m2 prednisone on days 1–5. In the (R)-ACVBP group (95 patients), the 4 cycles consisted of an induction part, each cycle containing 375 mg/m2 rituximab if B cell NHL, 75 mg/m2 doxorubicin, and 1200 mg/m2 cyclophosphamide on day 1; 2 mg/m2 vindesine and 10 mg bleomycin on days 1 and 5; and 60 mg/m2 prednisone on days 1–5. CNS prophylaxis was included in the sequential consolidation part, starting 4 weeks after completion of the fourth cycle of R-ACVBP, consisting of 2 cycles of MTX (3 g/m2), with four subsequent cycles of rituximab (375 mg/m2) combined with etoposide (300 mg/m2) and ifosfamide (1500 mg/m2).
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Selection criteria for a HD-MTX infusion in outpatient clinic
Our strategy for ambulatory HD-MTX administration was to monitor renal and hepatic functions only and not MTX clearance, as this MTX clearance is not available in the outpatient setting. We then carefully selected the patients based on 6 criteria. These 6 mandatory criteria were (1) patient younger than 60 years; (2) performance status of 0 or 1 at the HD-MTX time infusion; (3) normal renal ≥ 60 ml/min and hepatic functions in the 7 days prior to HD-MTX; (4) albumin level strictly greater than 34 g/l; (5) an absence of significant weight loss (less than10% compared to baseline); and (6) a good understanding of practical medical guidance such as oral hydratation at 2 l of alkaline water per day for 3 days, discontinuation of all drugs with potential for interaction with MTX [24], and guidelines for oral calcium folinate administration after infusion. The selection criteria for patients, in this population with a prophylactic indication, were based on the existing literature on the subject with the aim of a minimal toxicity risk [19, 25, 26].
Treatment administration
The HD-MTX infusion was managed with 3 well-defined periods: the period before infusion, the period during infusion, and the period after the infusion of the MTX. On the day before the HD-MTX infusion, patients were asked to initiate at home the urine alkalinization by drinking 2 l of alkaline water per day, as Vichy St Yorre, as well as during the 24 h following infusion. Cotrimoxazole was discontinued 2 days before HD-MTX until the end of calcium folinate administration. On the day of infusion, a 14% sodium bicarbonate solution was administered to obtain a urine pH > 7.5 within 1 h after administration. If necessary (pH > 7.5 not obtained after 1 h), we pursued alkalinization by increasing the infusion rate. Ondansetron was administered immediately before the infusion. Then, the HD-MTX was infused over a period of 2 h and followed by 1 l of 14% sodium bicarbonate over 1.5 h. After the HD-MTX infusion, the patient started the first dose of oral calcium folinate at the dose of 50 mg at H24 and pursued this treatment every 6 h during 3 days (until day 4) for a total of 12 administrations. An alkaline hyperhydratation with 2 l of alkaline water per day was also maintained during 24 h after administration. Biological analysis of creatinine clearance, ALT, AST was performed 48 h after the administration of HD-MTX and additional tests including a blood count; complete hepatic biology including ALT, AST, gamma GT, and phosphatase alkaline; and creatinine clearance was programmed once a week until the next cycle of chemotherapy. In case of increase in renal function greater than 50%, hepatotoxicity grade ≥ II, or clinical grade ≥ 2 reported toxicity (such as nausea, mucositis), the patient was contacted by the unit for inpatient hospitalization. In this procedure, MTX plasma levels were not monitored as renal and hepatic functions were precisely controlled after HD-MTX infusion (Fig. 1).Fig. 1 Measures associated with the administration of high-dose methotrexate on an outpatient basis
Data collection and statistical analysis
The characteristics of the patients collected included the comorbidities and the clinical and biological characteristics at lymphoma diagnosis (sex, age, histology according to the 2016 WHO classification [27], ECOG performance status (PS), Ann Arbor stage, LDH level, extranodal sites, age-adjusted International Prognostic Index (aaIPI), CNS-IPI, induction treatment). The type of toxicities per organ (renal, hepatic, hematological, skin and mucosa, digestive) and grades of toxicities were collected according to the according to Common Terminology Criteria for Adverse Events (CTCAE 5.0), after each infusion, the first and the second infusion, of HD-MTX.
The objective of the study was to evaluate the toxicities with a HD-MTX administration in the outpatient clinic, in terms of incidence and grade per organ. All analyses were performed using Excel software.
Results
Characteristics of the patients
Characteristics of the 103 patients treated with HD-MTX in outpatient clinic are summarized in Table 1. The median age was 41 years old (range = 17; 60). The sex ratio was 1.4 with a larger proportion of males.Table 1 Demographic and baseline characteristics of the outclinic population treated with intravenous high-dose methotrexate
N = 103 Percentage
Sex M/F 60/43 58/42
Age (median) 41 (17–60)
Histology
- DLBCL 73 71
- PMBL 19 18
- T cell lymphoma 3 3
- Transformed follicular lymphoma 6 6
- Anaplastic lymphoma 2 2
PS
- 0 or 1 92 89
- > 2 11 11
Ann Arbor stage
- Stages I–II 18 17
- Stages III–IV 85 83
LDH level
- Normal 38 37
- Upper normal 65 63
Extranodal sites
- 0 or 1 66 64
- > 1 37 36
aaIPI
- 0 or 1 49 48
- > 2 54 52
CNS-IPI score
- Low risk 0 or 1 40 39
- Intermediate risk 2–3 53 51
- High risk 4–6 10 10
Induction treatment
- R-ACBVP 89 86
- ACBVP 3 3
- Obinutuzumab-ACBVP 3 3
- R-CHOP 6 6
- CHOP 2 2
PS, performance status; LDH, lactate dehydrogenase; aaIPI, age-adjusted International Prognosis Index; CNS-IPI, central nervous system IPI
Before the initiation of HD-MTX, comorbidities and usual treatments of patients were reviewed in order to determine a potential predisposition to known toxicities. At diagnosis, 31 patients (30.1%) presented comorbidities. These included 7 arterial hypertension, 3 prior history of solid tumors (1 thyroid adenocarcinoma and 2 basal cell carcinoma), 3 type 2 diabetes (1 insulino-requiring—2 non insulino-requiring), 2 psychiatric disorders (1 anorexia and 1 depression), 2 pulmonary diseases (1 asthma and 1 sleep apnea syndrome), 3 non-active chronic viral infections (2 chronic hepatitis B, 1 chronic hepatitis C), and 11 other diseases (3 patients with glaucoma, 3 patients with hypothyroidism, 2 patients with psoriasis, 1 patient with thromboembolic disease, and 1 patient with endometriosis). Three patients presented 2 comorbidities. All the patients had normal hepatic and renal function at time of HD-MTX infusion.
A majority of patients (n = 80, 78% patients) did not receive any concomitant treatment. Two patients received an antidiabetic treatment, 5 an antihypertensive drug, 1 an antiviral treatment, 3 a psychiatric treatment, and 7 others (painkillers, hormonal treatments, iron, thyroid substitution). Five female patients received oral contraception.
Histological subtypes were DLBCL or transformed follicular lymphoma for 79 patients (77%), PMBL for 19 patients (18%), T cell lymphoma (NOS or ALK anaplastic lymphoma) for 5 patients (5%). At presentation most of the patients had a good performance status (n = 92, 89%), a disseminated stage (n = 85, 82.5%), and elevated LDH levels (n = 65, 63%). The age-adjusted IPI (aaIPI) was 2–3 for 54 patients (52%). The CNS-IPI score was retrospectively calculated. A low risk (score 0–1) was found in 40 (39%) patients, an intermediate risk (score 2–3) in 53 (51%), and a high risk (score ≥ 4) in 10 (10%) patients.
Regarding the chemotherapy induction regimen, 95 (92%) patients received an ACVBP associated with anti-CD20 for 92 patients (89%) (rituximab, n = 89 or obinutuzumab, n = 3), and 8 (8%) a CHOP associated with anti-CD20 for 6 patients. Based on Cheson criteria 2014 [28], the response assessment at the end of the standard chemotherapy induction was a complete response for 91 (88%) patients and a partial response for 12 (12%). During induction, all the patients received prophylactic antibiotics (cotrimoxazole-atovaquone in all cases, except 1 who received atovaquone alone) and antiviral treatment (valaciclovir).
Incidence of toxicities
Among the 103 patients, 110 toxicities of any grade were reported during the 2 courses of HD-MTX chemotherapy for a total of 195 cycles. Among these toxicities, 92 (84) were grade I/II and 18 (16%) grade III/IV. Thirty-three (32%) patients presented no toxicity.
Most of the toxicities occurred after cycle 1 (n = 78 toxicities, 71%), including 67 toxicities grade I/II, and 11 grade III/IV, and 32 after cycle 2 including 25 grade I/II and 7 grade III/IV (Fig. 2).Fig. 2 Distribution of toxicities by organs and grades among the population of 103 patients
Toxicities per organs
Hepatic toxicity was the most frequent, occurring in 36 patients (35%); this toxicity was mainly an increase in blood liver enzymes. Among them, 14 toxicities were grade I, 14 grade II, and 8 grade III. There were no grade IV hepatic toxicities. Hepatic toxicity occurred mainly after the 1st cycle (32/36, 89%). Four patients presented hepatic toxicity after both 2 cycles, including 1 that presented grade III hepatic toxicities after both. All hepatic toxicities were reversible in less than 15 days.
Skin and mucosal toxicities including mucositis and conjunctivitis (n = 4) occurred in 11 patients (11%) with 8 grade I toxicities, 3 grade II toxicities, and no grade III/IV toxicities, mainly after the first cycle (9/11).
Digestive toxicities mainly included nausea, vomiting, diarrhea, and constipation. Fifteen (15%) patients presented a digestive toxicity with a total of 18 events. Digestive toxicity concerned 16 grade I, 1 grade II, and 1 grade III toxicities (reflex ileus). This occurred either after cycle 1 (9/18, 50%), or after cycle 2 (9/18, 50%). Three patients presented digestive toxicities after cycle 1 and 2.
Twenty-three patients (22%) presented a hematological toxicity with a total of 26 events, either after cycle 1 (14 events) or after cycle 2 (12 events). Seventeen toxicities were grade I/II (7 neutropenia grade I/II, 8 anemia grade I/II, and 2 thrombopenia grade I/II) and 9 were grade III/IV (8 neutropenia with only 1 grade IV and 1 patient with grade III anemia). Three patients presented a cytopenia after both cycles 1 and 2 and 1 patient presented a bicytopenia after cycle 1.
Transient grade I paresthesia occurred in 9 patients (9%) mainly after cycle 1 (7/9, 78%) patients. There was no grade III/IV neurological toxicities reported.
Renal toxicity occurred in 4 patients (3.9%) and was grade I in 2 patients and grade II in 2 patients and after the first cycle for 3 of the 4 patients. There was no grade III/IV renal toxicity.
The other toxicities included arthralgia grade I (1 patient), edema grade I (1 patient), and dyspnea grade II (1 patient).
Overall, only 2 patients (2%) were hospitalized after systemic HD-MTX. The reasons were a grade III reflex ileus (3-day hospitalization) for one patient, and one because of hepatic cytolysis (24-h hospitalization).
CNS relapses in the population
Among the 103 pts. of our study, 78 pts. remained in CR after 2 years of follow-up (76%). Five pts. in CR at the end of treatment were lost, with no follow-up. Twenty patients presented a relapse with 5 CNS relapses (4.9%) (1 was parenchymal, 1 ocular relapse, 3 leptomeningeal relapses) and 15 others relapses (15%). Three CNS relapses occur less than 6 months after the end of treatment, 1 at 1 year of follow-up, and 1 after 3 years.
Ambulatory HD-MTX administration
All patients except for 11 (89%) received the 2 cycles of systemic HD-MTX as an ambulatory administration. Among these 11 patients, 7 received only 1 cycle of HD-MTX because of toxicities and 4 because of lymphoma progression (3 patients) and viral infection (1 patient). The toxicities that induced an arrest of treatment was a grade I/II renal toxicity in 2 patients, a cytolysis in 2 patients (grade III cytolysis for 1, grade II for 1), a grade III neutropenia in 1 patient, and a grade III digestive toxicity in 1 patient.
Discussion
Results of our study highlighted the safety of outpatient HD-MTX administration associated with renal and hepatic monitoring only, in a highly selected population of patients aged less than 60. Overall, 89% of the patients completed the 2 cycles of HD-MTX, and 80% of the patients presented no toxicity or grade I/II toxicities. These results can be compared to other studies with patients with primary CNS lymphoma [26], or CNS prophylaxis with conventional hospitalization [29] in DLBCL patients. Other studies in pediatric osteosarcoma cohort with outpatient MTX administration showed higher level of grade III/IV toxicity, especially neutropenia (18% vs 8% in our cohort) and hepatic cytolysis (39% vs 8% in our cohort). However, the dose of HD-MTX administered in osteosarcoma is much higher, at 12 g/m2 in these series [30]. Only one other recent study [23] reported results on 49 de novo DLBCL outpatients receiving HD-MTX with a similar profile of toxicities. Authors reported no grade III/IV renal failure, in keeping with our observations. Also, 8% of neutropenia was reported which is in exact accordance with our study. Methotrexate serum concentrations were monitored daily starting 24 h after administration until clearance (level ≤ 0.1 μmol/l). Pampin et al. reported no MTX accumulation and no need for intensification of the rescue regimen. Our study, with a larger population (n = 103), supports a safe outpatient administration of HD-MTX in a highly selected population of patients, without MTX clearance monitoring, but with a very strict and careful monitoring of the renal and hepatic functions. Kidney function is a good indicator to monitor proper elimination of methotrexate [31] and should be monitored at 48 h and on day 7.
A key aspect of our work was to identify the selected population of patients eligible for an outpatient administration of H-MTX with no MTX clearance monitoring. This type of surveillance based on renal and hepatic monitoring is a novelty and requires a careful selection of the patient population. Young age less than 60, an albumin level ≥ 35 g/L, a good performance status (0–1), and a stable weight (< loss of 10% compared to baseline) are key parameters to avoid MTX clearance abnormalities [19, 32]. As usually required, a normal renal function, with a clearance ≥ 60 ml/min, is needed for a MTX clearance with no accumulation and subsequent complications. Finally, it is necessary to ensure the patient’s good understanding of practical medical guidance and compliance with the associated rules to allow the safety of outpatient treatment.
The number of any grade toxicity has been observed to be more frequent after cycle 1 than after cycle 2 of HD-MTX. This can be explained by the cumulative toxicity of prior cycles of immunochemotherapy during the induction period. A majority of patients received 4 cycles of R-ACBVP or 4 to 6 cycles of R-CHOP before the HD-MTX administration. Toxicity may be cumulative during this first cycle, especially for hematological and mucositis toxicities [10, 33]. To support this idea of cumulative toxicities after-ACVBP, Fitoussi et al. reported the toxicities after 4 cycles of R-ACVBP and highlighted the hematological (95% vs 43% grade III/IV neutropenia, 59% vs 14% anemia grade III/IV) and mucosal (30% vs 3% grade III/IV) toxicities of R-ACVBP regimen compared to R-CHOP [34, 35]. Only 11 patients did not receive the second cycle of HD-MTX. As this treatment is prophylactic, we recommended declining the second administration in case of any grade III–IV toxicity after the first infusion to avoid any cumulative toxicity.
DLBCL is a very aggressive lymphoma and most patients had a poor quality of life during the treatment, often related to repeated hospitalizations. Thanks to outpatient administration of HD-MTX, patients spent more time at home with a lower impact on their social functioning. Younger patients with DLBCL presented worse quality of life scores than more elderly patients, mainly because of social functioning alterations [36, 37]. Shorter hospitalizations are expected to be a significant factor to improve patient quality of life during the period of therapy.
In conclusion, we demonstrated that HD-MTX outpatient administration based on renal and hepatic monitoring only was feasible and safe in a selected population of patients. The selection is based on very practical and simple criteria. The organization necessary for this treatment can be easily adapted to different hospital settings.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | METHOTREXATE | DrugsGivenReaction | CC BY | 33608849 | 18,967,953 | 2021-04 |
What was the dosage of drug 'METHOTREXATE'? | Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma.
High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.
Introduction
CNS relapse is a serious event in patient with aggressive non-Hodgkin lymphoma (NHL) and associated with poor outcomes. CNS relapses in DLBCL occurs in 1 to 31% depending on the series and risk factors studied [1, 2]. In peripheral T cell lymphoma, the risk of CNS relapse has not been extensively studied and was estimated between 2.1 and 6.4% in two large retrospective series [3, 4].
The incidence of CNS relapses in both brain parenchyma and meninges is usually observed during the first 2 years of follow-up in DLBCL [5, 6]. The best strategy for preventing CNS relapse is still a matter of debate [7], in all subtypes of non-Hodgkin’s lymphoma, in particular in DLBCL. The value of prophylactic intrathecal chemotherapy is controversial since CNS relapses occur more frequently in brain parenchyma than in meninges and may be observed in patients who have received intrathecal chemotherapy [1, 8]. More aggressive CNS prophylaxis such as systemic high-dose methotrexate (HD-MTX) at > 3 g/m2 seems to be the best alternative in this context [9]. This strategy has been developed in the LYSA group since 1989, after an induction regimen including 4 cycles of intensified CHOP for patients with aggressive DLBCL [10]. The validation of the CNS-IPI score by Schmitz et al. [11] in 2016 rendered possible a better identification of patients with a high risk of CNS relapses.
An exhaustive review of available data about CNS prophylaxis highlights the efficiency of HD-MTX as CNS prophylaxis at a dose superior or equal to 3 g/m2 [12, 13]. HD-MTX administration (usually between 3 and 8 g/m2) is used for a variety of pediatric and adult cancers including osteosarcoma, acute lymphoblastic leukemia, and primary or secondary CNS lymphoma.
MTX is an antimetabolite-targeting folate metabolism and penetrates through cell membranes, particularly at doses where it crosses the blood-brain barrier. MTX is mainly bound (50 to 80%) to albumin in the plasma circulation and its essentially renal clearance explains the possible occurrence of severe toxicity after high-dose administration (> 500 mg/m2). When patients experience delayed MTX elimination, the prolonged exposure to toxic MTX concentrations can lead to significant morbidity. All of these toxicities may lead to non-reversible adverse events and mortality [14]. Regarding renal toxicities, HD-MTX can induce an acute tubular necrosis and precipitate with its metabolite in 2–4% of cases. This is a major complication of HD-MTX that may be reduced by using an antidote, the glucarpidase or carboxypeptidase G2. An increase of more than 50% in serum creatinine 36–48 h after administration of HD-MTX is considered to be predictive of a delay in the elimination of methotrexate [15]. Non-renal toxicities include hepatic, hematological, gastrointestinal, and neurological toxicities. Although severe hepatic cytolysis is rare, a simple increase of liver enzymes is frequently observed, which is usually transient and spontaneously reversible. Superficial ulcers and mucositis can affect the entire digestive tract. Neurological complications may arise because MTX interferes with transmethylation reactions which are crucial for the production of myelin. They may be either acute, immediately after treatment (3.8 to 7.8% in pediatric ALL patients) [16, 17] (mainly leukoencephalopathy) and most of the time reversible, or delayed with neurological and progressive cognitive impairment (necrotic leukoencephalopathy). MTX may also induce hematological toxicity. A study of an elderly population treated with HD-MTX for PCNSL reported 39% grade III/IV neutropenia, 16% grade III/IV anemia, and 6% grade III/IV thrombopenia [18]. Immunoallergic pneumonia leading to pulmonary fibrosis can be observed in very rare cases [19].
Selection of patients on clinical and biological features, clinical monitoring, hydratation urine alkalinization, and leucovorin rescue are associated with an improvement of morbidity and mortality related to HD-MTX [19]. An adapted patient selection and management of systemic HD-MTX administration is required [19]. Because of the risks associated with HD-MTX, most institutions in the world still require a minimum 72-h inpatient stay for administration and monitoring of serum concentrations of MTX. These hospitalizations reduce life quality of patients, and are associated with a significant cost. Several studies, especially in pediatric populations [20–22], have provided evidence that outpatient administration of HD-MTX represents a safe modality, on the condition that home intravenous hydration is administered. Few data are available for adult lymphoma populations with the indication of CNS prophylaxis. Recently, Pampin et al. reported an outpatient administration of HD-MTX with daily hospital visits to monitor creatinine value, pH level, and methotrexate levels at 24 h, 48 h, and 72 h [23].
This urged us to report our experience of an outpatient administration of HD-MTX as CNS prophylaxis without MTX clearance monitoring, but based on a careful monitoring of renal and hepatic functions and a strict selection of patients.
The aim of this study was to retrospectively analyze the procedure of an ambulatory administration of HD-MTX for CNS prophylaxis in first-line treatment, based on the renal and hepatic monitoring in a highly selected population of patients with aggressive lymphoma.
Patients and methods
Population
We performed a retrospective analysis of HD-MTX administration in the outpatient clinic among patients with aggressive B cell (n = 98) or T cell (n = 5) non-Hodgkin’s lymphoma (NHL) between January 2013 and December 2016 at Saint-Louis Hospital, Paris, France. All these patients were treated as first-line treatment with CHOP or ACBVP, in association with anti-CD20 for B cell lymphoma and were eligible for HD-MTX to benefit of CNS relapses prophylaxis [11]. CNS relapse prophylaxis was administrated to all patients with aaIPI ≥ 1 in (R)-ACBVP arm of treatment and as assessed by the practitioner for patients receiving (R)-CHOP based on known risk factors.
In the (R)-CHOP group (8 patients), HD-MTX was administered 21 days after the 4th (5 patients), or 6th cycle (3 patients) of R-CHOP − 375 mg/m2 rituximab, 50 mg/m2 doxorubicin, 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine (up to a maximum dose of 2 mg) on day 1, and 60 mg/m2 prednisone on days 1–5. In the (R)-ACVBP group (95 patients), the 4 cycles consisted of an induction part, each cycle containing 375 mg/m2 rituximab if B cell NHL, 75 mg/m2 doxorubicin, and 1200 mg/m2 cyclophosphamide on day 1; 2 mg/m2 vindesine and 10 mg bleomycin on days 1 and 5; and 60 mg/m2 prednisone on days 1–5. CNS prophylaxis was included in the sequential consolidation part, starting 4 weeks after completion of the fourth cycle of R-ACVBP, consisting of 2 cycles of MTX (3 g/m2), with four subsequent cycles of rituximab (375 mg/m2) combined with etoposide (300 mg/m2) and ifosfamide (1500 mg/m2).
All procedures performed were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Selection criteria for a HD-MTX infusion in outpatient clinic
Our strategy for ambulatory HD-MTX administration was to monitor renal and hepatic functions only and not MTX clearance, as this MTX clearance is not available in the outpatient setting. We then carefully selected the patients based on 6 criteria. These 6 mandatory criteria were (1) patient younger than 60 years; (2) performance status of 0 or 1 at the HD-MTX time infusion; (3) normal renal ≥ 60 ml/min and hepatic functions in the 7 days prior to HD-MTX; (4) albumin level strictly greater than 34 g/l; (5) an absence of significant weight loss (less than10% compared to baseline); and (6) a good understanding of practical medical guidance such as oral hydratation at 2 l of alkaline water per day for 3 days, discontinuation of all drugs with potential for interaction with MTX [24], and guidelines for oral calcium folinate administration after infusion. The selection criteria for patients, in this population with a prophylactic indication, were based on the existing literature on the subject with the aim of a minimal toxicity risk [19, 25, 26].
Treatment administration
The HD-MTX infusion was managed with 3 well-defined periods: the period before infusion, the period during infusion, and the period after the infusion of the MTX. On the day before the HD-MTX infusion, patients were asked to initiate at home the urine alkalinization by drinking 2 l of alkaline water per day, as Vichy St Yorre, as well as during the 24 h following infusion. Cotrimoxazole was discontinued 2 days before HD-MTX until the end of calcium folinate administration. On the day of infusion, a 14% sodium bicarbonate solution was administered to obtain a urine pH > 7.5 within 1 h after administration. If necessary (pH > 7.5 not obtained after 1 h), we pursued alkalinization by increasing the infusion rate. Ondansetron was administered immediately before the infusion. Then, the HD-MTX was infused over a period of 2 h and followed by 1 l of 14% sodium bicarbonate over 1.5 h. After the HD-MTX infusion, the patient started the first dose of oral calcium folinate at the dose of 50 mg at H24 and pursued this treatment every 6 h during 3 days (until day 4) for a total of 12 administrations. An alkaline hyperhydratation with 2 l of alkaline water per day was also maintained during 24 h after administration. Biological analysis of creatinine clearance, ALT, AST was performed 48 h after the administration of HD-MTX and additional tests including a blood count; complete hepatic biology including ALT, AST, gamma GT, and phosphatase alkaline; and creatinine clearance was programmed once a week until the next cycle of chemotherapy. In case of increase in renal function greater than 50%, hepatotoxicity grade ≥ II, or clinical grade ≥ 2 reported toxicity (such as nausea, mucositis), the patient was contacted by the unit for inpatient hospitalization. In this procedure, MTX plasma levels were not monitored as renal and hepatic functions were precisely controlled after HD-MTX infusion (Fig. 1).Fig. 1 Measures associated with the administration of high-dose methotrexate on an outpatient basis
Data collection and statistical analysis
The characteristics of the patients collected included the comorbidities and the clinical and biological characteristics at lymphoma diagnosis (sex, age, histology according to the 2016 WHO classification [27], ECOG performance status (PS), Ann Arbor stage, LDH level, extranodal sites, age-adjusted International Prognostic Index (aaIPI), CNS-IPI, induction treatment). The type of toxicities per organ (renal, hepatic, hematological, skin and mucosa, digestive) and grades of toxicities were collected according to the according to Common Terminology Criteria for Adverse Events (CTCAE 5.0), after each infusion, the first and the second infusion, of HD-MTX.
The objective of the study was to evaluate the toxicities with a HD-MTX administration in the outpatient clinic, in terms of incidence and grade per organ. All analyses were performed using Excel software.
Results
Characteristics of the patients
Characteristics of the 103 patients treated with HD-MTX in outpatient clinic are summarized in Table 1. The median age was 41 years old (range = 17; 60). The sex ratio was 1.4 with a larger proportion of males.Table 1 Demographic and baseline characteristics of the outclinic population treated with intravenous high-dose methotrexate
N = 103 Percentage
Sex M/F 60/43 58/42
Age (median) 41 (17–60)
Histology
- DLBCL 73 71
- PMBL 19 18
- T cell lymphoma 3 3
- Transformed follicular lymphoma 6 6
- Anaplastic lymphoma 2 2
PS
- 0 or 1 92 89
- > 2 11 11
Ann Arbor stage
- Stages I–II 18 17
- Stages III–IV 85 83
LDH level
- Normal 38 37
- Upper normal 65 63
Extranodal sites
- 0 or 1 66 64
- > 1 37 36
aaIPI
- 0 or 1 49 48
- > 2 54 52
CNS-IPI score
- Low risk 0 or 1 40 39
- Intermediate risk 2–3 53 51
- High risk 4–6 10 10
Induction treatment
- R-ACBVP 89 86
- ACBVP 3 3
- Obinutuzumab-ACBVP 3 3
- R-CHOP 6 6
- CHOP 2 2
PS, performance status; LDH, lactate dehydrogenase; aaIPI, age-adjusted International Prognosis Index; CNS-IPI, central nervous system IPI
Before the initiation of HD-MTX, comorbidities and usual treatments of patients were reviewed in order to determine a potential predisposition to known toxicities. At diagnosis, 31 patients (30.1%) presented comorbidities. These included 7 arterial hypertension, 3 prior history of solid tumors (1 thyroid adenocarcinoma and 2 basal cell carcinoma), 3 type 2 diabetes (1 insulino-requiring—2 non insulino-requiring), 2 psychiatric disorders (1 anorexia and 1 depression), 2 pulmonary diseases (1 asthma and 1 sleep apnea syndrome), 3 non-active chronic viral infections (2 chronic hepatitis B, 1 chronic hepatitis C), and 11 other diseases (3 patients with glaucoma, 3 patients with hypothyroidism, 2 patients with psoriasis, 1 patient with thromboembolic disease, and 1 patient with endometriosis). Three patients presented 2 comorbidities. All the patients had normal hepatic and renal function at time of HD-MTX infusion.
A majority of patients (n = 80, 78% patients) did not receive any concomitant treatment. Two patients received an antidiabetic treatment, 5 an antihypertensive drug, 1 an antiviral treatment, 3 a psychiatric treatment, and 7 others (painkillers, hormonal treatments, iron, thyroid substitution). Five female patients received oral contraception.
Histological subtypes were DLBCL or transformed follicular lymphoma for 79 patients (77%), PMBL for 19 patients (18%), T cell lymphoma (NOS or ALK anaplastic lymphoma) for 5 patients (5%). At presentation most of the patients had a good performance status (n = 92, 89%), a disseminated stage (n = 85, 82.5%), and elevated LDH levels (n = 65, 63%). The age-adjusted IPI (aaIPI) was 2–3 for 54 patients (52%). The CNS-IPI score was retrospectively calculated. A low risk (score 0–1) was found in 40 (39%) patients, an intermediate risk (score 2–3) in 53 (51%), and a high risk (score ≥ 4) in 10 (10%) patients.
Regarding the chemotherapy induction regimen, 95 (92%) patients received an ACVBP associated with anti-CD20 for 92 patients (89%) (rituximab, n = 89 or obinutuzumab, n = 3), and 8 (8%) a CHOP associated with anti-CD20 for 6 patients. Based on Cheson criteria 2014 [28], the response assessment at the end of the standard chemotherapy induction was a complete response for 91 (88%) patients and a partial response for 12 (12%). During induction, all the patients received prophylactic antibiotics (cotrimoxazole-atovaquone in all cases, except 1 who received atovaquone alone) and antiviral treatment (valaciclovir).
Incidence of toxicities
Among the 103 patients, 110 toxicities of any grade were reported during the 2 courses of HD-MTX chemotherapy for a total of 195 cycles. Among these toxicities, 92 (84) were grade I/II and 18 (16%) grade III/IV. Thirty-three (32%) patients presented no toxicity.
Most of the toxicities occurred after cycle 1 (n = 78 toxicities, 71%), including 67 toxicities grade I/II, and 11 grade III/IV, and 32 after cycle 2 including 25 grade I/II and 7 grade III/IV (Fig. 2).Fig. 2 Distribution of toxicities by organs and grades among the population of 103 patients
Toxicities per organs
Hepatic toxicity was the most frequent, occurring in 36 patients (35%); this toxicity was mainly an increase in blood liver enzymes. Among them, 14 toxicities were grade I, 14 grade II, and 8 grade III. There were no grade IV hepatic toxicities. Hepatic toxicity occurred mainly after the 1st cycle (32/36, 89%). Four patients presented hepatic toxicity after both 2 cycles, including 1 that presented grade III hepatic toxicities after both. All hepatic toxicities were reversible in less than 15 days.
Skin and mucosal toxicities including mucositis and conjunctivitis (n = 4) occurred in 11 patients (11%) with 8 grade I toxicities, 3 grade II toxicities, and no grade III/IV toxicities, mainly after the first cycle (9/11).
Digestive toxicities mainly included nausea, vomiting, diarrhea, and constipation. Fifteen (15%) patients presented a digestive toxicity with a total of 18 events. Digestive toxicity concerned 16 grade I, 1 grade II, and 1 grade III toxicities (reflex ileus). This occurred either after cycle 1 (9/18, 50%), or after cycle 2 (9/18, 50%). Three patients presented digestive toxicities after cycle 1 and 2.
Twenty-three patients (22%) presented a hematological toxicity with a total of 26 events, either after cycle 1 (14 events) or after cycle 2 (12 events). Seventeen toxicities were grade I/II (7 neutropenia grade I/II, 8 anemia grade I/II, and 2 thrombopenia grade I/II) and 9 were grade III/IV (8 neutropenia with only 1 grade IV and 1 patient with grade III anemia). Three patients presented a cytopenia after both cycles 1 and 2 and 1 patient presented a bicytopenia after cycle 1.
Transient grade I paresthesia occurred in 9 patients (9%) mainly after cycle 1 (7/9, 78%) patients. There was no grade III/IV neurological toxicities reported.
Renal toxicity occurred in 4 patients (3.9%) and was grade I in 2 patients and grade II in 2 patients and after the first cycle for 3 of the 4 patients. There was no grade III/IV renal toxicity.
The other toxicities included arthralgia grade I (1 patient), edema grade I (1 patient), and dyspnea grade II (1 patient).
Overall, only 2 patients (2%) were hospitalized after systemic HD-MTX. The reasons were a grade III reflex ileus (3-day hospitalization) for one patient, and one because of hepatic cytolysis (24-h hospitalization).
CNS relapses in the population
Among the 103 pts. of our study, 78 pts. remained in CR after 2 years of follow-up (76%). Five pts. in CR at the end of treatment were lost, with no follow-up. Twenty patients presented a relapse with 5 CNS relapses (4.9%) (1 was parenchymal, 1 ocular relapse, 3 leptomeningeal relapses) and 15 others relapses (15%). Three CNS relapses occur less than 6 months after the end of treatment, 1 at 1 year of follow-up, and 1 after 3 years.
Ambulatory HD-MTX administration
All patients except for 11 (89%) received the 2 cycles of systemic HD-MTX as an ambulatory administration. Among these 11 patients, 7 received only 1 cycle of HD-MTX because of toxicities and 4 because of lymphoma progression (3 patients) and viral infection (1 patient). The toxicities that induced an arrest of treatment was a grade I/II renal toxicity in 2 patients, a cytolysis in 2 patients (grade III cytolysis for 1, grade II for 1), a grade III neutropenia in 1 patient, and a grade III digestive toxicity in 1 patient.
Discussion
Results of our study highlighted the safety of outpatient HD-MTX administration associated with renal and hepatic monitoring only, in a highly selected population of patients aged less than 60. Overall, 89% of the patients completed the 2 cycles of HD-MTX, and 80% of the patients presented no toxicity or grade I/II toxicities. These results can be compared to other studies with patients with primary CNS lymphoma [26], or CNS prophylaxis with conventional hospitalization [29] in DLBCL patients. Other studies in pediatric osteosarcoma cohort with outpatient MTX administration showed higher level of grade III/IV toxicity, especially neutropenia (18% vs 8% in our cohort) and hepatic cytolysis (39% vs 8% in our cohort). However, the dose of HD-MTX administered in osteosarcoma is much higher, at 12 g/m2 in these series [30]. Only one other recent study [23] reported results on 49 de novo DLBCL outpatients receiving HD-MTX with a similar profile of toxicities. Authors reported no grade III/IV renal failure, in keeping with our observations. Also, 8% of neutropenia was reported which is in exact accordance with our study. Methotrexate serum concentrations were monitored daily starting 24 h after administration until clearance (level ≤ 0.1 μmol/l). Pampin et al. reported no MTX accumulation and no need for intensification of the rescue regimen. Our study, with a larger population (n = 103), supports a safe outpatient administration of HD-MTX in a highly selected population of patients, without MTX clearance monitoring, but with a very strict and careful monitoring of the renal and hepatic functions. Kidney function is a good indicator to monitor proper elimination of methotrexate [31] and should be monitored at 48 h and on day 7.
A key aspect of our work was to identify the selected population of patients eligible for an outpatient administration of H-MTX with no MTX clearance monitoring. This type of surveillance based on renal and hepatic monitoring is a novelty and requires a careful selection of the patient population. Young age less than 60, an albumin level ≥ 35 g/L, a good performance status (0–1), and a stable weight (< loss of 10% compared to baseline) are key parameters to avoid MTX clearance abnormalities [19, 32]. As usually required, a normal renal function, with a clearance ≥ 60 ml/min, is needed for a MTX clearance with no accumulation and subsequent complications. Finally, it is necessary to ensure the patient’s good understanding of practical medical guidance and compliance with the associated rules to allow the safety of outpatient treatment.
The number of any grade toxicity has been observed to be more frequent after cycle 1 than after cycle 2 of HD-MTX. This can be explained by the cumulative toxicity of prior cycles of immunochemotherapy during the induction period. A majority of patients received 4 cycles of R-ACBVP or 4 to 6 cycles of R-CHOP before the HD-MTX administration. Toxicity may be cumulative during this first cycle, especially for hematological and mucositis toxicities [10, 33]. To support this idea of cumulative toxicities after-ACVBP, Fitoussi et al. reported the toxicities after 4 cycles of R-ACVBP and highlighted the hematological (95% vs 43% grade III/IV neutropenia, 59% vs 14% anemia grade III/IV) and mucosal (30% vs 3% grade III/IV) toxicities of R-ACVBP regimen compared to R-CHOP [34, 35]. Only 11 patients did not receive the second cycle of HD-MTX. As this treatment is prophylactic, we recommended declining the second administration in case of any grade III–IV toxicity after the first infusion to avoid any cumulative toxicity.
DLBCL is a very aggressive lymphoma and most patients had a poor quality of life during the treatment, often related to repeated hospitalizations. Thanks to outpatient administration of HD-MTX, patients spent more time at home with a lower impact on their social functioning. Younger patients with DLBCL presented worse quality of life scores than more elderly patients, mainly because of social functioning alterations [36, 37]. Shorter hospitalizations are expected to be a significant factor to improve patient quality of life during the period of therapy.
In conclusion, we demonstrated that HD-MTX outpatient administration based on renal and hepatic monitoring only was feasible and safe in a selected population of patients. The selection is based on very practical and simple criteria. The organization necessary for this treatment can be easily adapted to different hospital settings.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | HD?MTX (3 G/M2) | DrugDosageText | CC BY | 33608849 | 18,968,535 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aortic aneurysm'. | Infected thoracoabdominal aortic aneurysm related to an implanted long-term arterial catheter for chemotherapy: a case report.
BACKGROUND
An infected aortic aneurysm is a rare and life-threatening vascular condition with a high incidence of arterial rupture and recurrence even after treatment. One of the most common causes of an infected aortic aneurysm is catheter-related bloodstream infection. Although infection due to indwelling catheters is possible, the incidence of this is rare, especially for long-term implanted arterial catheters.
METHODS
A 78-year-old Japanese man with a past medical history of rectal cancer with metastasis to the liver presented to our hospital as a result of low back pain. Remission had been achieved following surgery and adjuvant chemotherapy via an implanted catheter for arterial infusion. However, the original catheter that was inserted from the femoral artery to the hepatic artery via the celiac artery was still present more than 10 years after diagnosis, without being replaced, in case of a recurrence. On the day of admission, computed tomography scan of the chest and abdomen with contrast revealed an irregularly shaped aortic aneurysm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding along the implanted arterial catheter without extravasation. Although the initial impression was an impending rupture of the acute thoracoabdominal aortic aneurysm, a catheter-related infection was considered as a differential diagnosis. Surgery was performed, which revealed a catheter-related infected aortic aneurysm based on images along the catheter, pus cultures, and tissue pathology examination results.
CONCLUSIONS
This is an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter for chemotherapy. It should be noted that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Background
An infected aortic aneurysm a rare life-threatening vascular condition which can eventually result in rupture of the arterial wall if left untreated. When infected aortic aneurysm is suspected, immediate confirmatory diagnosis and definitive treatment are essential [1]. As there are no definitive diagnostic criteria for infected aneurysms, radiographic imaging, blood and tissue cultures, and tissue pathology examinations must be evaluated. Negative blood cultures are not enough to exclude infected aneurysm because positive blood cultures can be obtained in only 50–70% of patients with an infected aneurysm [2, 3]. Despite report of venous and arterial infections aneurysms due to catheters [4], we could not find published works reporting infected aneurysms due to long-term implanted catheters. This was an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter. This case report suggests that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Case presentation
A 78-year-old Japanese male presented to the emergency department of our hospital with low back pain on exertion for 1 week. The pain was described as dull and gradually worsens. Although the location was near the thoracolumbar spine, he denied radiation of the pain to any parts of the body. Severity of pain using a numerical rating scale was 10/10 at the day of admission. The character and intensity of the pain were not affected by changes in physical movement or by rest. He denied any other symptoms such as fever, nausea, dysuria, hematuria, abdominal pain, and leg numbness during his clinical course.
He had a past medical history of rectal cancer with liver metastasis and had undergone surgery and chemotherapy. At the time of diagnosis, rectal cancer was stage IV (TNM classification of malignant tumors; T3N2M1), grade 3, and was revealed to be adenocarcinoma during histopathology. Liver metastasis affected segments 3 and 6. He underwent low anterior resection of the rectum and resection of the affected liver segments. He then underwent chemotherapy using fluorouracil that was arterially infused through a catheter inserted into the femoral artery and implanted into the hepatic artery through the celiac artery. He initially had good response to treatment but 2 years after diagnosis, he had a recurrence of liver metastasis. He underwent partial resection of segment 6 of the liver and was followed by chemotherapy using FOLFOX6 + bevacizumab protocol instead of arterial infusion. After finishing chemotherapy, he achieved complete remission 11 years after initial diagnosis. As a result of the possibility of another recurrence, the catheter remained in place without being replaced. His other past medical history was hypertension and he remained on amlodipine 5 mg daily and imidapril 5 mg daily. Social history revealed that he had smoked approximately 10 cigarettes a day for 50 years and drank alcohol occasionally. Family and environmental history was unremarkable. His employment history was an office worker, but he retired at the age of 60 and has not worked since then.
On the day of admission, his blood pressure was 171/75 mmHg, heart rate was 67 bpm, SpO2 97% at ambient room air, and body temperature was 36.6 °C. He denied abdominal pain, and pain or numbness in the lower extremities. General appearance was not in acute distress. There was no conjunctiva pallor or icterus. Respiratory sounds were clear to auscultation bilaterally and there were no wheezes or crackles. Cardiovascular examination revealed normal S1 and S2. There was no S3, S4, or murmurs. Abdominal examination revealed a flat and soft abdomen with audible bowel sounds. There was no bruit. There was no abdominal tenderness or hepatosplenomegaly. There was no spinal tenderness or costovertebral angle tenderness on percussion. There was no edema of his lower extremities. There was no joint swelling bilaterally at the wrists, ankles, and knees. General physical examinations revealed no abnormalities. His neurologic examination 2 to 12 were intact. There were no abnormalities with sensation and strength throughout with normal reflexes. Although laboratory analysis revealed normal results for complete blood count, electrolyte level, creatinine level, liver function, and coagulation test, levels of beta-d-glucan were slightly elevated at 24 pg/mL (reference value, < 20 pg/mL) (Table 1). Urinalysis was negative for proteinuria, pyuria, and hematuria (Table 1). Blood culture of aerobic and anaerobic bacteria including fungi and urine culture were all negative (Table 1). Transthoracic echocardiography revealed no valve vegetation, no valve regurgitation, no stenosis, and a normal ejection fraction. Computed tomography (CT) of the chest and abdomen revealed an irregularly shaped aortic aneurysm measuring 45 × 33 mm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding; no extravasation was observed using contrast enhancement (Fig. 1). There was a high possibility that the aortic aneurysm was infected because it was at the site of the catheter that was inserted for the femoral artery via the common hepatic artery. The patient was diagnosed with impending rupture of acute thoracoabdominal aortic aneurysm and was admitted to the intensive care unit of our hospital. Graft replacement was performed for the thoracoabdominal aortic aneurysm, and the implanted catheter was removed during surgery and tested for culture. Pus was discharged from the aortic aneurysm wall incision and collected with swab for culture. The cultures of both the removed catheter and the pus of the aneurysm revealed Escherichia coli, Serratia marcescens, Eikenella corrodens, Streptococcus anginosus, α-Streptococcus, and Candida glabrata. The reported antimicrobial sensitivities of these organisms are shown in Table 2. Antimicrobial susceptibilities were determined by the disk diffusion method, and the results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Results of pathology examination of the wall tissue of the aneurysm were compatible with those of the infected aneurysm cultures because the former showed infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (Fig. 2). On the basis of these findings, a diagnosis of catheter-related thoracoabdominal infected aortic aneurysm was made.Table 1 Results of laboratory findings
Complete blood count Biochemistry test Urinalysis
White blood cell 7.6 103/μL Total protein 7.8 g/dL Dipstick
Neutrophils 69.1 % Albumin 3.6 g/dL Color Yellow
Lymphocytes 22.0 % Aspartate aminotransferase 16.0 IU/L Specific gravity 1.024
Eosinophils 0.8 % Alanine aminotransaminase 12.0 IU/L pH 5.5
Basophils 0.8 % Total bilirubin 0.4 mg/dL Glucose Negative
Monocytes 7.3 % Gamma-glutamyl transferase 20.0 IU/L Protein Negative
Hemoglobin 12.3 g/dL Alkaline phosphatase 341.0 IU/L Bilirubin Negative
Hematocrit 39.1 % Lactate dehydrogenase 216.0 IU/L Ketones +
Platelets 40.5 104/μL Urea nitrogen 12.4 mg/dL Hemoglobin Negative
Creatinine 0.6 mg/dL Nitrate Negative
Coagulation test Sodium 134.0 mEq/L Leukocyte esterase +
Prothrombin time 85.7 % Potassium 4.3 mEq/L Microscopy exam
International normalized ratio 1.1 Chloride 93.0 mEq/L Red blood cells 1–4 /HPF
d-Dimer 1.5 μg/mL Calcium 9.3 mg/dL White blood cells 1–4 /HPF
Fibrinogen 452.0 mg/dL Phosphate 3.1 mg/dL Epithelial cells 1–4 /HPF
Fibrin degradation products 3.9 μg/mL Creatine kinase 92.0 IU/L Casts 1–4 /HPF
C-reactive protein 1.6 mg/dL Crystals Negative
Procalcitonin 0.1 ng/mL
Beta-d-glucan 24.0 pg/mL
Interferon-gamma release assays Negative Cultures
Triglyceride 91.0 mg/dL Blood of aerobic Negative
Total cholesterol 108.0 mg/dL Blood of anaerobic Negative
LDL-cholesterol 54.0 mg/dL Urine Negative
HDL-cholesterol 41.0 mg/dL Removed implanted catheter *
HbA1c 5.9 % Aneurysm pus *
HBs antigen Negative
HCV antibody Negative
HIV antigen/antibody Negative
*Refer to Table 2
Fig. 1 Computed tomography of the chest and abdomen reveals the thoracoabdominal aortic aneurysm along with the implanted arterial catheter inserted from the left femoral artery to the hepatic artery (a, b arrow). An irregularly shaped aortic aneurysm was identified at the origin of the celiac artery, with partially expanded common hepatic artery with disproportionate fat stranding (c, d arrowhead) along the catheter (c, d arrow); no extravasation was observed using contrast enhancement (c, d)
Table 2 Result of antimicrobial susceptibility for causative pathogens from implanted catheter and aneurysm pus
Antimicrobial agent E. coli S. marcescens S. anginosus α-Streptococcus C. glabrata
MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization
Benzylpenicillin ≤ 0.06 S ≤ 0.06 S
Ampicillin ≤ 2 S 8 R ≤ 0.25 S ≤ 0.25 S
Piperacillin ≤ 4 S ≤ 4 S
Amoxicillin/clavulanate ≤ 2 S 4 R
Ampicillin/sulbactam S R
Piperacillin/tazobactam S S
Cefazolin ≤ 4 ≤ 4 R
Cefaclor S R
Cefmetazole ≤ 1 S 2 S
Cefotiam ≤ 8 S ≤ 8 S
Cefotaxime ≤ 1 S ≤ 1 S ≤ 0.12 S ≤ 0.12 S
Ceftriaxone 0.5 S ≤ 0.06 S
Ceftazidime ≤ 1 S ≤ 1 S
Cefepime ≤ 1 S ≤ 1 S
Cefditoren pivoxil S
Cefpodoxime proxetil ≤ 0.25 S 1 S
Imipenem/cilastatin ≤ 0.25 S ≤ 0.25 S
Meropenem ≤ 0.25 S ≤ 0.25 S
Doripenem S S
Gentamicin ≤ 1 S ≤ 1 S
Amikacin ≤ 2 S ≤ 2 S
Minocycline ≤ 1 S 2 S
Tetracycline 0.5 S 0.5 S
Erythromycin ≤ 0.12 S ≤ 0.12 S
Fosfomycin ≤16 S ≤ 16 S
Sulfamethoxazole/trimethoprim ≤ 20 S ≤ 20 S
Clindamycin ≤ 0.25 S ≤ 0.25 S
Levofloxacin ≤ 0.12 S 1 S
Ciprofloxacin ≤ 0.25 S ≤ 0.25 S
Vancomycin 0.5 S 0.5 S
Linezolid ≤ 2 S ≤ 2 S
Fluconazole ≤ 0.12 S ≤ 0.12 S 0.5 S 8 S
Amphotericin B ≤ 0.25 S
Flucytosine ≤ 1 S
Voriconazole 0.25 S
Micafungin ≤ 0.06 S
Caspofungin ≤ 0.25 S
Eikenella corrodes were not used for this antimicrobial susceptibility test
MIC minimum inhibitory concentration, S susceptible, R resistant
Fig. 2 Histopathology examination of the aortic aneurysm wall confirmed an infected aortic aneurysm based on infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (hematoxylin and eosin staining)
On the day of admission, antibiotics therapy was considered for implanted catheter-related infection. The patient was administered a combination of vancomycin 1.0 g intravenously every 12 hours, piperacillin/tazobactam 4.5 g every 6 hours, and micafungin 150 mg every 24 hours until all culture results were confirmed for a week at first. After determination of the drug susceptibilities of all strains, these antibiotics were found to be suitable and were continued. Although the thoracoabdominal aneurysm was resected and pus was drained, antibiotics were administered for 6 weeks in consideration of infection of the perivascular area from the celiac artery to the hepatic artery. His symptoms and laboratory test results improved after surgery and administration of antibiotics. The patient was discharged on day 45, and no recurrence of infected aortic aneurysm was observed on subsequent follow-up CTs as an outpatient for 1 year.
Discussion
Although there are some reports of infections and pseudoaneurysms due to catheters [4], to the best of our knowledge, no study has reported infected thoracoabdominal aneurysms that are associated with implanted long-term arterial catheters for chemotherapy. This case was a rare but extreme scenario caused by a long-term indwelling aortic catheter compounded by rare organisms responsible for the infection.
The most prevalent microorganisms present in the arterial wall that are likely to cause infection of an aneurysm are Staphylococcus spp. and Salmonella spp. [5]. Other microorganisms include Streptococcus pneumoniae, Treponema pallidum, and Mycobacterium tuberculosis, as well as other bacterial, fungal, and anaerobic pathogens [6]. Infected aneurysms can occur in any artery but are most observed in the extremities, splanchnic, and cerebral circulations, often at the points of vessel bifurcation [7]. In the present case, cultures of the aortic aneurysm wall tissue revealed the causative pathogens as E. coli, S. marcescens, E. corrodens, S. anginosus, α-Streptococcus, and C. glabrata. There were several possible routes of infection related to implanted long-term arterial catheters, and the more likely ones were through the transhepatic artery, transhepatic portal vein, and transdermal infections, including bloodstream infections. Although cultures from the removed catheter and aneurysm pus revealed several pathogens, transient bacteremia associated with an implanted arterial catheter could have been controlled by autoimmunity. In addition, multiple pathogens may exist in the aortic arterial wall and may have caused the infected aortic aneurysm. Interestingly, it is considered that the celiac artery had a damaged arterial wall during insertion of the catheter, which eventually developed into an aneurysm, with inflammation and microorganisms spreading to the thoracoabdominal aorta. This was an extremely rare occurrence, and an infectious aortic aneurysm was suspected from the distortion of the aneurysm shape.
Several reports have investigated the risk factors for an infected aneurysm, and these include arterial injury, trauma, antecedent infection, endocarditis, preexisting aneurysm, impaired immunity, and advanced age [8, 9]. The patient’s past medical history and clinical examination did not indicate the presence of these risk factors. Either a venous or arterial indwelling catheter has an obviously high risk of catheter-related infection. In general, the diagnosis of an infected aneurysm is based upon imaging the aneurysm, and infection is confirmed by culturing an organism from the blood. CT angiography definitively diagnoses the aneurysm, specific features suggest infection, and CT also simultaneously evaluates the status of the circulation [10]. In this case, we considered that the thoracoabdominal aortic aneurysm was highly likely to be related to the implanted catheter on the basis of findings from CT imaging, the catheter and pus from aortic wall tissue cultures, and pathology examinations.
The standard treatment of most infected aneurysms is antibiotic therapy combined with surgical debridement with or without revascularization [11]. The initial choice of antibiotic therapy should be guided by the most likely infecting organism on the basis of the clinical circumstances. Antibiotics should be tailored to culture and susceptibility results when they become available. If surgical drainage is performed, this time period commences from the day of surgery. However, there are no data to support a specific duration of antibiotic therapy. In this case, we administrated a combination of antibiotics for 6 weeks on the basis of physical examination, laboratory findings, and follow-up CT findings.
In this era, because the number of patients has been increasing with catheter-based examination and treatment options, the number of patients with indwelling catheter infections is also expected to increase. Immediate confirmatory diagnosis and appropriate treatment are essential. As a matter of course, it is important to remove the catheter as soon as possible at the end of procedure to avoid this critical illness.
Conclusion
This case was a rare but extreme scenario caused by a long-term indwelling catheter compounded by rare organisms responsible for the infection. Clinicians should be aware that long-term implanted arterial catheters can cause not only catheter-related bloodstream infections but may also be a risk factor for infected aortic aneurysms in rare cases.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KT wrote the initial and contributed to data collection and interpretation and critically reviewed the manuscript draft of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was conducted in the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | BEVACIZUMAB, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY | 33610163 | 19,648,394 | 2021-02-21 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Back pain'. | Infected thoracoabdominal aortic aneurysm related to an implanted long-term arterial catheter for chemotherapy: a case report.
BACKGROUND
An infected aortic aneurysm is a rare and life-threatening vascular condition with a high incidence of arterial rupture and recurrence even after treatment. One of the most common causes of an infected aortic aneurysm is catheter-related bloodstream infection. Although infection due to indwelling catheters is possible, the incidence of this is rare, especially for long-term implanted arterial catheters.
METHODS
A 78-year-old Japanese man with a past medical history of rectal cancer with metastasis to the liver presented to our hospital as a result of low back pain. Remission had been achieved following surgery and adjuvant chemotherapy via an implanted catheter for arterial infusion. However, the original catheter that was inserted from the femoral artery to the hepatic artery via the celiac artery was still present more than 10 years after diagnosis, without being replaced, in case of a recurrence. On the day of admission, computed tomography scan of the chest and abdomen with contrast revealed an irregularly shaped aortic aneurysm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding along the implanted arterial catheter without extravasation. Although the initial impression was an impending rupture of the acute thoracoabdominal aortic aneurysm, a catheter-related infection was considered as a differential diagnosis. Surgery was performed, which revealed a catheter-related infected aortic aneurysm based on images along the catheter, pus cultures, and tissue pathology examination results.
CONCLUSIONS
This is an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter for chemotherapy. It should be noted that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Background
An infected aortic aneurysm a rare life-threatening vascular condition which can eventually result in rupture of the arterial wall if left untreated. When infected aortic aneurysm is suspected, immediate confirmatory diagnosis and definitive treatment are essential [1]. As there are no definitive diagnostic criteria for infected aneurysms, radiographic imaging, blood and tissue cultures, and tissue pathology examinations must be evaluated. Negative blood cultures are not enough to exclude infected aneurysm because positive blood cultures can be obtained in only 50–70% of patients with an infected aneurysm [2, 3]. Despite report of venous and arterial infections aneurysms due to catheters [4], we could not find published works reporting infected aneurysms due to long-term implanted catheters. This was an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter. This case report suggests that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Case presentation
A 78-year-old Japanese male presented to the emergency department of our hospital with low back pain on exertion for 1 week. The pain was described as dull and gradually worsens. Although the location was near the thoracolumbar spine, he denied radiation of the pain to any parts of the body. Severity of pain using a numerical rating scale was 10/10 at the day of admission. The character and intensity of the pain were not affected by changes in physical movement or by rest. He denied any other symptoms such as fever, nausea, dysuria, hematuria, abdominal pain, and leg numbness during his clinical course.
He had a past medical history of rectal cancer with liver metastasis and had undergone surgery and chemotherapy. At the time of diagnosis, rectal cancer was stage IV (TNM classification of malignant tumors; T3N2M1), grade 3, and was revealed to be adenocarcinoma during histopathology. Liver metastasis affected segments 3 and 6. He underwent low anterior resection of the rectum and resection of the affected liver segments. He then underwent chemotherapy using fluorouracil that was arterially infused through a catheter inserted into the femoral artery and implanted into the hepatic artery through the celiac artery. He initially had good response to treatment but 2 years after diagnosis, he had a recurrence of liver metastasis. He underwent partial resection of segment 6 of the liver and was followed by chemotherapy using FOLFOX6 + bevacizumab protocol instead of arterial infusion. After finishing chemotherapy, he achieved complete remission 11 years after initial diagnosis. As a result of the possibility of another recurrence, the catheter remained in place without being replaced. His other past medical history was hypertension and he remained on amlodipine 5 mg daily and imidapril 5 mg daily. Social history revealed that he had smoked approximately 10 cigarettes a day for 50 years and drank alcohol occasionally. Family and environmental history was unremarkable. His employment history was an office worker, but he retired at the age of 60 and has not worked since then.
On the day of admission, his blood pressure was 171/75 mmHg, heart rate was 67 bpm, SpO2 97% at ambient room air, and body temperature was 36.6 °C. He denied abdominal pain, and pain or numbness in the lower extremities. General appearance was not in acute distress. There was no conjunctiva pallor or icterus. Respiratory sounds were clear to auscultation bilaterally and there were no wheezes or crackles. Cardiovascular examination revealed normal S1 and S2. There was no S3, S4, or murmurs. Abdominal examination revealed a flat and soft abdomen with audible bowel sounds. There was no bruit. There was no abdominal tenderness or hepatosplenomegaly. There was no spinal tenderness or costovertebral angle tenderness on percussion. There was no edema of his lower extremities. There was no joint swelling bilaterally at the wrists, ankles, and knees. General physical examinations revealed no abnormalities. His neurologic examination 2 to 12 were intact. There were no abnormalities with sensation and strength throughout with normal reflexes. Although laboratory analysis revealed normal results for complete blood count, electrolyte level, creatinine level, liver function, and coagulation test, levels of beta-d-glucan were slightly elevated at 24 pg/mL (reference value, < 20 pg/mL) (Table 1). Urinalysis was negative for proteinuria, pyuria, and hematuria (Table 1). Blood culture of aerobic and anaerobic bacteria including fungi and urine culture were all negative (Table 1). Transthoracic echocardiography revealed no valve vegetation, no valve regurgitation, no stenosis, and a normal ejection fraction. Computed tomography (CT) of the chest and abdomen revealed an irregularly shaped aortic aneurysm measuring 45 × 33 mm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding; no extravasation was observed using contrast enhancement (Fig. 1). There was a high possibility that the aortic aneurysm was infected because it was at the site of the catheter that was inserted for the femoral artery via the common hepatic artery. The patient was diagnosed with impending rupture of acute thoracoabdominal aortic aneurysm and was admitted to the intensive care unit of our hospital. Graft replacement was performed for the thoracoabdominal aortic aneurysm, and the implanted catheter was removed during surgery and tested for culture. Pus was discharged from the aortic aneurysm wall incision and collected with swab for culture. The cultures of both the removed catheter and the pus of the aneurysm revealed Escherichia coli, Serratia marcescens, Eikenella corrodens, Streptococcus anginosus, α-Streptococcus, and Candida glabrata. The reported antimicrobial sensitivities of these organisms are shown in Table 2. Antimicrobial susceptibilities were determined by the disk diffusion method, and the results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Results of pathology examination of the wall tissue of the aneurysm were compatible with those of the infected aneurysm cultures because the former showed infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (Fig. 2). On the basis of these findings, a diagnosis of catheter-related thoracoabdominal infected aortic aneurysm was made.Table 1 Results of laboratory findings
Complete blood count Biochemistry test Urinalysis
White blood cell 7.6 103/μL Total protein 7.8 g/dL Dipstick
Neutrophils 69.1 % Albumin 3.6 g/dL Color Yellow
Lymphocytes 22.0 % Aspartate aminotransferase 16.0 IU/L Specific gravity 1.024
Eosinophils 0.8 % Alanine aminotransaminase 12.0 IU/L pH 5.5
Basophils 0.8 % Total bilirubin 0.4 mg/dL Glucose Negative
Monocytes 7.3 % Gamma-glutamyl transferase 20.0 IU/L Protein Negative
Hemoglobin 12.3 g/dL Alkaline phosphatase 341.0 IU/L Bilirubin Negative
Hematocrit 39.1 % Lactate dehydrogenase 216.0 IU/L Ketones +
Platelets 40.5 104/μL Urea nitrogen 12.4 mg/dL Hemoglobin Negative
Creatinine 0.6 mg/dL Nitrate Negative
Coagulation test Sodium 134.0 mEq/L Leukocyte esterase +
Prothrombin time 85.7 % Potassium 4.3 mEq/L Microscopy exam
International normalized ratio 1.1 Chloride 93.0 mEq/L Red blood cells 1–4 /HPF
d-Dimer 1.5 μg/mL Calcium 9.3 mg/dL White blood cells 1–4 /HPF
Fibrinogen 452.0 mg/dL Phosphate 3.1 mg/dL Epithelial cells 1–4 /HPF
Fibrin degradation products 3.9 μg/mL Creatine kinase 92.0 IU/L Casts 1–4 /HPF
C-reactive protein 1.6 mg/dL Crystals Negative
Procalcitonin 0.1 ng/mL
Beta-d-glucan 24.0 pg/mL
Interferon-gamma release assays Negative Cultures
Triglyceride 91.0 mg/dL Blood of aerobic Negative
Total cholesterol 108.0 mg/dL Blood of anaerobic Negative
LDL-cholesterol 54.0 mg/dL Urine Negative
HDL-cholesterol 41.0 mg/dL Removed implanted catheter *
HbA1c 5.9 % Aneurysm pus *
HBs antigen Negative
HCV antibody Negative
HIV antigen/antibody Negative
*Refer to Table 2
Fig. 1 Computed tomography of the chest and abdomen reveals the thoracoabdominal aortic aneurysm along with the implanted arterial catheter inserted from the left femoral artery to the hepatic artery (a, b arrow). An irregularly shaped aortic aneurysm was identified at the origin of the celiac artery, with partially expanded common hepatic artery with disproportionate fat stranding (c, d arrowhead) along the catheter (c, d arrow); no extravasation was observed using contrast enhancement (c, d)
Table 2 Result of antimicrobial susceptibility for causative pathogens from implanted catheter and aneurysm pus
Antimicrobial agent E. coli S. marcescens S. anginosus α-Streptococcus C. glabrata
MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization
Benzylpenicillin ≤ 0.06 S ≤ 0.06 S
Ampicillin ≤ 2 S 8 R ≤ 0.25 S ≤ 0.25 S
Piperacillin ≤ 4 S ≤ 4 S
Amoxicillin/clavulanate ≤ 2 S 4 R
Ampicillin/sulbactam S R
Piperacillin/tazobactam S S
Cefazolin ≤ 4 ≤ 4 R
Cefaclor S R
Cefmetazole ≤ 1 S 2 S
Cefotiam ≤ 8 S ≤ 8 S
Cefotaxime ≤ 1 S ≤ 1 S ≤ 0.12 S ≤ 0.12 S
Ceftriaxone 0.5 S ≤ 0.06 S
Ceftazidime ≤ 1 S ≤ 1 S
Cefepime ≤ 1 S ≤ 1 S
Cefditoren pivoxil S
Cefpodoxime proxetil ≤ 0.25 S 1 S
Imipenem/cilastatin ≤ 0.25 S ≤ 0.25 S
Meropenem ≤ 0.25 S ≤ 0.25 S
Doripenem S S
Gentamicin ≤ 1 S ≤ 1 S
Amikacin ≤ 2 S ≤ 2 S
Minocycline ≤ 1 S 2 S
Tetracycline 0.5 S 0.5 S
Erythromycin ≤ 0.12 S ≤ 0.12 S
Fosfomycin ≤16 S ≤ 16 S
Sulfamethoxazole/trimethoprim ≤ 20 S ≤ 20 S
Clindamycin ≤ 0.25 S ≤ 0.25 S
Levofloxacin ≤ 0.12 S 1 S
Ciprofloxacin ≤ 0.25 S ≤ 0.25 S
Vancomycin 0.5 S 0.5 S
Linezolid ≤ 2 S ≤ 2 S
Fluconazole ≤ 0.12 S ≤ 0.12 S 0.5 S 8 S
Amphotericin B ≤ 0.25 S
Flucytosine ≤ 1 S
Voriconazole 0.25 S
Micafungin ≤ 0.06 S
Caspofungin ≤ 0.25 S
Eikenella corrodes were not used for this antimicrobial susceptibility test
MIC minimum inhibitory concentration, S susceptible, R resistant
Fig. 2 Histopathology examination of the aortic aneurysm wall confirmed an infected aortic aneurysm based on infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (hematoxylin and eosin staining)
On the day of admission, antibiotics therapy was considered for implanted catheter-related infection. The patient was administered a combination of vancomycin 1.0 g intravenously every 12 hours, piperacillin/tazobactam 4.5 g every 6 hours, and micafungin 150 mg every 24 hours until all culture results were confirmed for a week at first. After determination of the drug susceptibilities of all strains, these antibiotics were found to be suitable and were continued. Although the thoracoabdominal aneurysm was resected and pus was drained, antibiotics were administered for 6 weeks in consideration of infection of the perivascular area from the celiac artery to the hepatic artery. His symptoms and laboratory test results improved after surgery and administration of antibiotics. The patient was discharged on day 45, and no recurrence of infected aortic aneurysm was observed on subsequent follow-up CTs as an outpatient for 1 year.
Discussion
Although there are some reports of infections and pseudoaneurysms due to catheters [4], to the best of our knowledge, no study has reported infected thoracoabdominal aneurysms that are associated with implanted long-term arterial catheters for chemotherapy. This case was a rare but extreme scenario caused by a long-term indwelling aortic catheter compounded by rare organisms responsible for the infection.
The most prevalent microorganisms present in the arterial wall that are likely to cause infection of an aneurysm are Staphylococcus spp. and Salmonella spp. [5]. Other microorganisms include Streptococcus pneumoniae, Treponema pallidum, and Mycobacterium tuberculosis, as well as other bacterial, fungal, and anaerobic pathogens [6]. Infected aneurysms can occur in any artery but are most observed in the extremities, splanchnic, and cerebral circulations, often at the points of vessel bifurcation [7]. In the present case, cultures of the aortic aneurysm wall tissue revealed the causative pathogens as E. coli, S. marcescens, E. corrodens, S. anginosus, α-Streptococcus, and C. glabrata. There were several possible routes of infection related to implanted long-term arterial catheters, and the more likely ones were through the transhepatic artery, transhepatic portal vein, and transdermal infections, including bloodstream infections. Although cultures from the removed catheter and aneurysm pus revealed several pathogens, transient bacteremia associated with an implanted arterial catheter could have been controlled by autoimmunity. In addition, multiple pathogens may exist in the aortic arterial wall and may have caused the infected aortic aneurysm. Interestingly, it is considered that the celiac artery had a damaged arterial wall during insertion of the catheter, which eventually developed into an aneurysm, with inflammation and microorganisms spreading to the thoracoabdominal aorta. This was an extremely rare occurrence, and an infectious aortic aneurysm was suspected from the distortion of the aneurysm shape.
Several reports have investigated the risk factors for an infected aneurysm, and these include arterial injury, trauma, antecedent infection, endocarditis, preexisting aneurysm, impaired immunity, and advanced age [8, 9]. The patient’s past medical history and clinical examination did not indicate the presence of these risk factors. Either a venous or arterial indwelling catheter has an obviously high risk of catheter-related infection. In general, the diagnosis of an infected aneurysm is based upon imaging the aneurysm, and infection is confirmed by culturing an organism from the blood. CT angiography definitively diagnoses the aneurysm, specific features suggest infection, and CT also simultaneously evaluates the status of the circulation [10]. In this case, we considered that the thoracoabdominal aortic aneurysm was highly likely to be related to the implanted catheter on the basis of findings from CT imaging, the catheter and pus from aortic wall tissue cultures, and pathology examinations.
The standard treatment of most infected aneurysms is antibiotic therapy combined with surgical debridement with or without revascularization [11]. The initial choice of antibiotic therapy should be guided by the most likely infecting organism on the basis of the clinical circumstances. Antibiotics should be tailored to culture and susceptibility results when they become available. If surgical drainage is performed, this time period commences from the day of surgery. However, there are no data to support a specific duration of antibiotic therapy. In this case, we administrated a combination of antibiotics for 6 weeks on the basis of physical examination, laboratory findings, and follow-up CT findings.
In this era, because the number of patients has been increasing with catheter-based examination and treatment options, the number of patients with indwelling catheter infections is also expected to increase. Immediate confirmatory diagnosis and appropriate treatment are essential. As a matter of course, it is important to remove the catheter as soon as possible at the end of procedure to avoid this critical illness.
Conclusion
This case was a rare but extreme scenario caused by a long-term indwelling catheter compounded by rare organisms responsible for the infection. Clinicians should be aware that long-term implanted arterial catheters can cause not only catheter-related bloodstream infections but may also be a risk factor for infected aortic aneurysms in rare cases.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KT wrote the initial and contributed to data collection and interpretation and critically reviewed the manuscript draft of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was conducted in the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | BEVACIZUMAB, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY | 33610163 | 19,648,394 | 2021-02-21 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Device related infection'. | Infected thoracoabdominal aortic aneurysm related to an implanted long-term arterial catheter for chemotherapy: a case report.
BACKGROUND
An infected aortic aneurysm is a rare and life-threatening vascular condition with a high incidence of arterial rupture and recurrence even after treatment. One of the most common causes of an infected aortic aneurysm is catheter-related bloodstream infection. Although infection due to indwelling catheters is possible, the incidence of this is rare, especially for long-term implanted arterial catheters.
METHODS
A 78-year-old Japanese man with a past medical history of rectal cancer with metastasis to the liver presented to our hospital as a result of low back pain. Remission had been achieved following surgery and adjuvant chemotherapy via an implanted catheter for arterial infusion. However, the original catheter that was inserted from the femoral artery to the hepatic artery via the celiac artery was still present more than 10 years after diagnosis, without being replaced, in case of a recurrence. On the day of admission, computed tomography scan of the chest and abdomen with contrast revealed an irregularly shaped aortic aneurysm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding along the implanted arterial catheter without extravasation. Although the initial impression was an impending rupture of the acute thoracoabdominal aortic aneurysm, a catheter-related infection was considered as a differential diagnosis. Surgery was performed, which revealed a catheter-related infected aortic aneurysm based on images along the catheter, pus cultures, and tissue pathology examination results.
CONCLUSIONS
This is an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter for chemotherapy. It should be noted that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Background
An infected aortic aneurysm a rare life-threatening vascular condition which can eventually result in rupture of the arterial wall if left untreated. When infected aortic aneurysm is suspected, immediate confirmatory diagnosis and definitive treatment are essential [1]. As there are no definitive diagnostic criteria for infected aneurysms, radiographic imaging, blood and tissue cultures, and tissue pathology examinations must be evaluated. Negative blood cultures are not enough to exclude infected aneurysm because positive blood cultures can be obtained in only 50–70% of patients with an infected aneurysm [2, 3]. Despite report of venous and arterial infections aneurysms due to catheters [4], we could not find published works reporting infected aneurysms due to long-term implanted catheters. This was an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter. This case report suggests that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Case presentation
A 78-year-old Japanese male presented to the emergency department of our hospital with low back pain on exertion for 1 week. The pain was described as dull and gradually worsens. Although the location was near the thoracolumbar spine, he denied radiation of the pain to any parts of the body. Severity of pain using a numerical rating scale was 10/10 at the day of admission. The character and intensity of the pain were not affected by changes in physical movement or by rest. He denied any other symptoms such as fever, nausea, dysuria, hematuria, abdominal pain, and leg numbness during his clinical course.
He had a past medical history of rectal cancer with liver metastasis and had undergone surgery and chemotherapy. At the time of diagnosis, rectal cancer was stage IV (TNM classification of malignant tumors; T3N2M1), grade 3, and was revealed to be adenocarcinoma during histopathology. Liver metastasis affected segments 3 and 6. He underwent low anterior resection of the rectum and resection of the affected liver segments. He then underwent chemotherapy using fluorouracil that was arterially infused through a catheter inserted into the femoral artery and implanted into the hepatic artery through the celiac artery. He initially had good response to treatment but 2 years after diagnosis, he had a recurrence of liver metastasis. He underwent partial resection of segment 6 of the liver and was followed by chemotherapy using FOLFOX6 + bevacizumab protocol instead of arterial infusion. After finishing chemotherapy, he achieved complete remission 11 years after initial diagnosis. As a result of the possibility of another recurrence, the catheter remained in place without being replaced. His other past medical history was hypertension and he remained on amlodipine 5 mg daily and imidapril 5 mg daily. Social history revealed that he had smoked approximately 10 cigarettes a day for 50 years and drank alcohol occasionally. Family and environmental history was unremarkable. His employment history was an office worker, but he retired at the age of 60 and has not worked since then.
On the day of admission, his blood pressure was 171/75 mmHg, heart rate was 67 bpm, SpO2 97% at ambient room air, and body temperature was 36.6 °C. He denied abdominal pain, and pain or numbness in the lower extremities. General appearance was not in acute distress. There was no conjunctiva pallor or icterus. Respiratory sounds were clear to auscultation bilaterally and there were no wheezes or crackles. Cardiovascular examination revealed normal S1 and S2. There was no S3, S4, or murmurs. Abdominal examination revealed a flat and soft abdomen with audible bowel sounds. There was no bruit. There was no abdominal tenderness or hepatosplenomegaly. There was no spinal tenderness or costovertebral angle tenderness on percussion. There was no edema of his lower extremities. There was no joint swelling bilaterally at the wrists, ankles, and knees. General physical examinations revealed no abnormalities. His neurologic examination 2 to 12 were intact. There were no abnormalities with sensation and strength throughout with normal reflexes. Although laboratory analysis revealed normal results for complete blood count, electrolyte level, creatinine level, liver function, and coagulation test, levels of beta-d-glucan were slightly elevated at 24 pg/mL (reference value, < 20 pg/mL) (Table 1). Urinalysis was negative for proteinuria, pyuria, and hematuria (Table 1). Blood culture of aerobic and anaerobic bacteria including fungi and urine culture were all negative (Table 1). Transthoracic echocardiography revealed no valve vegetation, no valve regurgitation, no stenosis, and a normal ejection fraction. Computed tomography (CT) of the chest and abdomen revealed an irregularly shaped aortic aneurysm measuring 45 × 33 mm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding; no extravasation was observed using contrast enhancement (Fig. 1). There was a high possibility that the aortic aneurysm was infected because it was at the site of the catheter that was inserted for the femoral artery via the common hepatic artery. The patient was diagnosed with impending rupture of acute thoracoabdominal aortic aneurysm and was admitted to the intensive care unit of our hospital. Graft replacement was performed for the thoracoabdominal aortic aneurysm, and the implanted catheter was removed during surgery and tested for culture. Pus was discharged from the aortic aneurysm wall incision and collected with swab for culture. The cultures of both the removed catheter and the pus of the aneurysm revealed Escherichia coli, Serratia marcescens, Eikenella corrodens, Streptococcus anginosus, α-Streptococcus, and Candida glabrata. The reported antimicrobial sensitivities of these organisms are shown in Table 2. Antimicrobial susceptibilities were determined by the disk diffusion method, and the results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Results of pathology examination of the wall tissue of the aneurysm were compatible with those of the infected aneurysm cultures because the former showed infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (Fig. 2). On the basis of these findings, a diagnosis of catheter-related thoracoabdominal infected aortic aneurysm was made.Table 1 Results of laboratory findings
Complete blood count Biochemistry test Urinalysis
White blood cell 7.6 103/μL Total protein 7.8 g/dL Dipstick
Neutrophils 69.1 % Albumin 3.6 g/dL Color Yellow
Lymphocytes 22.0 % Aspartate aminotransferase 16.0 IU/L Specific gravity 1.024
Eosinophils 0.8 % Alanine aminotransaminase 12.0 IU/L pH 5.5
Basophils 0.8 % Total bilirubin 0.4 mg/dL Glucose Negative
Monocytes 7.3 % Gamma-glutamyl transferase 20.0 IU/L Protein Negative
Hemoglobin 12.3 g/dL Alkaline phosphatase 341.0 IU/L Bilirubin Negative
Hematocrit 39.1 % Lactate dehydrogenase 216.0 IU/L Ketones +
Platelets 40.5 104/μL Urea nitrogen 12.4 mg/dL Hemoglobin Negative
Creatinine 0.6 mg/dL Nitrate Negative
Coagulation test Sodium 134.0 mEq/L Leukocyte esterase +
Prothrombin time 85.7 % Potassium 4.3 mEq/L Microscopy exam
International normalized ratio 1.1 Chloride 93.0 mEq/L Red blood cells 1–4 /HPF
d-Dimer 1.5 μg/mL Calcium 9.3 mg/dL White blood cells 1–4 /HPF
Fibrinogen 452.0 mg/dL Phosphate 3.1 mg/dL Epithelial cells 1–4 /HPF
Fibrin degradation products 3.9 μg/mL Creatine kinase 92.0 IU/L Casts 1–4 /HPF
C-reactive protein 1.6 mg/dL Crystals Negative
Procalcitonin 0.1 ng/mL
Beta-d-glucan 24.0 pg/mL
Interferon-gamma release assays Negative Cultures
Triglyceride 91.0 mg/dL Blood of aerobic Negative
Total cholesterol 108.0 mg/dL Blood of anaerobic Negative
LDL-cholesterol 54.0 mg/dL Urine Negative
HDL-cholesterol 41.0 mg/dL Removed implanted catheter *
HbA1c 5.9 % Aneurysm pus *
HBs antigen Negative
HCV antibody Negative
HIV antigen/antibody Negative
*Refer to Table 2
Fig. 1 Computed tomography of the chest and abdomen reveals the thoracoabdominal aortic aneurysm along with the implanted arterial catheter inserted from the left femoral artery to the hepatic artery (a, b arrow). An irregularly shaped aortic aneurysm was identified at the origin of the celiac artery, with partially expanded common hepatic artery with disproportionate fat stranding (c, d arrowhead) along the catheter (c, d arrow); no extravasation was observed using contrast enhancement (c, d)
Table 2 Result of antimicrobial susceptibility for causative pathogens from implanted catheter and aneurysm pus
Antimicrobial agent E. coli S. marcescens S. anginosus α-Streptococcus C. glabrata
MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization
Benzylpenicillin ≤ 0.06 S ≤ 0.06 S
Ampicillin ≤ 2 S 8 R ≤ 0.25 S ≤ 0.25 S
Piperacillin ≤ 4 S ≤ 4 S
Amoxicillin/clavulanate ≤ 2 S 4 R
Ampicillin/sulbactam S R
Piperacillin/tazobactam S S
Cefazolin ≤ 4 ≤ 4 R
Cefaclor S R
Cefmetazole ≤ 1 S 2 S
Cefotiam ≤ 8 S ≤ 8 S
Cefotaxime ≤ 1 S ≤ 1 S ≤ 0.12 S ≤ 0.12 S
Ceftriaxone 0.5 S ≤ 0.06 S
Ceftazidime ≤ 1 S ≤ 1 S
Cefepime ≤ 1 S ≤ 1 S
Cefditoren pivoxil S
Cefpodoxime proxetil ≤ 0.25 S 1 S
Imipenem/cilastatin ≤ 0.25 S ≤ 0.25 S
Meropenem ≤ 0.25 S ≤ 0.25 S
Doripenem S S
Gentamicin ≤ 1 S ≤ 1 S
Amikacin ≤ 2 S ≤ 2 S
Minocycline ≤ 1 S 2 S
Tetracycline 0.5 S 0.5 S
Erythromycin ≤ 0.12 S ≤ 0.12 S
Fosfomycin ≤16 S ≤ 16 S
Sulfamethoxazole/trimethoprim ≤ 20 S ≤ 20 S
Clindamycin ≤ 0.25 S ≤ 0.25 S
Levofloxacin ≤ 0.12 S 1 S
Ciprofloxacin ≤ 0.25 S ≤ 0.25 S
Vancomycin 0.5 S 0.5 S
Linezolid ≤ 2 S ≤ 2 S
Fluconazole ≤ 0.12 S ≤ 0.12 S 0.5 S 8 S
Amphotericin B ≤ 0.25 S
Flucytosine ≤ 1 S
Voriconazole 0.25 S
Micafungin ≤ 0.06 S
Caspofungin ≤ 0.25 S
Eikenella corrodes were not used for this antimicrobial susceptibility test
MIC minimum inhibitory concentration, S susceptible, R resistant
Fig. 2 Histopathology examination of the aortic aneurysm wall confirmed an infected aortic aneurysm based on infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (hematoxylin and eosin staining)
On the day of admission, antibiotics therapy was considered for implanted catheter-related infection. The patient was administered a combination of vancomycin 1.0 g intravenously every 12 hours, piperacillin/tazobactam 4.5 g every 6 hours, and micafungin 150 mg every 24 hours until all culture results were confirmed for a week at first. After determination of the drug susceptibilities of all strains, these antibiotics were found to be suitable and were continued. Although the thoracoabdominal aneurysm was resected and pus was drained, antibiotics were administered for 6 weeks in consideration of infection of the perivascular area from the celiac artery to the hepatic artery. His symptoms and laboratory test results improved after surgery and administration of antibiotics. The patient was discharged on day 45, and no recurrence of infected aortic aneurysm was observed on subsequent follow-up CTs as an outpatient for 1 year.
Discussion
Although there are some reports of infections and pseudoaneurysms due to catheters [4], to the best of our knowledge, no study has reported infected thoracoabdominal aneurysms that are associated with implanted long-term arterial catheters for chemotherapy. This case was a rare but extreme scenario caused by a long-term indwelling aortic catheter compounded by rare organisms responsible for the infection.
The most prevalent microorganisms present in the arterial wall that are likely to cause infection of an aneurysm are Staphylococcus spp. and Salmonella spp. [5]. Other microorganisms include Streptococcus pneumoniae, Treponema pallidum, and Mycobacterium tuberculosis, as well as other bacterial, fungal, and anaerobic pathogens [6]. Infected aneurysms can occur in any artery but are most observed in the extremities, splanchnic, and cerebral circulations, often at the points of vessel bifurcation [7]. In the present case, cultures of the aortic aneurysm wall tissue revealed the causative pathogens as E. coli, S. marcescens, E. corrodens, S. anginosus, α-Streptococcus, and C. glabrata. There were several possible routes of infection related to implanted long-term arterial catheters, and the more likely ones were through the transhepatic artery, transhepatic portal vein, and transdermal infections, including bloodstream infections. Although cultures from the removed catheter and aneurysm pus revealed several pathogens, transient bacteremia associated with an implanted arterial catheter could have been controlled by autoimmunity. In addition, multiple pathogens may exist in the aortic arterial wall and may have caused the infected aortic aneurysm. Interestingly, it is considered that the celiac artery had a damaged arterial wall during insertion of the catheter, which eventually developed into an aneurysm, with inflammation and microorganisms spreading to the thoracoabdominal aorta. This was an extremely rare occurrence, and an infectious aortic aneurysm was suspected from the distortion of the aneurysm shape.
Several reports have investigated the risk factors for an infected aneurysm, and these include arterial injury, trauma, antecedent infection, endocarditis, preexisting aneurysm, impaired immunity, and advanced age [8, 9]. The patient’s past medical history and clinical examination did not indicate the presence of these risk factors. Either a venous or arterial indwelling catheter has an obviously high risk of catheter-related infection. In general, the diagnosis of an infected aneurysm is based upon imaging the aneurysm, and infection is confirmed by culturing an organism from the blood. CT angiography definitively diagnoses the aneurysm, specific features suggest infection, and CT also simultaneously evaluates the status of the circulation [10]. In this case, we considered that the thoracoabdominal aortic aneurysm was highly likely to be related to the implanted catheter on the basis of findings from CT imaging, the catheter and pus from aortic wall tissue cultures, and pathology examinations.
The standard treatment of most infected aneurysms is antibiotic therapy combined with surgical debridement with or without revascularization [11]. The initial choice of antibiotic therapy should be guided by the most likely infecting organism on the basis of the clinical circumstances. Antibiotics should be tailored to culture and susceptibility results when they become available. If surgical drainage is performed, this time period commences from the day of surgery. However, there are no data to support a specific duration of antibiotic therapy. In this case, we administrated a combination of antibiotics for 6 weeks on the basis of physical examination, laboratory findings, and follow-up CT findings.
In this era, because the number of patients has been increasing with catheter-based examination and treatment options, the number of patients with indwelling catheter infections is also expected to increase. Immediate confirmatory diagnosis and appropriate treatment are essential. As a matter of course, it is important to remove the catheter as soon as possible at the end of procedure to avoid this critical illness.
Conclusion
This case was a rare but extreme scenario caused by a long-term indwelling catheter compounded by rare organisms responsible for the infection. Clinicians should be aware that long-term implanted arterial catheters can cause not only catheter-related bloodstream infections but may also be a risk factor for infected aortic aneurysms in rare cases.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KT wrote the initial and contributed to data collection and interpretation and critically reviewed the manuscript draft of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was conducted in the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | BEVACIZUMAB, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY | 33610163 | 19,648,394 | 2021-02-21 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic artery aneurysm'. | Infected thoracoabdominal aortic aneurysm related to an implanted long-term arterial catheter for chemotherapy: a case report.
BACKGROUND
An infected aortic aneurysm is a rare and life-threatening vascular condition with a high incidence of arterial rupture and recurrence even after treatment. One of the most common causes of an infected aortic aneurysm is catheter-related bloodstream infection. Although infection due to indwelling catheters is possible, the incidence of this is rare, especially for long-term implanted arterial catheters.
METHODS
A 78-year-old Japanese man with a past medical history of rectal cancer with metastasis to the liver presented to our hospital as a result of low back pain. Remission had been achieved following surgery and adjuvant chemotherapy via an implanted catheter for arterial infusion. However, the original catheter that was inserted from the femoral artery to the hepatic artery via the celiac artery was still present more than 10 years after diagnosis, without being replaced, in case of a recurrence. On the day of admission, computed tomography scan of the chest and abdomen with contrast revealed an irregularly shaped aortic aneurysm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding along the implanted arterial catheter without extravasation. Although the initial impression was an impending rupture of the acute thoracoabdominal aortic aneurysm, a catheter-related infection was considered as a differential diagnosis. Surgery was performed, which revealed a catheter-related infected aortic aneurysm based on images along the catheter, pus cultures, and tissue pathology examination results.
CONCLUSIONS
This is an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter for chemotherapy. It should be noted that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Background
An infected aortic aneurysm a rare life-threatening vascular condition which can eventually result in rupture of the arterial wall if left untreated. When infected aortic aneurysm is suspected, immediate confirmatory diagnosis and definitive treatment are essential [1]. As there are no definitive diagnostic criteria for infected aneurysms, radiographic imaging, blood and tissue cultures, and tissue pathology examinations must be evaluated. Negative blood cultures are not enough to exclude infected aneurysm because positive blood cultures can be obtained in only 50–70% of patients with an infected aneurysm [2, 3]. Despite report of venous and arterial infections aneurysms due to catheters [4], we could not find published works reporting infected aneurysms due to long-term implanted catheters. This was an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter. This case report suggests that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Case presentation
A 78-year-old Japanese male presented to the emergency department of our hospital with low back pain on exertion for 1 week. The pain was described as dull and gradually worsens. Although the location was near the thoracolumbar spine, he denied radiation of the pain to any parts of the body. Severity of pain using a numerical rating scale was 10/10 at the day of admission. The character and intensity of the pain were not affected by changes in physical movement or by rest. He denied any other symptoms such as fever, nausea, dysuria, hematuria, abdominal pain, and leg numbness during his clinical course.
He had a past medical history of rectal cancer with liver metastasis and had undergone surgery and chemotherapy. At the time of diagnosis, rectal cancer was stage IV (TNM classification of malignant tumors; T3N2M1), grade 3, and was revealed to be adenocarcinoma during histopathology. Liver metastasis affected segments 3 and 6. He underwent low anterior resection of the rectum and resection of the affected liver segments. He then underwent chemotherapy using fluorouracil that was arterially infused through a catheter inserted into the femoral artery and implanted into the hepatic artery through the celiac artery. He initially had good response to treatment but 2 years after diagnosis, he had a recurrence of liver metastasis. He underwent partial resection of segment 6 of the liver and was followed by chemotherapy using FOLFOX6 + bevacizumab protocol instead of arterial infusion. After finishing chemotherapy, he achieved complete remission 11 years after initial diagnosis. As a result of the possibility of another recurrence, the catheter remained in place without being replaced. His other past medical history was hypertension and he remained on amlodipine 5 mg daily and imidapril 5 mg daily. Social history revealed that he had smoked approximately 10 cigarettes a day for 50 years and drank alcohol occasionally. Family and environmental history was unremarkable. His employment history was an office worker, but he retired at the age of 60 and has not worked since then.
On the day of admission, his blood pressure was 171/75 mmHg, heart rate was 67 bpm, SpO2 97% at ambient room air, and body temperature was 36.6 °C. He denied abdominal pain, and pain or numbness in the lower extremities. General appearance was not in acute distress. There was no conjunctiva pallor or icterus. Respiratory sounds were clear to auscultation bilaterally and there were no wheezes or crackles. Cardiovascular examination revealed normal S1 and S2. There was no S3, S4, or murmurs. Abdominal examination revealed a flat and soft abdomen with audible bowel sounds. There was no bruit. There was no abdominal tenderness or hepatosplenomegaly. There was no spinal tenderness or costovertebral angle tenderness on percussion. There was no edema of his lower extremities. There was no joint swelling bilaterally at the wrists, ankles, and knees. General physical examinations revealed no abnormalities. His neurologic examination 2 to 12 were intact. There were no abnormalities with sensation and strength throughout with normal reflexes. Although laboratory analysis revealed normal results for complete blood count, electrolyte level, creatinine level, liver function, and coagulation test, levels of beta-d-glucan were slightly elevated at 24 pg/mL (reference value, < 20 pg/mL) (Table 1). Urinalysis was negative for proteinuria, pyuria, and hematuria (Table 1). Blood culture of aerobic and anaerobic bacteria including fungi and urine culture were all negative (Table 1). Transthoracic echocardiography revealed no valve vegetation, no valve regurgitation, no stenosis, and a normal ejection fraction. Computed tomography (CT) of the chest and abdomen revealed an irregularly shaped aortic aneurysm measuring 45 × 33 mm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding; no extravasation was observed using contrast enhancement (Fig. 1). There was a high possibility that the aortic aneurysm was infected because it was at the site of the catheter that was inserted for the femoral artery via the common hepatic artery. The patient was diagnosed with impending rupture of acute thoracoabdominal aortic aneurysm and was admitted to the intensive care unit of our hospital. Graft replacement was performed for the thoracoabdominal aortic aneurysm, and the implanted catheter was removed during surgery and tested for culture. Pus was discharged from the aortic aneurysm wall incision and collected with swab for culture. The cultures of both the removed catheter and the pus of the aneurysm revealed Escherichia coli, Serratia marcescens, Eikenella corrodens, Streptococcus anginosus, α-Streptococcus, and Candida glabrata. The reported antimicrobial sensitivities of these organisms are shown in Table 2. Antimicrobial susceptibilities were determined by the disk diffusion method, and the results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Results of pathology examination of the wall tissue of the aneurysm were compatible with those of the infected aneurysm cultures because the former showed infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (Fig. 2). On the basis of these findings, a diagnosis of catheter-related thoracoabdominal infected aortic aneurysm was made.Table 1 Results of laboratory findings
Complete blood count Biochemistry test Urinalysis
White blood cell 7.6 103/μL Total protein 7.8 g/dL Dipstick
Neutrophils 69.1 % Albumin 3.6 g/dL Color Yellow
Lymphocytes 22.0 % Aspartate aminotransferase 16.0 IU/L Specific gravity 1.024
Eosinophils 0.8 % Alanine aminotransaminase 12.0 IU/L pH 5.5
Basophils 0.8 % Total bilirubin 0.4 mg/dL Glucose Negative
Monocytes 7.3 % Gamma-glutamyl transferase 20.0 IU/L Protein Negative
Hemoglobin 12.3 g/dL Alkaline phosphatase 341.0 IU/L Bilirubin Negative
Hematocrit 39.1 % Lactate dehydrogenase 216.0 IU/L Ketones +
Platelets 40.5 104/μL Urea nitrogen 12.4 mg/dL Hemoglobin Negative
Creatinine 0.6 mg/dL Nitrate Negative
Coagulation test Sodium 134.0 mEq/L Leukocyte esterase +
Prothrombin time 85.7 % Potassium 4.3 mEq/L Microscopy exam
International normalized ratio 1.1 Chloride 93.0 mEq/L Red blood cells 1–4 /HPF
d-Dimer 1.5 μg/mL Calcium 9.3 mg/dL White blood cells 1–4 /HPF
Fibrinogen 452.0 mg/dL Phosphate 3.1 mg/dL Epithelial cells 1–4 /HPF
Fibrin degradation products 3.9 μg/mL Creatine kinase 92.0 IU/L Casts 1–4 /HPF
C-reactive protein 1.6 mg/dL Crystals Negative
Procalcitonin 0.1 ng/mL
Beta-d-glucan 24.0 pg/mL
Interferon-gamma release assays Negative Cultures
Triglyceride 91.0 mg/dL Blood of aerobic Negative
Total cholesterol 108.0 mg/dL Blood of anaerobic Negative
LDL-cholesterol 54.0 mg/dL Urine Negative
HDL-cholesterol 41.0 mg/dL Removed implanted catheter *
HbA1c 5.9 % Aneurysm pus *
HBs antigen Negative
HCV antibody Negative
HIV antigen/antibody Negative
*Refer to Table 2
Fig. 1 Computed tomography of the chest and abdomen reveals the thoracoabdominal aortic aneurysm along with the implanted arterial catheter inserted from the left femoral artery to the hepatic artery (a, b arrow). An irregularly shaped aortic aneurysm was identified at the origin of the celiac artery, with partially expanded common hepatic artery with disproportionate fat stranding (c, d arrowhead) along the catheter (c, d arrow); no extravasation was observed using contrast enhancement (c, d)
Table 2 Result of antimicrobial susceptibility for causative pathogens from implanted catheter and aneurysm pus
Antimicrobial agent E. coli S. marcescens S. anginosus α-Streptococcus C. glabrata
MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization
Benzylpenicillin ≤ 0.06 S ≤ 0.06 S
Ampicillin ≤ 2 S 8 R ≤ 0.25 S ≤ 0.25 S
Piperacillin ≤ 4 S ≤ 4 S
Amoxicillin/clavulanate ≤ 2 S 4 R
Ampicillin/sulbactam S R
Piperacillin/tazobactam S S
Cefazolin ≤ 4 ≤ 4 R
Cefaclor S R
Cefmetazole ≤ 1 S 2 S
Cefotiam ≤ 8 S ≤ 8 S
Cefotaxime ≤ 1 S ≤ 1 S ≤ 0.12 S ≤ 0.12 S
Ceftriaxone 0.5 S ≤ 0.06 S
Ceftazidime ≤ 1 S ≤ 1 S
Cefepime ≤ 1 S ≤ 1 S
Cefditoren pivoxil S
Cefpodoxime proxetil ≤ 0.25 S 1 S
Imipenem/cilastatin ≤ 0.25 S ≤ 0.25 S
Meropenem ≤ 0.25 S ≤ 0.25 S
Doripenem S S
Gentamicin ≤ 1 S ≤ 1 S
Amikacin ≤ 2 S ≤ 2 S
Minocycline ≤ 1 S 2 S
Tetracycline 0.5 S 0.5 S
Erythromycin ≤ 0.12 S ≤ 0.12 S
Fosfomycin ≤16 S ≤ 16 S
Sulfamethoxazole/trimethoprim ≤ 20 S ≤ 20 S
Clindamycin ≤ 0.25 S ≤ 0.25 S
Levofloxacin ≤ 0.12 S 1 S
Ciprofloxacin ≤ 0.25 S ≤ 0.25 S
Vancomycin 0.5 S 0.5 S
Linezolid ≤ 2 S ≤ 2 S
Fluconazole ≤ 0.12 S ≤ 0.12 S 0.5 S 8 S
Amphotericin B ≤ 0.25 S
Flucytosine ≤ 1 S
Voriconazole 0.25 S
Micafungin ≤ 0.06 S
Caspofungin ≤ 0.25 S
Eikenella corrodes were not used for this antimicrobial susceptibility test
MIC minimum inhibitory concentration, S susceptible, R resistant
Fig. 2 Histopathology examination of the aortic aneurysm wall confirmed an infected aortic aneurysm based on infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (hematoxylin and eosin staining)
On the day of admission, antibiotics therapy was considered for implanted catheter-related infection. The patient was administered a combination of vancomycin 1.0 g intravenously every 12 hours, piperacillin/tazobactam 4.5 g every 6 hours, and micafungin 150 mg every 24 hours until all culture results were confirmed for a week at first. After determination of the drug susceptibilities of all strains, these antibiotics were found to be suitable and were continued. Although the thoracoabdominal aneurysm was resected and pus was drained, antibiotics were administered for 6 weeks in consideration of infection of the perivascular area from the celiac artery to the hepatic artery. His symptoms and laboratory test results improved after surgery and administration of antibiotics. The patient was discharged on day 45, and no recurrence of infected aortic aneurysm was observed on subsequent follow-up CTs as an outpatient for 1 year.
Discussion
Although there are some reports of infections and pseudoaneurysms due to catheters [4], to the best of our knowledge, no study has reported infected thoracoabdominal aneurysms that are associated with implanted long-term arterial catheters for chemotherapy. This case was a rare but extreme scenario caused by a long-term indwelling aortic catheter compounded by rare organisms responsible for the infection.
The most prevalent microorganisms present in the arterial wall that are likely to cause infection of an aneurysm are Staphylococcus spp. and Salmonella spp. [5]. Other microorganisms include Streptococcus pneumoniae, Treponema pallidum, and Mycobacterium tuberculosis, as well as other bacterial, fungal, and anaerobic pathogens [6]. Infected aneurysms can occur in any artery but are most observed in the extremities, splanchnic, and cerebral circulations, often at the points of vessel bifurcation [7]. In the present case, cultures of the aortic aneurysm wall tissue revealed the causative pathogens as E. coli, S. marcescens, E. corrodens, S. anginosus, α-Streptococcus, and C. glabrata. There were several possible routes of infection related to implanted long-term arterial catheters, and the more likely ones were through the transhepatic artery, transhepatic portal vein, and transdermal infections, including bloodstream infections. Although cultures from the removed catheter and aneurysm pus revealed several pathogens, transient bacteremia associated with an implanted arterial catheter could have been controlled by autoimmunity. In addition, multiple pathogens may exist in the aortic arterial wall and may have caused the infected aortic aneurysm. Interestingly, it is considered that the celiac artery had a damaged arterial wall during insertion of the catheter, which eventually developed into an aneurysm, with inflammation and microorganisms spreading to the thoracoabdominal aorta. This was an extremely rare occurrence, and an infectious aortic aneurysm was suspected from the distortion of the aneurysm shape.
Several reports have investigated the risk factors for an infected aneurysm, and these include arterial injury, trauma, antecedent infection, endocarditis, preexisting aneurysm, impaired immunity, and advanced age [8, 9]. The patient’s past medical history and clinical examination did not indicate the presence of these risk factors. Either a venous or arterial indwelling catheter has an obviously high risk of catheter-related infection. In general, the diagnosis of an infected aneurysm is based upon imaging the aneurysm, and infection is confirmed by culturing an organism from the blood. CT angiography definitively diagnoses the aneurysm, specific features suggest infection, and CT also simultaneously evaluates the status of the circulation [10]. In this case, we considered that the thoracoabdominal aortic aneurysm was highly likely to be related to the implanted catheter on the basis of findings from CT imaging, the catheter and pus from aortic wall tissue cultures, and pathology examinations.
The standard treatment of most infected aneurysms is antibiotic therapy combined with surgical debridement with or without revascularization [11]. The initial choice of antibiotic therapy should be guided by the most likely infecting organism on the basis of the clinical circumstances. Antibiotics should be tailored to culture and susceptibility results when they become available. If surgical drainage is performed, this time period commences from the day of surgery. However, there are no data to support a specific duration of antibiotic therapy. In this case, we administrated a combination of antibiotics for 6 weeks on the basis of physical examination, laboratory findings, and follow-up CT findings.
In this era, because the number of patients has been increasing with catheter-based examination and treatment options, the number of patients with indwelling catheter infections is also expected to increase. Immediate confirmatory diagnosis and appropriate treatment are essential. As a matter of course, it is important to remove the catheter as soon as possible at the end of procedure to avoid this critical illness.
Conclusion
This case was a rare but extreme scenario caused by a long-term indwelling catheter compounded by rare organisms responsible for the infection. Clinicians should be aware that long-term implanted arterial catheters can cause not only catheter-related bloodstream infections but may also be a risk factor for infected aortic aneurysms in rare cases.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KT wrote the initial and contributed to data collection and interpretation and critically reviewed the manuscript draft of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was conducted in the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | BEVACIZUMAB, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY | 33610163 | 19,648,394 | 2021-02-21 |
What was the outcome of reaction 'Aortic aneurysm'? | Infected thoracoabdominal aortic aneurysm related to an implanted long-term arterial catheter for chemotherapy: a case report.
BACKGROUND
An infected aortic aneurysm is a rare and life-threatening vascular condition with a high incidence of arterial rupture and recurrence even after treatment. One of the most common causes of an infected aortic aneurysm is catheter-related bloodstream infection. Although infection due to indwelling catheters is possible, the incidence of this is rare, especially for long-term implanted arterial catheters.
METHODS
A 78-year-old Japanese man with a past medical history of rectal cancer with metastasis to the liver presented to our hospital as a result of low back pain. Remission had been achieved following surgery and adjuvant chemotherapy via an implanted catheter for arterial infusion. However, the original catheter that was inserted from the femoral artery to the hepatic artery via the celiac artery was still present more than 10 years after diagnosis, without being replaced, in case of a recurrence. On the day of admission, computed tomography scan of the chest and abdomen with contrast revealed an irregularly shaped aortic aneurysm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding along the implanted arterial catheter without extravasation. Although the initial impression was an impending rupture of the acute thoracoabdominal aortic aneurysm, a catheter-related infection was considered as a differential diagnosis. Surgery was performed, which revealed a catheter-related infected aortic aneurysm based on images along the catheter, pus cultures, and tissue pathology examination results.
CONCLUSIONS
This is an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter for chemotherapy. It should be noted that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Background
An infected aortic aneurysm a rare life-threatening vascular condition which can eventually result in rupture of the arterial wall if left untreated. When infected aortic aneurysm is suspected, immediate confirmatory diagnosis and definitive treatment are essential [1]. As there are no definitive diagnostic criteria for infected aneurysms, radiographic imaging, blood and tissue cultures, and tissue pathology examinations must be evaluated. Negative blood cultures are not enough to exclude infected aneurysm because positive blood cultures can be obtained in only 50–70% of patients with an infected aneurysm [2, 3]. Despite report of venous and arterial infections aneurysms due to catheters [4], we could not find published works reporting infected aneurysms due to long-term implanted catheters. This was an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter. This case report suggests that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Case presentation
A 78-year-old Japanese male presented to the emergency department of our hospital with low back pain on exertion for 1 week. The pain was described as dull and gradually worsens. Although the location was near the thoracolumbar spine, he denied radiation of the pain to any parts of the body. Severity of pain using a numerical rating scale was 10/10 at the day of admission. The character and intensity of the pain were not affected by changes in physical movement or by rest. He denied any other symptoms such as fever, nausea, dysuria, hematuria, abdominal pain, and leg numbness during his clinical course.
He had a past medical history of rectal cancer with liver metastasis and had undergone surgery and chemotherapy. At the time of diagnosis, rectal cancer was stage IV (TNM classification of malignant tumors; T3N2M1), grade 3, and was revealed to be adenocarcinoma during histopathology. Liver metastasis affected segments 3 and 6. He underwent low anterior resection of the rectum and resection of the affected liver segments. He then underwent chemotherapy using fluorouracil that was arterially infused through a catheter inserted into the femoral artery and implanted into the hepatic artery through the celiac artery. He initially had good response to treatment but 2 years after diagnosis, he had a recurrence of liver metastasis. He underwent partial resection of segment 6 of the liver and was followed by chemotherapy using FOLFOX6 + bevacizumab protocol instead of arterial infusion. After finishing chemotherapy, he achieved complete remission 11 years after initial diagnosis. As a result of the possibility of another recurrence, the catheter remained in place without being replaced. His other past medical history was hypertension and he remained on amlodipine 5 mg daily and imidapril 5 mg daily. Social history revealed that he had smoked approximately 10 cigarettes a day for 50 years and drank alcohol occasionally. Family and environmental history was unremarkable. His employment history was an office worker, but he retired at the age of 60 and has not worked since then.
On the day of admission, his blood pressure was 171/75 mmHg, heart rate was 67 bpm, SpO2 97% at ambient room air, and body temperature was 36.6 °C. He denied abdominal pain, and pain or numbness in the lower extremities. General appearance was not in acute distress. There was no conjunctiva pallor or icterus. Respiratory sounds were clear to auscultation bilaterally and there were no wheezes or crackles. Cardiovascular examination revealed normal S1 and S2. There was no S3, S4, or murmurs. Abdominal examination revealed a flat and soft abdomen with audible bowel sounds. There was no bruit. There was no abdominal tenderness or hepatosplenomegaly. There was no spinal tenderness or costovertebral angle tenderness on percussion. There was no edema of his lower extremities. There was no joint swelling bilaterally at the wrists, ankles, and knees. General physical examinations revealed no abnormalities. His neurologic examination 2 to 12 were intact. There were no abnormalities with sensation and strength throughout with normal reflexes. Although laboratory analysis revealed normal results for complete blood count, electrolyte level, creatinine level, liver function, and coagulation test, levels of beta-d-glucan were slightly elevated at 24 pg/mL (reference value, < 20 pg/mL) (Table 1). Urinalysis was negative for proteinuria, pyuria, and hematuria (Table 1). Blood culture of aerobic and anaerobic bacteria including fungi and urine culture were all negative (Table 1). Transthoracic echocardiography revealed no valve vegetation, no valve regurgitation, no stenosis, and a normal ejection fraction. Computed tomography (CT) of the chest and abdomen revealed an irregularly shaped aortic aneurysm measuring 45 × 33 mm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding; no extravasation was observed using contrast enhancement (Fig. 1). There was a high possibility that the aortic aneurysm was infected because it was at the site of the catheter that was inserted for the femoral artery via the common hepatic artery. The patient was diagnosed with impending rupture of acute thoracoabdominal aortic aneurysm and was admitted to the intensive care unit of our hospital. Graft replacement was performed for the thoracoabdominal aortic aneurysm, and the implanted catheter was removed during surgery and tested for culture. Pus was discharged from the aortic aneurysm wall incision and collected with swab for culture. The cultures of both the removed catheter and the pus of the aneurysm revealed Escherichia coli, Serratia marcescens, Eikenella corrodens, Streptococcus anginosus, α-Streptococcus, and Candida glabrata. The reported antimicrobial sensitivities of these organisms are shown in Table 2. Antimicrobial susceptibilities were determined by the disk diffusion method, and the results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Results of pathology examination of the wall tissue of the aneurysm were compatible with those of the infected aneurysm cultures because the former showed infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (Fig. 2). On the basis of these findings, a diagnosis of catheter-related thoracoabdominal infected aortic aneurysm was made.Table 1 Results of laboratory findings
Complete blood count Biochemistry test Urinalysis
White blood cell 7.6 103/μL Total protein 7.8 g/dL Dipstick
Neutrophils 69.1 % Albumin 3.6 g/dL Color Yellow
Lymphocytes 22.0 % Aspartate aminotransferase 16.0 IU/L Specific gravity 1.024
Eosinophils 0.8 % Alanine aminotransaminase 12.0 IU/L pH 5.5
Basophils 0.8 % Total bilirubin 0.4 mg/dL Glucose Negative
Monocytes 7.3 % Gamma-glutamyl transferase 20.0 IU/L Protein Negative
Hemoglobin 12.3 g/dL Alkaline phosphatase 341.0 IU/L Bilirubin Negative
Hematocrit 39.1 % Lactate dehydrogenase 216.0 IU/L Ketones +
Platelets 40.5 104/μL Urea nitrogen 12.4 mg/dL Hemoglobin Negative
Creatinine 0.6 mg/dL Nitrate Negative
Coagulation test Sodium 134.0 mEq/L Leukocyte esterase +
Prothrombin time 85.7 % Potassium 4.3 mEq/L Microscopy exam
International normalized ratio 1.1 Chloride 93.0 mEq/L Red blood cells 1–4 /HPF
d-Dimer 1.5 μg/mL Calcium 9.3 mg/dL White blood cells 1–4 /HPF
Fibrinogen 452.0 mg/dL Phosphate 3.1 mg/dL Epithelial cells 1–4 /HPF
Fibrin degradation products 3.9 μg/mL Creatine kinase 92.0 IU/L Casts 1–4 /HPF
C-reactive protein 1.6 mg/dL Crystals Negative
Procalcitonin 0.1 ng/mL
Beta-d-glucan 24.0 pg/mL
Interferon-gamma release assays Negative Cultures
Triglyceride 91.0 mg/dL Blood of aerobic Negative
Total cholesterol 108.0 mg/dL Blood of anaerobic Negative
LDL-cholesterol 54.0 mg/dL Urine Negative
HDL-cholesterol 41.0 mg/dL Removed implanted catheter *
HbA1c 5.9 % Aneurysm pus *
HBs antigen Negative
HCV antibody Negative
HIV antigen/antibody Negative
*Refer to Table 2
Fig. 1 Computed tomography of the chest and abdomen reveals the thoracoabdominal aortic aneurysm along with the implanted arterial catheter inserted from the left femoral artery to the hepatic artery (a, b arrow). An irregularly shaped aortic aneurysm was identified at the origin of the celiac artery, with partially expanded common hepatic artery with disproportionate fat stranding (c, d arrowhead) along the catheter (c, d arrow); no extravasation was observed using contrast enhancement (c, d)
Table 2 Result of antimicrobial susceptibility for causative pathogens from implanted catheter and aneurysm pus
Antimicrobial agent E. coli S. marcescens S. anginosus α-Streptococcus C. glabrata
MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization
Benzylpenicillin ≤ 0.06 S ≤ 0.06 S
Ampicillin ≤ 2 S 8 R ≤ 0.25 S ≤ 0.25 S
Piperacillin ≤ 4 S ≤ 4 S
Amoxicillin/clavulanate ≤ 2 S 4 R
Ampicillin/sulbactam S R
Piperacillin/tazobactam S S
Cefazolin ≤ 4 ≤ 4 R
Cefaclor S R
Cefmetazole ≤ 1 S 2 S
Cefotiam ≤ 8 S ≤ 8 S
Cefotaxime ≤ 1 S ≤ 1 S ≤ 0.12 S ≤ 0.12 S
Ceftriaxone 0.5 S ≤ 0.06 S
Ceftazidime ≤ 1 S ≤ 1 S
Cefepime ≤ 1 S ≤ 1 S
Cefditoren pivoxil S
Cefpodoxime proxetil ≤ 0.25 S 1 S
Imipenem/cilastatin ≤ 0.25 S ≤ 0.25 S
Meropenem ≤ 0.25 S ≤ 0.25 S
Doripenem S S
Gentamicin ≤ 1 S ≤ 1 S
Amikacin ≤ 2 S ≤ 2 S
Minocycline ≤ 1 S 2 S
Tetracycline 0.5 S 0.5 S
Erythromycin ≤ 0.12 S ≤ 0.12 S
Fosfomycin ≤16 S ≤ 16 S
Sulfamethoxazole/trimethoprim ≤ 20 S ≤ 20 S
Clindamycin ≤ 0.25 S ≤ 0.25 S
Levofloxacin ≤ 0.12 S 1 S
Ciprofloxacin ≤ 0.25 S ≤ 0.25 S
Vancomycin 0.5 S 0.5 S
Linezolid ≤ 2 S ≤ 2 S
Fluconazole ≤ 0.12 S ≤ 0.12 S 0.5 S 8 S
Amphotericin B ≤ 0.25 S
Flucytosine ≤ 1 S
Voriconazole 0.25 S
Micafungin ≤ 0.06 S
Caspofungin ≤ 0.25 S
Eikenella corrodes were not used for this antimicrobial susceptibility test
MIC minimum inhibitory concentration, S susceptible, R resistant
Fig. 2 Histopathology examination of the aortic aneurysm wall confirmed an infected aortic aneurysm based on infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (hematoxylin and eosin staining)
On the day of admission, antibiotics therapy was considered for implanted catheter-related infection. The patient was administered a combination of vancomycin 1.0 g intravenously every 12 hours, piperacillin/tazobactam 4.5 g every 6 hours, and micafungin 150 mg every 24 hours until all culture results were confirmed for a week at first. After determination of the drug susceptibilities of all strains, these antibiotics were found to be suitable and were continued. Although the thoracoabdominal aneurysm was resected and pus was drained, antibiotics were administered for 6 weeks in consideration of infection of the perivascular area from the celiac artery to the hepatic artery. His symptoms and laboratory test results improved after surgery and administration of antibiotics. The patient was discharged on day 45, and no recurrence of infected aortic aneurysm was observed on subsequent follow-up CTs as an outpatient for 1 year.
Discussion
Although there are some reports of infections and pseudoaneurysms due to catheters [4], to the best of our knowledge, no study has reported infected thoracoabdominal aneurysms that are associated with implanted long-term arterial catheters for chemotherapy. This case was a rare but extreme scenario caused by a long-term indwelling aortic catheter compounded by rare organisms responsible for the infection.
The most prevalent microorganisms present in the arterial wall that are likely to cause infection of an aneurysm are Staphylococcus spp. and Salmonella spp. [5]. Other microorganisms include Streptococcus pneumoniae, Treponema pallidum, and Mycobacterium tuberculosis, as well as other bacterial, fungal, and anaerobic pathogens [6]. Infected aneurysms can occur in any artery but are most observed in the extremities, splanchnic, and cerebral circulations, often at the points of vessel bifurcation [7]. In the present case, cultures of the aortic aneurysm wall tissue revealed the causative pathogens as E. coli, S. marcescens, E. corrodens, S. anginosus, α-Streptococcus, and C. glabrata. There were several possible routes of infection related to implanted long-term arterial catheters, and the more likely ones were through the transhepatic artery, transhepatic portal vein, and transdermal infections, including bloodstream infections. Although cultures from the removed catheter and aneurysm pus revealed several pathogens, transient bacteremia associated with an implanted arterial catheter could have been controlled by autoimmunity. In addition, multiple pathogens may exist in the aortic arterial wall and may have caused the infected aortic aneurysm. Interestingly, it is considered that the celiac artery had a damaged arterial wall during insertion of the catheter, which eventually developed into an aneurysm, with inflammation and microorganisms spreading to the thoracoabdominal aorta. This was an extremely rare occurrence, and an infectious aortic aneurysm was suspected from the distortion of the aneurysm shape.
Several reports have investigated the risk factors for an infected aneurysm, and these include arterial injury, trauma, antecedent infection, endocarditis, preexisting aneurysm, impaired immunity, and advanced age [8, 9]. The patient’s past medical history and clinical examination did not indicate the presence of these risk factors. Either a venous or arterial indwelling catheter has an obviously high risk of catheter-related infection. In general, the diagnosis of an infected aneurysm is based upon imaging the aneurysm, and infection is confirmed by culturing an organism from the blood. CT angiography definitively diagnoses the aneurysm, specific features suggest infection, and CT also simultaneously evaluates the status of the circulation [10]. In this case, we considered that the thoracoabdominal aortic aneurysm was highly likely to be related to the implanted catheter on the basis of findings from CT imaging, the catheter and pus from aortic wall tissue cultures, and pathology examinations.
The standard treatment of most infected aneurysms is antibiotic therapy combined with surgical debridement with or without revascularization [11]. The initial choice of antibiotic therapy should be guided by the most likely infecting organism on the basis of the clinical circumstances. Antibiotics should be tailored to culture and susceptibility results when they become available. If surgical drainage is performed, this time period commences from the day of surgery. However, there are no data to support a specific duration of antibiotic therapy. In this case, we administrated a combination of antibiotics for 6 weeks on the basis of physical examination, laboratory findings, and follow-up CT findings.
In this era, because the number of patients has been increasing with catheter-based examination and treatment options, the number of patients with indwelling catheter infections is also expected to increase. Immediate confirmatory diagnosis and appropriate treatment are essential. As a matter of course, it is important to remove the catheter as soon as possible at the end of procedure to avoid this critical illness.
Conclusion
This case was a rare but extreme scenario caused by a long-term indwelling catheter compounded by rare organisms responsible for the infection. Clinicians should be aware that long-term implanted arterial catheters can cause not only catheter-related bloodstream infections but may also be a risk factor for infected aortic aneurysms in rare cases.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KT wrote the initial and contributed to data collection and interpretation and critically reviewed the manuscript draft of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was conducted in the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33610163 | 19,648,394 | 2021-02-21 |
What was the outcome of reaction 'Back pain'? | Infected thoracoabdominal aortic aneurysm related to an implanted long-term arterial catheter for chemotherapy: a case report.
BACKGROUND
An infected aortic aneurysm is a rare and life-threatening vascular condition with a high incidence of arterial rupture and recurrence even after treatment. One of the most common causes of an infected aortic aneurysm is catheter-related bloodstream infection. Although infection due to indwelling catheters is possible, the incidence of this is rare, especially for long-term implanted arterial catheters.
METHODS
A 78-year-old Japanese man with a past medical history of rectal cancer with metastasis to the liver presented to our hospital as a result of low back pain. Remission had been achieved following surgery and adjuvant chemotherapy via an implanted catheter for arterial infusion. However, the original catheter that was inserted from the femoral artery to the hepatic artery via the celiac artery was still present more than 10 years after diagnosis, without being replaced, in case of a recurrence. On the day of admission, computed tomography scan of the chest and abdomen with contrast revealed an irregularly shaped aortic aneurysm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding along the implanted arterial catheter without extravasation. Although the initial impression was an impending rupture of the acute thoracoabdominal aortic aneurysm, a catheter-related infection was considered as a differential diagnosis. Surgery was performed, which revealed a catheter-related infected aortic aneurysm based on images along the catheter, pus cultures, and tissue pathology examination results.
CONCLUSIONS
This is an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter for chemotherapy. It should be noted that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Background
An infected aortic aneurysm a rare life-threatening vascular condition which can eventually result in rupture of the arterial wall if left untreated. When infected aortic aneurysm is suspected, immediate confirmatory diagnosis and definitive treatment are essential [1]. As there are no definitive diagnostic criteria for infected aneurysms, radiographic imaging, blood and tissue cultures, and tissue pathology examinations must be evaluated. Negative blood cultures are not enough to exclude infected aneurysm because positive blood cultures can be obtained in only 50–70% of patients with an infected aneurysm [2, 3]. Despite report of venous and arterial infections aneurysms due to catheters [4], we could not find published works reporting infected aneurysms due to long-term implanted catheters. This was an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter. This case report suggests that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Case presentation
A 78-year-old Japanese male presented to the emergency department of our hospital with low back pain on exertion for 1 week. The pain was described as dull and gradually worsens. Although the location was near the thoracolumbar spine, he denied radiation of the pain to any parts of the body. Severity of pain using a numerical rating scale was 10/10 at the day of admission. The character and intensity of the pain were not affected by changes in physical movement or by rest. He denied any other symptoms such as fever, nausea, dysuria, hematuria, abdominal pain, and leg numbness during his clinical course.
He had a past medical history of rectal cancer with liver metastasis and had undergone surgery and chemotherapy. At the time of diagnosis, rectal cancer was stage IV (TNM classification of malignant tumors; T3N2M1), grade 3, and was revealed to be adenocarcinoma during histopathology. Liver metastasis affected segments 3 and 6. He underwent low anterior resection of the rectum and resection of the affected liver segments. He then underwent chemotherapy using fluorouracil that was arterially infused through a catheter inserted into the femoral artery and implanted into the hepatic artery through the celiac artery. He initially had good response to treatment but 2 years after diagnosis, he had a recurrence of liver metastasis. He underwent partial resection of segment 6 of the liver and was followed by chemotherapy using FOLFOX6 + bevacizumab protocol instead of arterial infusion. After finishing chemotherapy, he achieved complete remission 11 years after initial diagnosis. As a result of the possibility of another recurrence, the catheter remained in place without being replaced. His other past medical history was hypertension and he remained on amlodipine 5 mg daily and imidapril 5 mg daily. Social history revealed that he had smoked approximately 10 cigarettes a day for 50 years and drank alcohol occasionally. Family and environmental history was unremarkable. His employment history was an office worker, but he retired at the age of 60 and has not worked since then.
On the day of admission, his blood pressure was 171/75 mmHg, heart rate was 67 bpm, SpO2 97% at ambient room air, and body temperature was 36.6 °C. He denied abdominal pain, and pain or numbness in the lower extremities. General appearance was not in acute distress. There was no conjunctiva pallor or icterus. Respiratory sounds were clear to auscultation bilaterally and there were no wheezes or crackles. Cardiovascular examination revealed normal S1 and S2. There was no S3, S4, or murmurs. Abdominal examination revealed a flat and soft abdomen with audible bowel sounds. There was no bruit. There was no abdominal tenderness or hepatosplenomegaly. There was no spinal tenderness or costovertebral angle tenderness on percussion. There was no edema of his lower extremities. There was no joint swelling bilaterally at the wrists, ankles, and knees. General physical examinations revealed no abnormalities. His neurologic examination 2 to 12 were intact. There were no abnormalities with sensation and strength throughout with normal reflexes. Although laboratory analysis revealed normal results for complete blood count, electrolyte level, creatinine level, liver function, and coagulation test, levels of beta-d-glucan were slightly elevated at 24 pg/mL (reference value, < 20 pg/mL) (Table 1). Urinalysis was negative for proteinuria, pyuria, and hematuria (Table 1). Blood culture of aerobic and anaerobic bacteria including fungi and urine culture were all negative (Table 1). Transthoracic echocardiography revealed no valve vegetation, no valve regurgitation, no stenosis, and a normal ejection fraction. Computed tomography (CT) of the chest and abdomen revealed an irregularly shaped aortic aneurysm measuring 45 × 33 mm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding; no extravasation was observed using contrast enhancement (Fig. 1). There was a high possibility that the aortic aneurysm was infected because it was at the site of the catheter that was inserted for the femoral artery via the common hepatic artery. The patient was diagnosed with impending rupture of acute thoracoabdominal aortic aneurysm and was admitted to the intensive care unit of our hospital. Graft replacement was performed for the thoracoabdominal aortic aneurysm, and the implanted catheter was removed during surgery and tested for culture. Pus was discharged from the aortic aneurysm wall incision and collected with swab for culture. The cultures of both the removed catheter and the pus of the aneurysm revealed Escherichia coli, Serratia marcescens, Eikenella corrodens, Streptococcus anginosus, α-Streptococcus, and Candida glabrata. The reported antimicrobial sensitivities of these organisms are shown in Table 2. Antimicrobial susceptibilities were determined by the disk diffusion method, and the results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Results of pathology examination of the wall tissue of the aneurysm were compatible with those of the infected aneurysm cultures because the former showed infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (Fig. 2). On the basis of these findings, a diagnosis of catheter-related thoracoabdominal infected aortic aneurysm was made.Table 1 Results of laboratory findings
Complete blood count Biochemistry test Urinalysis
White blood cell 7.6 103/μL Total protein 7.8 g/dL Dipstick
Neutrophils 69.1 % Albumin 3.6 g/dL Color Yellow
Lymphocytes 22.0 % Aspartate aminotransferase 16.0 IU/L Specific gravity 1.024
Eosinophils 0.8 % Alanine aminotransaminase 12.0 IU/L pH 5.5
Basophils 0.8 % Total bilirubin 0.4 mg/dL Glucose Negative
Monocytes 7.3 % Gamma-glutamyl transferase 20.0 IU/L Protein Negative
Hemoglobin 12.3 g/dL Alkaline phosphatase 341.0 IU/L Bilirubin Negative
Hematocrit 39.1 % Lactate dehydrogenase 216.0 IU/L Ketones +
Platelets 40.5 104/μL Urea nitrogen 12.4 mg/dL Hemoglobin Negative
Creatinine 0.6 mg/dL Nitrate Negative
Coagulation test Sodium 134.0 mEq/L Leukocyte esterase +
Prothrombin time 85.7 % Potassium 4.3 mEq/L Microscopy exam
International normalized ratio 1.1 Chloride 93.0 mEq/L Red blood cells 1–4 /HPF
d-Dimer 1.5 μg/mL Calcium 9.3 mg/dL White blood cells 1–4 /HPF
Fibrinogen 452.0 mg/dL Phosphate 3.1 mg/dL Epithelial cells 1–4 /HPF
Fibrin degradation products 3.9 μg/mL Creatine kinase 92.0 IU/L Casts 1–4 /HPF
C-reactive protein 1.6 mg/dL Crystals Negative
Procalcitonin 0.1 ng/mL
Beta-d-glucan 24.0 pg/mL
Interferon-gamma release assays Negative Cultures
Triglyceride 91.0 mg/dL Blood of aerobic Negative
Total cholesterol 108.0 mg/dL Blood of anaerobic Negative
LDL-cholesterol 54.0 mg/dL Urine Negative
HDL-cholesterol 41.0 mg/dL Removed implanted catheter *
HbA1c 5.9 % Aneurysm pus *
HBs antigen Negative
HCV antibody Negative
HIV antigen/antibody Negative
*Refer to Table 2
Fig. 1 Computed tomography of the chest and abdomen reveals the thoracoabdominal aortic aneurysm along with the implanted arterial catheter inserted from the left femoral artery to the hepatic artery (a, b arrow). An irregularly shaped aortic aneurysm was identified at the origin of the celiac artery, with partially expanded common hepatic artery with disproportionate fat stranding (c, d arrowhead) along the catheter (c, d arrow); no extravasation was observed using contrast enhancement (c, d)
Table 2 Result of antimicrobial susceptibility for causative pathogens from implanted catheter and aneurysm pus
Antimicrobial agent E. coli S. marcescens S. anginosus α-Streptococcus C. glabrata
MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization
Benzylpenicillin ≤ 0.06 S ≤ 0.06 S
Ampicillin ≤ 2 S 8 R ≤ 0.25 S ≤ 0.25 S
Piperacillin ≤ 4 S ≤ 4 S
Amoxicillin/clavulanate ≤ 2 S 4 R
Ampicillin/sulbactam S R
Piperacillin/tazobactam S S
Cefazolin ≤ 4 ≤ 4 R
Cefaclor S R
Cefmetazole ≤ 1 S 2 S
Cefotiam ≤ 8 S ≤ 8 S
Cefotaxime ≤ 1 S ≤ 1 S ≤ 0.12 S ≤ 0.12 S
Ceftriaxone 0.5 S ≤ 0.06 S
Ceftazidime ≤ 1 S ≤ 1 S
Cefepime ≤ 1 S ≤ 1 S
Cefditoren pivoxil S
Cefpodoxime proxetil ≤ 0.25 S 1 S
Imipenem/cilastatin ≤ 0.25 S ≤ 0.25 S
Meropenem ≤ 0.25 S ≤ 0.25 S
Doripenem S S
Gentamicin ≤ 1 S ≤ 1 S
Amikacin ≤ 2 S ≤ 2 S
Minocycline ≤ 1 S 2 S
Tetracycline 0.5 S 0.5 S
Erythromycin ≤ 0.12 S ≤ 0.12 S
Fosfomycin ≤16 S ≤ 16 S
Sulfamethoxazole/trimethoprim ≤ 20 S ≤ 20 S
Clindamycin ≤ 0.25 S ≤ 0.25 S
Levofloxacin ≤ 0.12 S 1 S
Ciprofloxacin ≤ 0.25 S ≤ 0.25 S
Vancomycin 0.5 S 0.5 S
Linezolid ≤ 2 S ≤ 2 S
Fluconazole ≤ 0.12 S ≤ 0.12 S 0.5 S 8 S
Amphotericin B ≤ 0.25 S
Flucytosine ≤ 1 S
Voriconazole 0.25 S
Micafungin ≤ 0.06 S
Caspofungin ≤ 0.25 S
Eikenella corrodes were not used for this antimicrobial susceptibility test
MIC minimum inhibitory concentration, S susceptible, R resistant
Fig. 2 Histopathology examination of the aortic aneurysm wall confirmed an infected aortic aneurysm based on infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (hematoxylin and eosin staining)
On the day of admission, antibiotics therapy was considered for implanted catheter-related infection. The patient was administered a combination of vancomycin 1.0 g intravenously every 12 hours, piperacillin/tazobactam 4.5 g every 6 hours, and micafungin 150 mg every 24 hours until all culture results were confirmed for a week at first. After determination of the drug susceptibilities of all strains, these antibiotics were found to be suitable and were continued. Although the thoracoabdominal aneurysm was resected and pus was drained, antibiotics were administered for 6 weeks in consideration of infection of the perivascular area from the celiac artery to the hepatic artery. His symptoms and laboratory test results improved after surgery and administration of antibiotics. The patient was discharged on day 45, and no recurrence of infected aortic aneurysm was observed on subsequent follow-up CTs as an outpatient for 1 year.
Discussion
Although there are some reports of infections and pseudoaneurysms due to catheters [4], to the best of our knowledge, no study has reported infected thoracoabdominal aneurysms that are associated with implanted long-term arterial catheters for chemotherapy. This case was a rare but extreme scenario caused by a long-term indwelling aortic catheter compounded by rare organisms responsible for the infection.
The most prevalent microorganisms present in the arterial wall that are likely to cause infection of an aneurysm are Staphylococcus spp. and Salmonella spp. [5]. Other microorganisms include Streptococcus pneumoniae, Treponema pallidum, and Mycobacterium tuberculosis, as well as other bacterial, fungal, and anaerobic pathogens [6]. Infected aneurysms can occur in any artery but are most observed in the extremities, splanchnic, and cerebral circulations, often at the points of vessel bifurcation [7]. In the present case, cultures of the aortic aneurysm wall tissue revealed the causative pathogens as E. coli, S. marcescens, E. corrodens, S. anginosus, α-Streptococcus, and C. glabrata. There were several possible routes of infection related to implanted long-term arterial catheters, and the more likely ones were through the transhepatic artery, transhepatic portal vein, and transdermal infections, including bloodstream infections. Although cultures from the removed catheter and aneurysm pus revealed several pathogens, transient bacteremia associated with an implanted arterial catheter could have been controlled by autoimmunity. In addition, multiple pathogens may exist in the aortic arterial wall and may have caused the infected aortic aneurysm. Interestingly, it is considered that the celiac artery had a damaged arterial wall during insertion of the catheter, which eventually developed into an aneurysm, with inflammation and microorganisms spreading to the thoracoabdominal aorta. This was an extremely rare occurrence, and an infectious aortic aneurysm was suspected from the distortion of the aneurysm shape.
Several reports have investigated the risk factors for an infected aneurysm, and these include arterial injury, trauma, antecedent infection, endocarditis, preexisting aneurysm, impaired immunity, and advanced age [8, 9]. The patient’s past medical history and clinical examination did not indicate the presence of these risk factors. Either a venous or arterial indwelling catheter has an obviously high risk of catheter-related infection. In general, the diagnosis of an infected aneurysm is based upon imaging the aneurysm, and infection is confirmed by culturing an organism from the blood. CT angiography definitively diagnoses the aneurysm, specific features suggest infection, and CT also simultaneously evaluates the status of the circulation [10]. In this case, we considered that the thoracoabdominal aortic aneurysm was highly likely to be related to the implanted catheter on the basis of findings from CT imaging, the catheter and pus from aortic wall tissue cultures, and pathology examinations.
The standard treatment of most infected aneurysms is antibiotic therapy combined with surgical debridement with or without revascularization [11]. The initial choice of antibiotic therapy should be guided by the most likely infecting organism on the basis of the clinical circumstances. Antibiotics should be tailored to culture and susceptibility results when they become available. If surgical drainage is performed, this time period commences from the day of surgery. However, there are no data to support a specific duration of antibiotic therapy. In this case, we administrated a combination of antibiotics for 6 weeks on the basis of physical examination, laboratory findings, and follow-up CT findings.
In this era, because the number of patients has been increasing with catheter-based examination and treatment options, the number of patients with indwelling catheter infections is also expected to increase. Immediate confirmatory diagnosis and appropriate treatment are essential. As a matter of course, it is important to remove the catheter as soon as possible at the end of procedure to avoid this critical illness.
Conclusion
This case was a rare but extreme scenario caused by a long-term indwelling catheter compounded by rare organisms responsible for the infection. Clinicians should be aware that long-term implanted arterial catheters can cause not only catheter-related bloodstream infections but may also be a risk factor for infected aortic aneurysms in rare cases.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KT wrote the initial and contributed to data collection and interpretation and critically reviewed the manuscript draft of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was conducted in the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33610163 | 19,648,394 | 2021-02-21 |
What was the outcome of reaction 'Device related infection'? | Infected thoracoabdominal aortic aneurysm related to an implanted long-term arterial catheter for chemotherapy: a case report.
BACKGROUND
An infected aortic aneurysm is a rare and life-threatening vascular condition with a high incidence of arterial rupture and recurrence even after treatment. One of the most common causes of an infected aortic aneurysm is catheter-related bloodstream infection. Although infection due to indwelling catheters is possible, the incidence of this is rare, especially for long-term implanted arterial catheters.
METHODS
A 78-year-old Japanese man with a past medical history of rectal cancer with metastasis to the liver presented to our hospital as a result of low back pain. Remission had been achieved following surgery and adjuvant chemotherapy via an implanted catheter for arterial infusion. However, the original catheter that was inserted from the femoral artery to the hepatic artery via the celiac artery was still present more than 10 years after diagnosis, without being replaced, in case of a recurrence. On the day of admission, computed tomography scan of the chest and abdomen with contrast revealed an irregularly shaped aortic aneurysm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding along the implanted arterial catheter without extravasation. Although the initial impression was an impending rupture of the acute thoracoabdominal aortic aneurysm, a catheter-related infection was considered as a differential diagnosis. Surgery was performed, which revealed a catheter-related infected aortic aneurysm based on images along the catheter, pus cultures, and tissue pathology examination results.
CONCLUSIONS
This is an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter for chemotherapy. It should be noted that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Background
An infected aortic aneurysm a rare life-threatening vascular condition which can eventually result in rupture of the arterial wall if left untreated. When infected aortic aneurysm is suspected, immediate confirmatory diagnosis and definitive treatment are essential [1]. As there are no definitive diagnostic criteria for infected aneurysms, radiographic imaging, blood and tissue cultures, and tissue pathology examinations must be evaluated. Negative blood cultures are not enough to exclude infected aneurysm because positive blood cultures can be obtained in only 50–70% of patients with an infected aneurysm [2, 3]. Despite report of venous and arterial infections aneurysms due to catheters [4], we could not find published works reporting infected aneurysms due to long-term implanted catheters. This was an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter. This case report suggests that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Case presentation
A 78-year-old Japanese male presented to the emergency department of our hospital with low back pain on exertion for 1 week. The pain was described as dull and gradually worsens. Although the location was near the thoracolumbar spine, he denied radiation of the pain to any parts of the body. Severity of pain using a numerical rating scale was 10/10 at the day of admission. The character and intensity of the pain were not affected by changes in physical movement or by rest. He denied any other symptoms such as fever, nausea, dysuria, hematuria, abdominal pain, and leg numbness during his clinical course.
He had a past medical history of rectal cancer with liver metastasis and had undergone surgery and chemotherapy. At the time of diagnosis, rectal cancer was stage IV (TNM classification of malignant tumors; T3N2M1), grade 3, and was revealed to be adenocarcinoma during histopathology. Liver metastasis affected segments 3 and 6. He underwent low anterior resection of the rectum and resection of the affected liver segments. He then underwent chemotherapy using fluorouracil that was arterially infused through a catheter inserted into the femoral artery and implanted into the hepatic artery through the celiac artery. He initially had good response to treatment but 2 years after diagnosis, he had a recurrence of liver metastasis. He underwent partial resection of segment 6 of the liver and was followed by chemotherapy using FOLFOX6 + bevacizumab protocol instead of arterial infusion. After finishing chemotherapy, he achieved complete remission 11 years after initial diagnosis. As a result of the possibility of another recurrence, the catheter remained in place without being replaced. His other past medical history was hypertension and he remained on amlodipine 5 mg daily and imidapril 5 mg daily. Social history revealed that he had smoked approximately 10 cigarettes a day for 50 years and drank alcohol occasionally. Family and environmental history was unremarkable. His employment history was an office worker, but he retired at the age of 60 and has not worked since then.
On the day of admission, his blood pressure was 171/75 mmHg, heart rate was 67 bpm, SpO2 97% at ambient room air, and body temperature was 36.6 °C. He denied abdominal pain, and pain or numbness in the lower extremities. General appearance was not in acute distress. There was no conjunctiva pallor or icterus. Respiratory sounds were clear to auscultation bilaterally and there were no wheezes or crackles. Cardiovascular examination revealed normal S1 and S2. There was no S3, S4, or murmurs. Abdominal examination revealed a flat and soft abdomen with audible bowel sounds. There was no bruit. There was no abdominal tenderness or hepatosplenomegaly. There was no spinal tenderness or costovertebral angle tenderness on percussion. There was no edema of his lower extremities. There was no joint swelling bilaterally at the wrists, ankles, and knees. General physical examinations revealed no abnormalities. His neurologic examination 2 to 12 were intact. There were no abnormalities with sensation and strength throughout with normal reflexes. Although laboratory analysis revealed normal results for complete blood count, electrolyte level, creatinine level, liver function, and coagulation test, levels of beta-d-glucan were slightly elevated at 24 pg/mL (reference value, < 20 pg/mL) (Table 1). Urinalysis was negative for proteinuria, pyuria, and hematuria (Table 1). Blood culture of aerobic and anaerobic bacteria including fungi and urine culture were all negative (Table 1). Transthoracic echocardiography revealed no valve vegetation, no valve regurgitation, no stenosis, and a normal ejection fraction. Computed tomography (CT) of the chest and abdomen revealed an irregularly shaped aortic aneurysm measuring 45 × 33 mm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding; no extravasation was observed using contrast enhancement (Fig. 1). There was a high possibility that the aortic aneurysm was infected because it was at the site of the catheter that was inserted for the femoral artery via the common hepatic artery. The patient was diagnosed with impending rupture of acute thoracoabdominal aortic aneurysm and was admitted to the intensive care unit of our hospital. Graft replacement was performed for the thoracoabdominal aortic aneurysm, and the implanted catheter was removed during surgery and tested for culture. Pus was discharged from the aortic aneurysm wall incision and collected with swab for culture. The cultures of both the removed catheter and the pus of the aneurysm revealed Escherichia coli, Serratia marcescens, Eikenella corrodens, Streptococcus anginosus, α-Streptococcus, and Candida glabrata. The reported antimicrobial sensitivities of these organisms are shown in Table 2. Antimicrobial susceptibilities were determined by the disk diffusion method, and the results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Results of pathology examination of the wall tissue of the aneurysm were compatible with those of the infected aneurysm cultures because the former showed infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (Fig. 2). On the basis of these findings, a diagnosis of catheter-related thoracoabdominal infected aortic aneurysm was made.Table 1 Results of laboratory findings
Complete blood count Biochemistry test Urinalysis
White blood cell 7.6 103/μL Total protein 7.8 g/dL Dipstick
Neutrophils 69.1 % Albumin 3.6 g/dL Color Yellow
Lymphocytes 22.0 % Aspartate aminotransferase 16.0 IU/L Specific gravity 1.024
Eosinophils 0.8 % Alanine aminotransaminase 12.0 IU/L pH 5.5
Basophils 0.8 % Total bilirubin 0.4 mg/dL Glucose Negative
Monocytes 7.3 % Gamma-glutamyl transferase 20.0 IU/L Protein Negative
Hemoglobin 12.3 g/dL Alkaline phosphatase 341.0 IU/L Bilirubin Negative
Hematocrit 39.1 % Lactate dehydrogenase 216.0 IU/L Ketones +
Platelets 40.5 104/μL Urea nitrogen 12.4 mg/dL Hemoglobin Negative
Creatinine 0.6 mg/dL Nitrate Negative
Coagulation test Sodium 134.0 mEq/L Leukocyte esterase +
Prothrombin time 85.7 % Potassium 4.3 mEq/L Microscopy exam
International normalized ratio 1.1 Chloride 93.0 mEq/L Red blood cells 1–4 /HPF
d-Dimer 1.5 μg/mL Calcium 9.3 mg/dL White blood cells 1–4 /HPF
Fibrinogen 452.0 mg/dL Phosphate 3.1 mg/dL Epithelial cells 1–4 /HPF
Fibrin degradation products 3.9 μg/mL Creatine kinase 92.0 IU/L Casts 1–4 /HPF
C-reactive protein 1.6 mg/dL Crystals Negative
Procalcitonin 0.1 ng/mL
Beta-d-glucan 24.0 pg/mL
Interferon-gamma release assays Negative Cultures
Triglyceride 91.0 mg/dL Blood of aerobic Negative
Total cholesterol 108.0 mg/dL Blood of anaerobic Negative
LDL-cholesterol 54.0 mg/dL Urine Negative
HDL-cholesterol 41.0 mg/dL Removed implanted catheter *
HbA1c 5.9 % Aneurysm pus *
HBs antigen Negative
HCV antibody Negative
HIV antigen/antibody Negative
*Refer to Table 2
Fig. 1 Computed tomography of the chest and abdomen reveals the thoracoabdominal aortic aneurysm along with the implanted arterial catheter inserted from the left femoral artery to the hepatic artery (a, b arrow). An irregularly shaped aortic aneurysm was identified at the origin of the celiac artery, with partially expanded common hepatic artery with disproportionate fat stranding (c, d arrowhead) along the catheter (c, d arrow); no extravasation was observed using contrast enhancement (c, d)
Table 2 Result of antimicrobial susceptibility for causative pathogens from implanted catheter and aneurysm pus
Antimicrobial agent E. coli S. marcescens S. anginosus α-Streptococcus C. glabrata
MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization
Benzylpenicillin ≤ 0.06 S ≤ 0.06 S
Ampicillin ≤ 2 S 8 R ≤ 0.25 S ≤ 0.25 S
Piperacillin ≤ 4 S ≤ 4 S
Amoxicillin/clavulanate ≤ 2 S 4 R
Ampicillin/sulbactam S R
Piperacillin/tazobactam S S
Cefazolin ≤ 4 ≤ 4 R
Cefaclor S R
Cefmetazole ≤ 1 S 2 S
Cefotiam ≤ 8 S ≤ 8 S
Cefotaxime ≤ 1 S ≤ 1 S ≤ 0.12 S ≤ 0.12 S
Ceftriaxone 0.5 S ≤ 0.06 S
Ceftazidime ≤ 1 S ≤ 1 S
Cefepime ≤ 1 S ≤ 1 S
Cefditoren pivoxil S
Cefpodoxime proxetil ≤ 0.25 S 1 S
Imipenem/cilastatin ≤ 0.25 S ≤ 0.25 S
Meropenem ≤ 0.25 S ≤ 0.25 S
Doripenem S S
Gentamicin ≤ 1 S ≤ 1 S
Amikacin ≤ 2 S ≤ 2 S
Minocycline ≤ 1 S 2 S
Tetracycline 0.5 S 0.5 S
Erythromycin ≤ 0.12 S ≤ 0.12 S
Fosfomycin ≤16 S ≤ 16 S
Sulfamethoxazole/trimethoprim ≤ 20 S ≤ 20 S
Clindamycin ≤ 0.25 S ≤ 0.25 S
Levofloxacin ≤ 0.12 S 1 S
Ciprofloxacin ≤ 0.25 S ≤ 0.25 S
Vancomycin 0.5 S 0.5 S
Linezolid ≤ 2 S ≤ 2 S
Fluconazole ≤ 0.12 S ≤ 0.12 S 0.5 S 8 S
Amphotericin B ≤ 0.25 S
Flucytosine ≤ 1 S
Voriconazole 0.25 S
Micafungin ≤ 0.06 S
Caspofungin ≤ 0.25 S
Eikenella corrodes were not used for this antimicrobial susceptibility test
MIC minimum inhibitory concentration, S susceptible, R resistant
Fig. 2 Histopathology examination of the aortic aneurysm wall confirmed an infected aortic aneurysm based on infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (hematoxylin and eosin staining)
On the day of admission, antibiotics therapy was considered for implanted catheter-related infection. The patient was administered a combination of vancomycin 1.0 g intravenously every 12 hours, piperacillin/tazobactam 4.5 g every 6 hours, and micafungin 150 mg every 24 hours until all culture results were confirmed for a week at first. After determination of the drug susceptibilities of all strains, these antibiotics were found to be suitable and were continued. Although the thoracoabdominal aneurysm was resected and pus was drained, antibiotics were administered for 6 weeks in consideration of infection of the perivascular area from the celiac artery to the hepatic artery. His symptoms and laboratory test results improved after surgery and administration of antibiotics. The patient was discharged on day 45, and no recurrence of infected aortic aneurysm was observed on subsequent follow-up CTs as an outpatient for 1 year.
Discussion
Although there are some reports of infections and pseudoaneurysms due to catheters [4], to the best of our knowledge, no study has reported infected thoracoabdominal aneurysms that are associated with implanted long-term arterial catheters for chemotherapy. This case was a rare but extreme scenario caused by a long-term indwelling aortic catheter compounded by rare organisms responsible for the infection.
The most prevalent microorganisms present in the arterial wall that are likely to cause infection of an aneurysm are Staphylococcus spp. and Salmonella spp. [5]. Other microorganisms include Streptococcus pneumoniae, Treponema pallidum, and Mycobacterium tuberculosis, as well as other bacterial, fungal, and anaerobic pathogens [6]. Infected aneurysms can occur in any artery but are most observed in the extremities, splanchnic, and cerebral circulations, often at the points of vessel bifurcation [7]. In the present case, cultures of the aortic aneurysm wall tissue revealed the causative pathogens as E. coli, S. marcescens, E. corrodens, S. anginosus, α-Streptococcus, and C. glabrata. There were several possible routes of infection related to implanted long-term arterial catheters, and the more likely ones were through the transhepatic artery, transhepatic portal vein, and transdermal infections, including bloodstream infections. Although cultures from the removed catheter and aneurysm pus revealed several pathogens, transient bacteremia associated with an implanted arterial catheter could have been controlled by autoimmunity. In addition, multiple pathogens may exist in the aortic arterial wall and may have caused the infected aortic aneurysm. Interestingly, it is considered that the celiac artery had a damaged arterial wall during insertion of the catheter, which eventually developed into an aneurysm, with inflammation and microorganisms spreading to the thoracoabdominal aorta. This was an extremely rare occurrence, and an infectious aortic aneurysm was suspected from the distortion of the aneurysm shape.
Several reports have investigated the risk factors for an infected aneurysm, and these include arterial injury, trauma, antecedent infection, endocarditis, preexisting aneurysm, impaired immunity, and advanced age [8, 9]. The patient’s past medical history and clinical examination did not indicate the presence of these risk factors. Either a venous or arterial indwelling catheter has an obviously high risk of catheter-related infection. In general, the diagnosis of an infected aneurysm is based upon imaging the aneurysm, and infection is confirmed by culturing an organism from the blood. CT angiography definitively diagnoses the aneurysm, specific features suggest infection, and CT also simultaneously evaluates the status of the circulation [10]. In this case, we considered that the thoracoabdominal aortic aneurysm was highly likely to be related to the implanted catheter on the basis of findings from CT imaging, the catheter and pus from aortic wall tissue cultures, and pathology examinations.
The standard treatment of most infected aneurysms is antibiotic therapy combined with surgical debridement with or without revascularization [11]. The initial choice of antibiotic therapy should be guided by the most likely infecting organism on the basis of the clinical circumstances. Antibiotics should be tailored to culture and susceptibility results when they become available. If surgical drainage is performed, this time period commences from the day of surgery. However, there are no data to support a specific duration of antibiotic therapy. In this case, we administrated a combination of antibiotics for 6 weeks on the basis of physical examination, laboratory findings, and follow-up CT findings.
In this era, because the number of patients has been increasing with catheter-based examination and treatment options, the number of patients with indwelling catheter infections is also expected to increase. Immediate confirmatory diagnosis and appropriate treatment are essential. As a matter of course, it is important to remove the catheter as soon as possible at the end of procedure to avoid this critical illness.
Conclusion
This case was a rare but extreme scenario caused by a long-term indwelling catheter compounded by rare organisms responsible for the infection. Clinicians should be aware that long-term implanted arterial catheters can cause not only catheter-related bloodstream infections but may also be a risk factor for infected aortic aneurysms in rare cases.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KT wrote the initial and contributed to data collection and interpretation and critically reviewed the manuscript draft of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was conducted in the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33610163 | 19,648,394 | 2021-02-21 |
What was the outcome of reaction 'Hepatic artery aneurysm'? | Infected thoracoabdominal aortic aneurysm related to an implanted long-term arterial catheter for chemotherapy: a case report.
BACKGROUND
An infected aortic aneurysm is a rare and life-threatening vascular condition with a high incidence of arterial rupture and recurrence even after treatment. One of the most common causes of an infected aortic aneurysm is catheter-related bloodstream infection. Although infection due to indwelling catheters is possible, the incidence of this is rare, especially for long-term implanted arterial catheters.
METHODS
A 78-year-old Japanese man with a past medical history of rectal cancer with metastasis to the liver presented to our hospital as a result of low back pain. Remission had been achieved following surgery and adjuvant chemotherapy via an implanted catheter for arterial infusion. However, the original catheter that was inserted from the femoral artery to the hepatic artery via the celiac artery was still present more than 10 years after diagnosis, without being replaced, in case of a recurrence. On the day of admission, computed tomography scan of the chest and abdomen with contrast revealed an irregularly shaped aortic aneurysm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding along the implanted arterial catheter without extravasation. Although the initial impression was an impending rupture of the acute thoracoabdominal aortic aneurysm, a catheter-related infection was considered as a differential diagnosis. Surgery was performed, which revealed a catheter-related infected aortic aneurysm based on images along the catheter, pus cultures, and tissue pathology examination results.
CONCLUSIONS
This is an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter for chemotherapy. It should be noted that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Background
An infected aortic aneurysm a rare life-threatening vascular condition which can eventually result in rupture of the arterial wall if left untreated. When infected aortic aneurysm is suspected, immediate confirmatory diagnosis and definitive treatment are essential [1]. As there are no definitive diagnostic criteria for infected aneurysms, radiographic imaging, blood and tissue cultures, and tissue pathology examinations must be evaluated. Negative blood cultures are not enough to exclude infected aneurysm because positive blood cultures can be obtained in only 50–70% of patients with an infected aneurysm [2, 3]. Despite report of venous and arterial infections aneurysms due to catheters [4], we could not find published works reporting infected aneurysms due to long-term implanted catheters. This was an extremely rare case of an infectious aneurysm caused by prolonged implantation of an arterial catheter. This case report suggests that an indwelling arterial catheter not only causes bloodstream infections but can also cause an infection of a thoracoabdominal aortic aneurysm.
Case presentation
A 78-year-old Japanese male presented to the emergency department of our hospital with low back pain on exertion for 1 week. The pain was described as dull and gradually worsens. Although the location was near the thoracolumbar spine, he denied radiation of the pain to any parts of the body. Severity of pain using a numerical rating scale was 10/10 at the day of admission. The character and intensity of the pain were not affected by changes in physical movement or by rest. He denied any other symptoms such as fever, nausea, dysuria, hematuria, abdominal pain, and leg numbness during his clinical course.
He had a past medical history of rectal cancer with liver metastasis and had undergone surgery and chemotherapy. At the time of diagnosis, rectal cancer was stage IV (TNM classification of malignant tumors; T3N2M1), grade 3, and was revealed to be adenocarcinoma during histopathology. Liver metastasis affected segments 3 and 6. He underwent low anterior resection of the rectum and resection of the affected liver segments. He then underwent chemotherapy using fluorouracil that was arterially infused through a catheter inserted into the femoral artery and implanted into the hepatic artery through the celiac artery. He initially had good response to treatment but 2 years after diagnosis, he had a recurrence of liver metastasis. He underwent partial resection of segment 6 of the liver and was followed by chemotherapy using FOLFOX6 + bevacizumab protocol instead of arterial infusion. After finishing chemotherapy, he achieved complete remission 11 years after initial diagnosis. As a result of the possibility of another recurrence, the catheter remained in place without being replaced. His other past medical history was hypertension and he remained on amlodipine 5 mg daily and imidapril 5 mg daily. Social history revealed that he had smoked approximately 10 cigarettes a day for 50 years and drank alcohol occasionally. Family and environmental history was unremarkable. His employment history was an office worker, but he retired at the age of 60 and has not worked since then.
On the day of admission, his blood pressure was 171/75 mmHg, heart rate was 67 bpm, SpO2 97% at ambient room air, and body temperature was 36.6 °C. He denied abdominal pain, and pain or numbness in the lower extremities. General appearance was not in acute distress. There was no conjunctiva pallor or icterus. Respiratory sounds were clear to auscultation bilaterally and there were no wheezes or crackles. Cardiovascular examination revealed normal S1 and S2. There was no S3, S4, or murmurs. Abdominal examination revealed a flat and soft abdomen with audible bowel sounds. There was no bruit. There was no abdominal tenderness or hepatosplenomegaly. There was no spinal tenderness or costovertebral angle tenderness on percussion. There was no edema of his lower extremities. There was no joint swelling bilaterally at the wrists, ankles, and knees. General physical examinations revealed no abnormalities. His neurologic examination 2 to 12 were intact. There were no abnormalities with sensation and strength throughout with normal reflexes. Although laboratory analysis revealed normal results for complete blood count, electrolyte level, creatinine level, liver function, and coagulation test, levels of beta-d-glucan were slightly elevated at 24 pg/mL (reference value, < 20 pg/mL) (Table 1). Urinalysis was negative for proteinuria, pyuria, and hematuria (Table 1). Blood culture of aerobic and anaerobic bacteria including fungi and urine culture were all negative (Table 1). Transthoracic echocardiography revealed no valve vegetation, no valve regurgitation, no stenosis, and a normal ejection fraction. Computed tomography (CT) of the chest and abdomen revealed an irregularly shaped aortic aneurysm measuring 45 × 33 mm at the origin of the celiac artery and a partially expanded common hepatic artery with disproportionate fat stranding; no extravasation was observed using contrast enhancement (Fig. 1). There was a high possibility that the aortic aneurysm was infected because it was at the site of the catheter that was inserted for the femoral artery via the common hepatic artery. The patient was diagnosed with impending rupture of acute thoracoabdominal aortic aneurysm and was admitted to the intensive care unit of our hospital. Graft replacement was performed for the thoracoabdominal aortic aneurysm, and the implanted catheter was removed during surgery and tested for culture. Pus was discharged from the aortic aneurysm wall incision and collected with swab for culture. The cultures of both the removed catheter and the pus of the aneurysm revealed Escherichia coli, Serratia marcescens, Eikenella corrodens, Streptococcus anginosus, α-Streptococcus, and Candida glabrata. The reported antimicrobial sensitivities of these organisms are shown in Table 2. Antimicrobial susceptibilities were determined by the disk diffusion method, and the results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Results of pathology examination of the wall tissue of the aneurysm were compatible with those of the infected aneurysm cultures because the former showed infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (Fig. 2). On the basis of these findings, a diagnosis of catheter-related thoracoabdominal infected aortic aneurysm was made.Table 1 Results of laboratory findings
Complete blood count Biochemistry test Urinalysis
White blood cell 7.6 103/μL Total protein 7.8 g/dL Dipstick
Neutrophils 69.1 % Albumin 3.6 g/dL Color Yellow
Lymphocytes 22.0 % Aspartate aminotransferase 16.0 IU/L Specific gravity 1.024
Eosinophils 0.8 % Alanine aminotransaminase 12.0 IU/L pH 5.5
Basophils 0.8 % Total bilirubin 0.4 mg/dL Glucose Negative
Monocytes 7.3 % Gamma-glutamyl transferase 20.0 IU/L Protein Negative
Hemoglobin 12.3 g/dL Alkaline phosphatase 341.0 IU/L Bilirubin Negative
Hematocrit 39.1 % Lactate dehydrogenase 216.0 IU/L Ketones +
Platelets 40.5 104/μL Urea nitrogen 12.4 mg/dL Hemoglobin Negative
Creatinine 0.6 mg/dL Nitrate Negative
Coagulation test Sodium 134.0 mEq/L Leukocyte esterase +
Prothrombin time 85.7 % Potassium 4.3 mEq/L Microscopy exam
International normalized ratio 1.1 Chloride 93.0 mEq/L Red blood cells 1–4 /HPF
d-Dimer 1.5 μg/mL Calcium 9.3 mg/dL White blood cells 1–4 /HPF
Fibrinogen 452.0 mg/dL Phosphate 3.1 mg/dL Epithelial cells 1–4 /HPF
Fibrin degradation products 3.9 μg/mL Creatine kinase 92.0 IU/L Casts 1–4 /HPF
C-reactive protein 1.6 mg/dL Crystals Negative
Procalcitonin 0.1 ng/mL
Beta-d-glucan 24.0 pg/mL
Interferon-gamma release assays Negative Cultures
Triglyceride 91.0 mg/dL Blood of aerobic Negative
Total cholesterol 108.0 mg/dL Blood of anaerobic Negative
LDL-cholesterol 54.0 mg/dL Urine Negative
HDL-cholesterol 41.0 mg/dL Removed implanted catheter *
HbA1c 5.9 % Aneurysm pus *
HBs antigen Negative
HCV antibody Negative
HIV antigen/antibody Negative
*Refer to Table 2
Fig. 1 Computed tomography of the chest and abdomen reveals the thoracoabdominal aortic aneurysm along with the implanted arterial catheter inserted from the left femoral artery to the hepatic artery (a, b arrow). An irregularly shaped aortic aneurysm was identified at the origin of the celiac artery, with partially expanded common hepatic artery with disproportionate fat stranding (c, d arrowhead) along the catheter (c, d arrow); no extravasation was observed using contrast enhancement (c, d)
Table 2 Result of antimicrobial susceptibility for causative pathogens from implanted catheter and aneurysm pus
Antimicrobial agent E. coli S. marcescens S. anginosus α-Streptococcus C. glabrata
MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization MIC (μg/mL) Categorization
Benzylpenicillin ≤ 0.06 S ≤ 0.06 S
Ampicillin ≤ 2 S 8 R ≤ 0.25 S ≤ 0.25 S
Piperacillin ≤ 4 S ≤ 4 S
Amoxicillin/clavulanate ≤ 2 S 4 R
Ampicillin/sulbactam S R
Piperacillin/tazobactam S S
Cefazolin ≤ 4 ≤ 4 R
Cefaclor S R
Cefmetazole ≤ 1 S 2 S
Cefotiam ≤ 8 S ≤ 8 S
Cefotaxime ≤ 1 S ≤ 1 S ≤ 0.12 S ≤ 0.12 S
Ceftriaxone 0.5 S ≤ 0.06 S
Ceftazidime ≤ 1 S ≤ 1 S
Cefepime ≤ 1 S ≤ 1 S
Cefditoren pivoxil S
Cefpodoxime proxetil ≤ 0.25 S 1 S
Imipenem/cilastatin ≤ 0.25 S ≤ 0.25 S
Meropenem ≤ 0.25 S ≤ 0.25 S
Doripenem S S
Gentamicin ≤ 1 S ≤ 1 S
Amikacin ≤ 2 S ≤ 2 S
Minocycline ≤ 1 S 2 S
Tetracycline 0.5 S 0.5 S
Erythromycin ≤ 0.12 S ≤ 0.12 S
Fosfomycin ≤16 S ≤ 16 S
Sulfamethoxazole/trimethoprim ≤ 20 S ≤ 20 S
Clindamycin ≤ 0.25 S ≤ 0.25 S
Levofloxacin ≤ 0.12 S 1 S
Ciprofloxacin ≤ 0.25 S ≤ 0.25 S
Vancomycin 0.5 S 0.5 S
Linezolid ≤ 2 S ≤ 2 S
Fluconazole ≤ 0.12 S ≤ 0.12 S 0.5 S 8 S
Amphotericin B ≤ 0.25 S
Flucytosine ≤ 1 S
Voriconazole 0.25 S
Micafungin ≤ 0.06 S
Caspofungin ≤ 0.25 S
Eikenella corrodes were not used for this antimicrobial susceptibility test
MIC minimum inhibitory concentration, S susceptible, R resistant
Fig. 2 Histopathology examination of the aortic aneurysm wall confirmed an infected aortic aneurysm based on infiltration of neutrophils mainly in the small blood vessels around the adventitia and infiltration of neutrophils, lymphocytes, and plasma cells in the media of the blood vessels (hematoxylin and eosin staining)
On the day of admission, antibiotics therapy was considered for implanted catheter-related infection. The patient was administered a combination of vancomycin 1.0 g intravenously every 12 hours, piperacillin/tazobactam 4.5 g every 6 hours, and micafungin 150 mg every 24 hours until all culture results were confirmed for a week at first. After determination of the drug susceptibilities of all strains, these antibiotics were found to be suitable and were continued. Although the thoracoabdominal aneurysm was resected and pus was drained, antibiotics were administered for 6 weeks in consideration of infection of the perivascular area from the celiac artery to the hepatic artery. His symptoms and laboratory test results improved after surgery and administration of antibiotics. The patient was discharged on day 45, and no recurrence of infected aortic aneurysm was observed on subsequent follow-up CTs as an outpatient for 1 year.
Discussion
Although there are some reports of infections and pseudoaneurysms due to catheters [4], to the best of our knowledge, no study has reported infected thoracoabdominal aneurysms that are associated with implanted long-term arterial catheters for chemotherapy. This case was a rare but extreme scenario caused by a long-term indwelling aortic catheter compounded by rare organisms responsible for the infection.
The most prevalent microorganisms present in the arterial wall that are likely to cause infection of an aneurysm are Staphylococcus spp. and Salmonella spp. [5]. Other microorganisms include Streptococcus pneumoniae, Treponema pallidum, and Mycobacterium tuberculosis, as well as other bacterial, fungal, and anaerobic pathogens [6]. Infected aneurysms can occur in any artery but are most observed in the extremities, splanchnic, and cerebral circulations, often at the points of vessel bifurcation [7]. In the present case, cultures of the aortic aneurysm wall tissue revealed the causative pathogens as E. coli, S. marcescens, E. corrodens, S. anginosus, α-Streptococcus, and C. glabrata. There were several possible routes of infection related to implanted long-term arterial catheters, and the more likely ones were through the transhepatic artery, transhepatic portal vein, and transdermal infections, including bloodstream infections. Although cultures from the removed catheter and aneurysm pus revealed several pathogens, transient bacteremia associated with an implanted arterial catheter could have been controlled by autoimmunity. In addition, multiple pathogens may exist in the aortic arterial wall and may have caused the infected aortic aneurysm. Interestingly, it is considered that the celiac artery had a damaged arterial wall during insertion of the catheter, which eventually developed into an aneurysm, with inflammation and microorganisms spreading to the thoracoabdominal aorta. This was an extremely rare occurrence, and an infectious aortic aneurysm was suspected from the distortion of the aneurysm shape.
Several reports have investigated the risk factors for an infected aneurysm, and these include arterial injury, trauma, antecedent infection, endocarditis, preexisting aneurysm, impaired immunity, and advanced age [8, 9]. The patient’s past medical history and clinical examination did not indicate the presence of these risk factors. Either a venous or arterial indwelling catheter has an obviously high risk of catheter-related infection. In general, the diagnosis of an infected aneurysm is based upon imaging the aneurysm, and infection is confirmed by culturing an organism from the blood. CT angiography definitively diagnoses the aneurysm, specific features suggest infection, and CT also simultaneously evaluates the status of the circulation [10]. In this case, we considered that the thoracoabdominal aortic aneurysm was highly likely to be related to the implanted catheter on the basis of findings from CT imaging, the catheter and pus from aortic wall tissue cultures, and pathology examinations.
The standard treatment of most infected aneurysms is antibiotic therapy combined with surgical debridement with or without revascularization [11]. The initial choice of antibiotic therapy should be guided by the most likely infecting organism on the basis of the clinical circumstances. Antibiotics should be tailored to culture and susceptibility results when they become available. If surgical drainage is performed, this time period commences from the day of surgery. However, there are no data to support a specific duration of antibiotic therapy. In this case, we administrated a combination of antibiotics for 6 weeks on the basis of physical examination, laboratory findings, and follow-up CT findings.
In this era, because the number of patients has been increasing with catheter-based examination and treatment options, the number of patients with indwelling catheter infections is also expected to increase. Immediate confirmatory diagnosis and appropriate treatment are essential. As a matter of course, it is important to remove the catheter as soon as possible at the end of procedure to avoid this critical illness.
Conclusion
This case was a rare but extreme scenario caused by a long-term indwelling catheter compounded by rare organisms responsible for the infection. Clinicians should be aware that long-term implanted arterial catheters can cause not only catheter-related bloodstream infections but may also be a risk factor for infected aortic aneurysms in rare cases.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KT wrote the initial and contributed to data collection and interpretation and critically reviewed the manuscript draft of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was conducted in the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33610163 | 19,648,394 | 2021-02-21 |
What was the administration route of drug 'DEXTROSE'? | Burkitt lymphoma and lactic acidosis: A case report and review of the literature.
Type A lactic acidosis is a potentially life-threatening complication in critically ill patients and is the hallmark of a shock state as a result of tissue hypoperfusion and dysoxia. Type B lactic acidosis results from mechanisms other than dysoxia and is a rare condition in patients with solid tumors or hematological malignancies. We present a case of a 60-year-old man with lactic acidosis who was found to have a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Lactagenic cancers are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Warburg in 1923 that is correlated with cancer aggressiveness and poor survival. There is increased glucose utilization with the purpose of lactagenesis under fully oxygenated conditions, as lactate seems to be a potent signaling molecule for angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, which are five essential steps of carcinogenesis. Type B lactic acidosis in association with malignancies carries an extremely poor prognosis. Currently, effective chemotherapy seems to be the only hope for survival.
1 INTRODUCTION
A high arterial lactate level in critically ill patients has been associated with significant morbidity and mortality ever since the first description two centuries ago (Kompanje et al., 2007). Hyperlactatemia in the critically ill is the hallmark of shock states (Kraut & Madias, 2014; Levy, 2006; Nichol et al., 2010; Vincent & De Backer, 2013; Vincent et al., 2016), and the degree of increase in arterial lactate concentrations is directly related to the severity of the shock state (Haas et al., 2016; Nichol et al., 2011; Vincent et al., 2016). In this regard, the prognostic value of arterial lactate levels seems to be independent of the underlying critical illness (Jansen et al., 2010). Serial lactate measurements are widely used in intensive care medicine in the evaluation of the progression of a shock state and the response to intensive and urgent therapy (Levy et al., 2018; Vincent et al., 2016).
Although high lactate levels have been widely used as a marker of altered tissue perfusion in critically ill patients, this condition does not always simply reflect the development of anaerobic metabolism and cellular dysoxia better known as Type A lactic acidosis (Kraut & Madias, 2014; Vincent et al., 2016). While a lack of oxygen forbids the continuation of oxidative phosphorylation in the Krebs cycle, a normal oxygen supply does not impose a complete cessation of anaerobic metabolism. Type B lactic acidosis results from mechanisms other than dysoxia, including inborn errors of metabolism, drugs and toxins, systemic diseases (i.e., diabetes and sepsis), and less commonly malignancy. In this case report, we try to emphasize the pathophysiology leading to hyperlactatemia, and we will focus on the hyperlactatemia caused by lactagenic cancers and the Warburg effect.
2 CASE SUMMARY
A 60‐year‐old‐male patient presented at the emergency department with increasing abdominal girth, abdominal discomfort, severe asthenia, malaise, and profuse diaphoresis without fever. His medical history highlighted chronic renal failure (stage G3bA1) and a cardiac transplant 4 years ago due to terminal ischemic cardiomyopathy. His recent cardiac biopsy was free from any signs of rejection. He was taking immunosuppression with cyclosporine and mycophenolic acid. On admission, the clinical examination revealed a tense and distended abdomen with abdominal ascites. Initial vital signs were stable except for tachycardia at 110 beat per minute. The respiratory rate was 22 breath per minute, and the temperature was within the normal range. Physical exam was otherwise normal.
Laboratory analysis showed leukocytosis with a left shift, signs of hepatocellular injury without cholestasis, and chronic renal failure. His white blood count count was 14.8 G/L, C‐reactive protein was 45 mg/L (normal <10 mg/L), aspartate aminotransferase (AST) was 144 IU/L (normal, 14–50 IU/L), alanine aminotransferase (ALT) was 79 IU/L (normal, 12–50 IU/L), lactate dehydrogenase (LDH) was 1082 IU/L (normal, 87–210 IU/L), total bilirubin was 4 μmol/L (normal, 7–25 μmol/L), alkaline phosphatase was 82 IU/L (normal, 25–102 IU/L), gamma‐glutamyl transferase was 41 IU/L (normal, 9–40 IU/L), creatinine was 198 µmol/L (normal, 62–106 µmol/L), with an estimated glomerular filtration rate of 31 ml/min/1.73 m2. An ultrasound assessment confirmed the presence of moderate ascites in all four abdominal quadrants. Ascites liquid puncture showed leukocytosis, but the liquid culture remained sterile. Abdominal CT was then performed following a rapid clinical deterioration for abdominal sepsis, showing signs of diffuse peritonitis with a pelvic abscess located adjacent to the small intestine. The patient was therefore immediately started on broad‐spectrum antibiotics and antifungal treatment. In addition, a median laparotomy was performed to remove the pelvic abscess. The resected mass (suspect for any neoplasm) was sent for an extemporaneous analysis that elicited a high‐grade lymphoma. Later pathology testing confirmed a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Following emergency department admission and immediate surgery, the patient was admitted to the intensive care unit for high anion gap lactic acidosis, with a pH of 7.29 and a lactate level of 7.4 mmol/L on the arterial blood gas analysis. However, the patient's vital signs remained stable, and he could be extubated on the same day. Signs of hypoxia or circulatory failure were absent, capillary refill time was within normal limits and there was no skin mottling. Moreover, lactate/pyruvate ratio value was 19.0. In contrast, he simultaneously developed profuse hypoglycemia necessitating continuous high‐dose intravenous glucose supplementation. Cardiac output measured with bedside echocardiography appeared to be within the normal ranges. A new postoperative abdominal CT angiography was performed to exclude abdominal ischemia. The lactic acidosis (mean pH 7.3) remained for several days with lactate levels fluctuating around approximately 7 mmol/L. A concomitant thiamine deficiency was excluded by intravenous supplementation. Lactic acidosis started to decrease once chemotherapy with cyclophosphamide and vincristine, initiated 5 days after surgical resection, began to have an effect.
The interpretation of an initial positron emission tomography–computed tomography (PET‐CT) (Figures 1, 2, 3) 6 days after surgery was not clear due to the difficult differentiation between an infectious versus an oncological process. In addition to diffuse hypermetabolism in the peritoneal cavity associated with retroperitoneal adenopathies, it revealed supradiaphragmatic invasion of the lymphoma with a mass located in the right cardiophrenic recess, left mammary adenopathies, and pleural and pericardial nodules. There were also two hypermetabolic, osseous spots, suspected of metastasis, one in the second cervical vertebrae and one in the left scapula.
FIGURE 1 Left: Transversal image from patient's abdominal positron emission tomography–computed tomography (PET‐CT) post tumoral resection revealing diffuse peritoneal hypermetabolism with difficult differentiation between an infectious versus an oncological process. Middle: Transversal image from patients thoracic PET‐CT revealing supradiafragmatic invasion of the lymphoma with a mass and a nodule located in the right cardiophrenic recess with diffuse bilateral pleural nodular thickening. Right: Transversal image from patient's abdominal PET‐CT showing retroperitoneal adenopathies.
FIGURE 2 Lactate production and destination. Glycolysis takes place in the cellular cytosol. The preparatory phase consists of the generation of 1–3 diphosphoglycerate by hekoxinase and phosphofructokinase (PFK), the rate‐limiting enzyme. The pay off phase consists of the generation of pyruvate by pyruvate kinase. Pyruvate can be reduced to lactate by lactate dehydrogenase (LDH) or it can be converted to acetyl‐Co A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. Pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by alanine aminotransferase, resulting in the formation of alanine. Lactate either locally formed after reduction of pyruvate or coming from a distant source, can be consumed in the mitochondria by reformation of pyruvate by mitochondrial lactate dehydrogenase (mLDH) after diffusion across membranes via monocarboxylate transporters (MCTs). This concept is better known as the cell‐to‐cell lactate shuttle.
FIGURE 3 Lactate/pyruvate ratio. In aerobic glycolysis, the physiologic ratio of lactate/pyruvate is approximately 10 and is warranted by lactate dehydrogenase (LDH) catalyzing the reduction of pyruvate in lactate. When there is any perturbation of tissular oxygenation, cellular oxygenation is inhibited causing and acceleration of the reduction in pyruvate into lactate by LDH which results in a pathological lactate/pyruvate ratio above 10. The inhibition of the oxidative phosphorylation avoids any proton recycling leading to high anion gap lactic acidosis. Lactate is mostly converted into glucose through neoglucogenesis in the Cori cycle taking place in the liver and the kidneys. In case of insufficient hepatic perfusion or hepatic failure, lactate will be less cleared causing a variable lactate/pyruvate ratio depending on the source of production of lactate. Protons, normally recycled in the Cori cycle, will accumulate causing acidosis. MTC, monocarboxylate transporter.
He underwent intensive inpatient chemotherapy with one cycle of R‐CHP and six cycles of R‐CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride, O = vincristine sulfate, P = prednisone) and 10 prophylactic intrathecal injections of methotrexate. Chemotherapy was complicated with multiple episodes of febrile agranulocytosis, anemia and thrombocytopenia, which resolved after treatment with antibiotics in combination with filgrastim and multiple transfusions. The patient could be discharged with closed outpatient follow‐up after 5 months of admission. A PET‐CT was carried out 2 months after discharge and showed complete regression of all the lesions. A thoraco‐abdominal CT performed 1 year after the diagnosis seemed to be completely normal.
3 DISCUSSION
3.1 Lactate homeostasis
As with the blood levels of any substance, elevated lactate levels can be the result of increased production or reduced clearance, or both. Under physiological conditions, 1500 mmol of lactate or 20 mmol/kg of body weight is produced daily from various organs, including the muscle, intestine, red blood cells, brain, and skin (Kraut & Madias, 2014). Lactate is metabolized by the liver (60%), kidneys (30%), and other organs. The normal arterial blood lactate level is approximately 1 mmol/L (Kraut & Madias, 2014; Vincent et al., 2016).
3.2 Lactate production
Lactate formation is closely related to glycolysis. Glycolysis takes place in ten steps, five of which are in the preparatory phase and five in the payoff phase. Phosphofructokinase (PFK) is the rate‐limiting enzyme. Two net ATP molecules are generated by phosphorylation by high‐energy compounds. The final product of glycolysis is pyruvate and lactate, to which pyruvate can be reduced. LDH catalyzes the reduction of pyruvate into lactate at a well‐defined rate so that in normal homeostasis, the physiological ratio of lactate/pyruvate is approximately 10. In the presence of oxygen, pyruvate can be converted into acetyl‐coenzyme A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. This respiratory chain of reactions results in a net production of 36 ATP molecules per molecule of glucose. The metabolic yield of glycolysis when participating in the aerobic metabolic pathway (i.e., along with the Krebs cycle and oxidative phosphorylation) is superior to fermentation (without O2) into lactate (38 vs. 2 molecules of ATP). Anaerobic fermentation into lactate may be inefficient compared to oxidative phosphorylation, however, the rate of glucose metabolism into lactate is 10–100 times faster than the complete oxidation of glucose in the mitochondria (Liberti & Locasale, 2016). In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is utilized (Liberti & Locasale, 2016). In addition to the better‐known reduction to lactate and the oxidation to acetyl‐coenzyme A, for the completeness of this review, we need to mention that pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by ALT, resulting in the formation of alanine (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
Experiments by Pasteur (Platt, 1988), Meyerhof (1927), and A.V. Hill (Bassett, 2002) led to the widespread understanding of the glycolytic pathway and the notion that only a limitation of oxygen availability leads to fermentation and lactate accumulation. Out of this early work came the idea that lactate is just an anaerobic waste product that must be cleared from the muscles and blood, preferably by being converted to glucose in the liver via the Cori cycle. However, it has been demonstrated that lactate is a potent fuel and signaling molecule and is constantly being produced and circulated throughout the body, even and most often when there is adequate oxygen. Lactate is more than just a “hypoxic waste product.” Lactate as a result of dysoxia is often the exception rather than the rule, even in critically ill patients (Goodwin et al., 2014).
3.3 Lactate metabolism
Any time glycolysis is active, lactate is formed and equilibrates with local lactate gradients. Lactate equilibrates mainly by diffusing across membranes via monocarboxylate transporters (MCTs). In lactate‐producing tissues, this means exporting lactate into the circulation where both local and distant tissues can take it up and use it.
Lactate is metabolized by the liver (60%), kidneys (30%) and other organs. Lactate can be used for gluconeogenesis by reformation of pyruvate and glucose in the Cori cycle, which takes place in the liver and kidneys. In addition, lactate can readily replace glucose as a fuel for almost all cells of the body (any cell with mitochondria) by reformation and subsequent oxidation of pyruvate in the mitochondria. Lactate clearance occurs in the heart, liver, skeletal muscle and even brain. This observation that lactate is constantly being produced and consumed formed the basis of the cell‐to‐cell lactate shuttle, an energy exchange hypothesis originally introduced by Brooks in 1984 (Brooks, 1986). Lactate seems to be a key intermediate metabolite in whole body metabolism (Ben‐Hamouda et al., 2013; Goodwin et al., 2014; Kraut & Madias, 2014).
3.4 Hyperlactatemia (Table 1)
3.4.1 Elevated production of lactate
As mentioned earlier, normal lactate production is approximately 1 mmol/min or 1500 mmol/24 h, and the normal lactate level is approximately 1 mmol/L (Ben‐Hamouda et al., 2013; Vincent et al., 2016). Elevated lactate production can be the consequence of either an elevated pyruvate concentration (as seen in accelerated glycolysis, in elevated protein catabolism or through inhibition of PDH) or cellular dysoxia. Dysoxic lactic acidosis is better known as type‐A lactic acidosis, and all other nondysoxic causes of lactic acidosis are classified as type B according to the classification of Woods and Cohen (Ben‐Hamouda et al., 2013). Indeed, if lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics (i.e. normal blood pressure, normal volemia, normal blood oxygen, and oxygen‐carrying capacity), it is traditionally termed Type B lactic acidosis. In the present setting, the physiologic ratio value of lactate/pyruvate is around 10 or higher.
TABLE 1 Classification of hyperlactatemia according to Woods and Cohen
Type A: Hyperlactatemia associated with cellular dysoxia due to insufficient oxygen supply
Stagnant dysoxia Low cardiac output
Redistribution of cardiac output at the expense of certain tissues
Vascular occlusion
Dysoxia caused by elevated demand of oxygen Convulsions
Intensive exercise
Dysoxia caused by low oxygen carrying capacity Anemic dysoxia
Carbon monoxide intoxication
Hypoxic dysoxia (low PaO2)
Cytotoxic dysoxia due to inefficient mitochondrial consumption of oxygen Sepsis
Cyanide intoxication
Type B1: Hyperlactatemia due to an underlying disease
Accelerated glycolysis Hyperglycemia
Sepsis
Endogenous catecholamines
Lactagenic cancer
Elevated protein catabolism Burn victims
Severe septic shock
Acquired inhibition of pyruvate dehydrogenase (PDH) Sepsis
Thiamine deficiency
Lactagenic cancer
Reduced lactate clearance Reduced liver blood flow
Hepatic failure
Type B2: Hyperlactatemia due to drugs and toxins
Exogenous catecholamines (adrenaline, dobutamine, terbutaline) Cocaine, metamphetamines
Propofol Salicylates
Metformine Antiretroviral drugs
Linezolid Toxic alcohols (ethanol, methanol, propylene glycol, ethylene glycol)
Paracetamol
Type B3: Hyperlactatemia due to inborn errors of metabolism (enzymatic deficiencies)
Congenital PDH deficiency
Glucose‐6‐phosphatase deficiency (von Gierke disease)
Pyruvate carboxylase deficiency
Methylmalonic aciduria
Mitochondrial encephalomyopathies
John Wiley & Sons, LtdAccelerated glycolysis
Any cause of an accelerated level of glycolysis causes an expected elevation of pyruvate and thus of lactate, as the physiologic ratio of lactate/pyruvate of approximately 10 or higher is always warranted by LDH. Accelerated glycolysis is the case in hyperglycemia, sepsis, or other situations with elevated endogenous or exogenous catecholamines (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014). Finally, accelerated aerobic glycolysis may partially explain the hyperlactatemia caused by tumoral cells of lactagenic cancers, known as the Warburg effect (San‐Millán & Brooks, 2017), the cause of lactic acidosis in the present case.
Elevated protein catabolism
Elevated protein catabolism can also cause a rise in pyruvate levels. As mentioned earlier, pyruvate can be transaminated into alanine, and the reverse can be witnessed through the activity of the ALT enzyme, forming pyruvate in the liver. This mechanism contributes to hepatic neoglucogenesis. Accelerated protein catabolism is seen as muscle wasting, present in many critically ill patients, most severely in burn victims and in patients with severe septic shock. The elevated alanine supply in the liver contributes to the elevated pyruvate concentration and, ultimately, to hyperlactatemia, as the physiologic lactate/pyruvate ratio is always warranted by LDH (Ben‐Hamouda et al., 2013).
Inhibition of PDH
As discussed earlier, pyruvate is oxidized into acetyl‐coenzyme‐A by PDH. A congenital or an acquired reduction in the enzymatic activity of PDH can cause an accumulation of pyruvate and therefore of lactate. An acquired reduction in PDH can be caused by certain endotoxins and inflammatory cytokines in sepsis. This explains why hemodynamically stable patients with sepsis and normal liver function may have lactic acidosis (Kraut & Madias, 2014). It can also be caused by nucleoside reverse transcriptase inhibitors used to treat patients with HIV or by a thiamine deficiency, as in patients receiving parenteral nutrition or with severe Beri‐beri. Thiamine is an important cofactor in the PDH complex. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead, conversion into lactate takes place (Friedenberg et al., 2007). Finally, certain oncogenes express PDH kinase, which inactivates PDH and inhibits the Krebs cycle (San‐Millán & Brooks, 2017; Swenson, 2016) and partially explains the development of hyperlactatemia caused by tumoral cells.
Cellular dysoxia
Perturbations of tissular oxygenation, termed “cellular dysoxia”, are caused by insufficient oxygen supply. This dysoxia can be either generalized due to a low cardiac output, carbon monoxide intoxication, profound arterial hemoglobin desaturation, and reduced oxygen content or either localized in the context of redistribution of the cardiac output at the expense of certain tissues or due to a vascular occlusion (Swenson, 2016). It can also be caused by mitochondrial enzyme defects and by inhibitors of aerobic metabolism, such as cyanide. Every drop in cellular oxygenation causes an acceleration of the reduction in pyruvate to lactate by LDH, which results in a pathological augmentation of the lactate/pyruvate ratio above 10 (Ben‐Hamouda et al., 2013). Even if the pyruvate dosage is expensive, its use and the finding of a pathological L/P level confirm cellular dysoxia and excludes other causes.
3.4.2 Reduced lactate clearance
Lactate is partly transported to the liver and the kidneys and converted to glucose through gluconeogenesis (the Cori cycle). The hepatic clearance of lactate thus depends on hepatic extraction and hepatic functioning. Hepatic extraction is determined by the liver blood flow, which needs no less than one‐fourth of its normal flow. The capture of lactate by hepatocytes depends on its transportation by a family of MCTs with different isoforms (MCT1‐4). Thus, neoglucogenesis will depend on hepatic functioning. Its activity is decreased in hepatic failure and inhibited in shock states and severe acidosis (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
3.5 Distinction between hyperlactatemia and lactic acidosis
Hyperlactatemia and lactic acidosis are frequently mixed, which may cause confusion. However, the two are governed by a different concept. Glycolysis causes lactate formation without lactic acidosis when there is no net H+ production. The H+ protons may arise following ATP hydrolyzation and are produced through glycolysis. However, those protons are recycled by lactate consumption either through the Krebs cycle or through the hepatic Cori cycle, hence maintaining the internal acid‐base balance (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
In this regard, acquired or congenital inhibition of PDH, inhibition of oxidative phosphorylation due to cellular dysoxia, medication or intoxication and hepatic insufficiency are all causes of reduced proton recycling in either the Krebs or the Cori cycle, therefore causing high anion gap lactic acidosis. Other causes of hyperlactatemia, such as elevated glycolysis in hyperglycemia, arising from beta‐adrenergic stimulation or muscular catabolism, will only cause an elevated production of lactate without proton recycling impairment and without ensuing concomitant lactic acidosis (Kraut & Madias, 2014).
3.6 Lactagenic cancers
3.6.1 Warburg effect
In glycolytic tumors, lactate levels of cancer cells are markedly elevated up to 40‐fold and are highly associated with cancer aggressiveness and poor survival (Brizel et al., 2001; San‐Millán & Brooks, 2017). In fast‐growing malignancies, the rate of tumor metabolism may be great enough to exceed normal muscle and liver lactate clearance and cause systemic type B lactic acidosis (Sillos et al., 2001; Swenson, 2016). The majority of lactic acidosis in malignancies is reported in cases of hematologic malignancies. Only a few cases have been reported for solid tumors presenting with lactic acidosis (Nair & Shah, 2017).
In 1923, Warburg observed in his Nobel Prize winning studies that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions and that tumor cells live and grow in a more acidic milieu as a result of increased lactic acid production not generally tolerated by normal cells (San‐Millán & Brooks, 2017; Swenson, 2016). His discovery was named the “Warburg effect” by Racker in 1972 (San‐Millán & Brooks, 2017). The Warburg effect is a hallmark of cancer, and its significance is still apparent in the common cancer diagnostic test using fluorodeoxyglucose positron emission tomography, which has a high diagnostic accuracy (Potter et al., 2016).
From a contemporary perspective of cell metabolic efficiency, it seems difficult to understand why, despite fully aerobic conditions, cancer cells choose an inefficient pathway producing two ATP molecules per molecule of glucose instead of 38 via coupled mitochondrial respiration. However, as mentioned earlier, the amount of ATP synthesized over any given period of time is comparable in both ways of glucose metabolism because fermentation into lactate is 10–100 times faster than the completion of oxidative phosphorylation (Liberti & Locasale, 2016). Moreover, the stress of lactate production is simply passed on to the host. Then, the cancer cells proliferate, and the tumor grows and metastasizes because of host exploitation, ending in final host expiration (San‐Millán & Brooks, 2017).
3.6.2 Origin of tumoral lactagenesis
Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous and unstoppable glucose utilization to produce lactate involving five major steps: (i) an increase in glucose uptake; (ii) upregulation of PFK, the rate‐limiting enzyme of glycolysis; (iii) a decrease in mitochondrial respiration by upregulation of PDH kinase (PDK) that inhibits pyruvate uptake in mitochondria; (iv) increased lactate production by LDH upregulation; and (v) upregulation of MCT1 and MCT4 expression, the transmembrane transporters of lactate, for higher lactate plus H+ efflux and further lactate shuttling, thus mediating tumor growth and proliferation (Brahimi‐Horn et al., 2011; San‐Millán & Brooks, 2017; Swenson, 2016).
In our case, the Warburg effect was caused by a Burkitt lymphoma, a B‐cell derived malignancy. The main characteristic of a Burkitt lymphoma is an increased production of the MYC oncoprotein caused by chromosomal rearrangements. This translocation results in inappropriately high expression levels of MYC, which gives cells proliferative capacity. Moreover, MYC also activates the transcription of genes encoding glucose transporter, hexokinase, MCT, PDK, PK (pyruvate kinase), and LDH, resulting in the accelerated aerobic glycolysis or the Warburg effect. The MYC protein is the master regulator of the Warburg effect in BL cells (Mushtaq et al., 2015).
3.6.3 Aim of tumoral lactagenesis
The role of the Warburg effect in the pathogenesis of cancer has not yet been completely established. Lactate is the end product of the Warburg effect, but lactate production or lactagenesis is probably the purpose of the Warburg effect as well.
In addition to being a potent oxidative fuel, lactate is also a potent signaling molecule necessary for all the major steps in carcinogenesis, as follows: (i) angiogenesis, (ii) cell migration, (iii) metastasis, (iv) immune escape, and (v) self‐sufficiency of cancer cells (San‐Millán & Brooks, 2017).
Lactate released from tumor cells by MCT4 plays a role in stimulating angiogenesis (i) by increasing the expression of vascular endothelial growth factor protein in endothelial cells (Goodwin et al., 2014; San‐Millán & Brooks, 2017). Cell migration (ii) is another essential step in carcinogenesis and metastasis in which lactate seems to be a key element to increase cell migration. Marked extracellular acidosis appears to promote the migration and metastasis (iii) of cancer cells by disrupting normal cell‐matrix interactions that act to maintain stable growth patterns (Swenson, 2016). Lactate levels are highly associated with a high incidence of distant metastasis. Acidosis reduces host defense against malignant cells and contributes to immune escape (iv) in many different ways: first, by inhibiting the release of the cytokines tumor necrosis factor and interleukin‐6; and second, by inhibiting the activation of T‐cells with a decrease in the cytotoxic activity of T‐cells and inhibition of natural killer cell functioning. Lactate also plays a central role in the self‐sufficiency and sustainability (v) of cancer cells. Cancer cells at the hypoxic core might use glucose and produce lactate, whereas cells on the periphery, close to a robust vascular supply, might take up this lactate and oxidize it as a fuel. The self‐sufficiency depending upon high glycolytic flux also allows cancer cells to produce lactate for carcinogenesis by angiogenesis, immune escape, cell migration, and metastasis. A glucose to lactate shunt occurs in which the host bears the burden of providing a limitless glucose supply as well as a sink for disposal of lactate and hydrogen ions. This may even explain why the actual cause of cachexia and death due to cancer appears to be multifactorial, with organ failure rather than the tumor itself (San‐Millán & Brooks, 2017).
3.6.4 Targeting lactate production and shuttling: Future direction in cancer treatment
Given the profound changes in acid‐base balance in tumors and the role of pH in tumor survival and growth, altering the acid‐base milieu has presented itself as an interesting approach for treating cancer (Swenson, 2016), but the development of these new adjuvant therapies goes way beyond the scope of this article. Nevertheless, after explaining all the pathophysiology, it seems important to shed light on some future possible treatments: on the one hand, medication increasing PDH activity, such as dichloroacetate, seems to halt carcinogenesis by lowering cytosolic lactate production; on the other hand, MCT1 and MCT4 inhibitors seem to have enormous potential in cancer treatment by inhibiting lactate shuttling, even if there is still a lack of specificity (San‐Millán & Brooks, 2017). Furthermore, simpler approaches such as aerobic exercise seem to have beneficial effects by augmenting mitochondrial size and function and thus lactate clearance capacity. Further research is necessary to identify possible targets and create tumor‐specific treatments.
3.6.5 Treatment options in patients with type‐B LA due to malignancies
Lactic acidosis in association with malignancies carries an extremely poor prognosis with a mortality rate over 90% (Nair & Shah, 2017; Sillos et al., 2001). Moreover, the high mortality associated with lactic acidosis has prompted some oncologists to consider this an oncological emergency (Nair & Shah, 2017). The best treatment for patients with hematologic malignancies who develop type B lactic acidosis is not yet clear.
Chemotherapy
Initiating aggressive chemotherapy has been effective in correcting acute acidosis (Friedenberg et al., 2007). It is actually the only treatment modality that consistently leads to remission. Resolution of lactic acidosis was reported to occur as early as 15 h and up to 3 days after starting chemotherapy. This treatment would not be effective in patients whose tumors are unresponsive to chemotherapy. Lactic acidosis improves with chemotherapy, and resolution of the lactic acidosis could be a surrogate marker of inducing remission (Chan et al., 2009).
Intravenous bicarbonate
The use of IV bicarbonate as a treatment for profound acidosis has never shown a meaningful clinical benefit, even in the worst cases (Swenson, 2016). As severe acidosis can cause respiratory fatigue and hemodynamic instability, intravenous bicarbonate is often used to attenuate systemic acidosis and increase the responsiveness to catecholamines. However, it would appear that the benefits of sodium bicarbonate are outweighed by its disadvantages, such as hypernatremia and hyperosmolality (Swenson, 2016). Acidemia leads to unloading oxygen from hemoglobin by shifting the hemoglobin‐oxygen dissociation curve to the right, and reducing acidosis will hinder oxygen release. Studies have shown that intracellular acidosis tends to slow lactate production (Madias, 1986; Sillos et al., 2001). Alkalinization has been shown to potentiate lactate production in patients with malignancy‐induced chronic lactic acidosis (Fields et al., 1981; Fraley et al., 1980). The effect of IV bicarbonate on mortality or lactate concentration in the setting of malignancy‐induced type B lactic acidosis has not been studied directly, as the incidence is very low. In a case report by Fraley et al. (1980), administration of bicarbonate improved pH but not the serum bicarbonate level. Intravenous bicarbonate corrected the extracellular pH but did not affect the significant intracellular acid production due to high tumor cell turnover. The use of sodium bicarbonate may not be recommended in these patient groups.
Renal replacement therapy
Renal replacement therapy, continuous or intermittent, in patients with renal dysfunction may be useful in addition to chemotherapy to correct metabolic acidosis. Here, once again, since the prognosis of type B lactic acidosis related to malignancies is grim, the only chance for remission is starting cytoreductive chemotherapy. Intravenous bicarbonate and hemodialysis will no longer act as a bridge to stabilize the patient enough so that the underlying cause can be treated (Chan et al., 2009).
Intravenous insulin
Lactic acidosis has also been treated with intravenous administration of insulin, which increases the conversion of pyruvate to acetyl‐coenzyme A and consequently facilitates oxidation of lactate to pyruvate (Sillos et al., 2001). Administration of glucose can actually induce lactic acidosis by increasing the availability of glucose and thus increasing the production of lactate by the tumor. Returning to the case presented in this manuscript, the patient was severely hypoglycemic, which is the reason why we substituted for intravenous glucose to maintain the patient's euglycemia. However, in a provocative hypothesis in 2009, Nijsten & van Dam (2009) presented a hypothetical treatment whereby glucose might be systemically lowered. If tumors are glucose consumers and lactate producers and all other tissues in the body can actively take up and use lactate as a fuel, why not systemically induce hypoglycemia to starve tumor cells? In this configuration, lactate would provide salvage fuel for the other tissues (Goodwin et al., 2014). Work to investigate this concept should be pursued.
4 CONCLUSION
Lactic acidosis is a commonly encountered problem in intensive care units and is most commonly associated with dysoxia, better known as type A lactic acidosis. Type B is more uncommon and can be life‐threatening and sometimes even a lethal complication in patients with malignancies. Due to its rareness, it is likely to be under recognized and therefore underdiagnosed. If oncological patients develop high anion gap lactic acidosis without hemodynamic compromise associated with acute respiratory distress without a pulmonary source, the possibility for tumor‐induced type B lactic acidosis through the “Warburg effect” should be considered. Awareness about this condition is important in the clinical practice of intensive care physicians since it will allow a timely diagnosis and the implementation of subsequent therapy. Currently, effective chemotherapy seems to be the only hope for survival.
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
Carole Looyens, and Karim Bendjelid designed the present review. Carole Looyens, and Karim Bendjelid analyzed data and references. Carole Looyens, Raphael Giraud, Ivo Neto Silva, and Karim Bendjelid wrote the manuscript. All authors read and approved the final manuscript.
DATA AVAILABILITY STATEMENT
The data that support these findings are available upon reasonable request from the corresponding author. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33611854 | 19,181,715 | 2021-02 |
What was the administration route of drug 'METHOTREXATE SODIUM'? | Burkitt lymphoma and lactic acidosis: A case report and review of the literature.
Type A lactic acidosis is a potentially life-threatening complication in critically ill patients and is the hallmark of a shock state as a result of tissue hypoperfusion and dysoxia. Type B lactic acidosis results from mechanisms other than dysoxia and is a rare condition in patients with solid tumors or hematological malignancies. We present a case of a 60-year-old man with lactic acidosis who was found to have a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Lactagenic cancers are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Warburg in 1923 that is correlated with cancer aggressiveness and poor survival. There is increased glucose utilization with the purpose of lactagenesis under fully oxygenated conditions, as lactate seems to be a potent signaling molecule for angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, which are five essential steps of carcinogenesis. Type B lactic acidosis in association with malignancies carries an extremely poor prognosis. Currently, effective chemotherapy seems to be the only hope for survival.
1 INTRODUCTION
A high arterial lactate level in critically ill patients has been associated with significant morbidity and mortality ever since the first description two centuries ago (Kompanje et al., 2007). Hyperlactatemia in the critically ill is the hallmark of shock states (Kraut & Madias, 2014; Levy, 2006; Nichol et al., 2010; Vincent & De Backer, 2013; Vincent et al., 2016), and the degree of increase in arterial lactate concentrations is directly related to the severity of the shock state (Haas et al., 2016; Nichol et al., 2011; Vincent et al., 2016). In this regard, the prognostic value of arterial lactate levels seems to be independent of the underlying critical illness (Jansen et al., 2010). Serial lactate measurements are widely used in intensive care medicine in the evaluation of the progression of a shock state and the response to intensive and urgent therapy (Levy et al., 2018; Vincent et al., 2016).
Although high lactate levels have been widely used as a marker of altered tissue perfusion in critically ill patients, this condition does not always simply reflect the development of anaerobic metabolism and cellular dysoxia better known as Type A lactic acidosis (Kraut & Madias, 2014; Vincent et al., 2016). While a lack of oxygen forbids the continuation of oxidative phosphorylation in the Krebs cycle, a normal oxygen supply does not impose a complete cessation of anaerobic metabolism. Type B lactic acidosis results from mechanisms other than dysoxia, including inborn errors of metabolism, drugs and toxins, systemic diseases (i.e., diabetes and sepsis), and less commonly malignancy. In this case report, we try to emphasize the pathophysiology leading to hyperlactatemia, and we will focus on the hyperlactatemia caused by lactagenic cancers and the Warburg effect.
2 CASE SUMMARY
A 60‐year‐old‐male patient presented at the emergency department with increasing abdominal girth, abdominal discomfort, severe asthenia, malaise, and profuse diaphoresis without fever. His medical history highlighted chronic renal failure (stage G3bA1) and a cardiac transplant 4 years ago due to terminal ischemic cardiomyopathy. His recent cardiac biopsy was free from any signs of rejection. He was taking immunosuppression with cyclosporine and mycophenolic acid. On admission, the clinical examination revealed a tense and distended abdomen with abdominal ascites. Initial vital signs were stable except for tachycardia at 110 beat per minute. The respiratory rate was 22 breath per minute, and the temperature was within the normal range. Physical exam was otherwise normal.
Laboratory analysis showed leukocytosis with a left shift, signs of hepatocellular injury without cholestasis, and chronic renal failure. His white blood count count was 14.8 G/L, C‐reactive protein was 45 mg/L (normal <10 mg/L), aspartate aminotransferase (AST) was 144 IU/L (normal, 14–50 IU/L), alanine aminotransferase (ALT) was 79 IU/L (normal, 12–50 IU/L), lactate dehydrogenase (LDH) was 1082 IU/L (normal, 87–210 IU/L), total bilirubin was 4 μmol/L (normal, 7–25 μmol/L), alkaline phosphatase was 82 IU/L (normal, 25–102 IU/L), gamma‐glutamyl transferase was 41 IU/L (normal, 9–40 IU/L), creatinine was 198 µmol/L (normal, 62–106 µmol/L), with an estimated glomerular filtration rate of 31 ml/min/1.73 m2. An ultrasound assessment confirmed the presence of moderate ascites in all four abdominal quadrants. Ascites liquid puncture showed leukocytosis, but the liquid culture remained sterile. Abdominal CT was then performed following a rapid clinical deterioration for abdominal sepsis, showing signs of diffuse peritonitis with a pelvic abscess located adjacent to the small intestine. The patient was therefore immediately started on broad‐spectrum antibiotics and antifungal treatment. In addition, a median laparotomy was performed to remove the pelvic abscess. The resected mass (suspect for any neoplasm) was sent for an extemporaneous analysis that elicited a high‐grade lymphoma. Later pathology testing confirmed a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Following emergency department admission and immediate surgery, the patient was admitted to the intensive care unit for high anion gap lactic acidosis, with a pH of 7.29 and a lactate level of 7.4 mmol/L on the arterial blood gas analysis. However, the patient's vital signs remained stable, and he could be extubated on the same day. Signs of hypoxia or circulatory failure were absent, capillary refill time was within normal limits and there was no skin mottling. Moreover, lactate/pyruvate ratio value was 19.0. In contrast, he simultaneously developed profuse hypoglycemia necessitating continuous high‐dose intravenous glucose supplementation. Cardiac output measured with bedside echocardiography appeared to be within the normal ranges. A new postoperative abdominal CT angiography was performed to exclude abdominal ischemia. The lactic acidosis (mean pH 7.3) remained for several days with lactate levels fluctuating around approximately 7 mmol/L. A concomitant thiamine deficiency was excluded by intravenous supplementation. Lactic acidosis started to decrease once chemotherapy with cyclophosphamide and vincristine, initiated 5 days after surgical resection, began to have an effect.
The interpretation of an initial positron emission tomography–computed tomography (PET‐CT) (Figures 1, 2, 3) 6 days after surgery was not clear due to the difficult differentiation between an infectious versus an oncological process. In addition to diffuse hypermetabolism in the peritoneal cavity associated with retroperitoneal adenopathies, it revealed supradiaphragmatic invasion of the lymphoma with a mass located in the right cardiophrenic recess, left mammary adenopathies, and pleural and pericardial nodules. There were also two hypermetabolic, osseous spots, suspected of metastasis, one in the second cervical vertebrae and one in the left scapula.
FIGURE 1 Left: Transversal image from patient's abdominal positron emission tomography–computed tomography (PET‐CT) post tumoral resection revealing diffuse peritoneal hypermetabolism with difficult differentiation between an infectious versus an oncological process. Middle: Transversal image from patients thoracic PET‐CT revealing supradiafragmatic invasion of the lymphoma with a mass and a nodule located in the right cardiophrenic recess with diffuse bilateral pleural nodular thickening. Right: Transversal image from patient's abdominal PET‐CT showing retroperitoneal adenopathies.
FIGURE 2 Lactate production and destination. Glycolysis takes place in the cellular cytosol. The preparatory phase consists of the generation of 1–3 diphosphoglycerate by hekoxinase and phosphofructokinase (PFK), the rate‐limiting enzyme. The pay off phase consists of the generation of pyruvate by pyruvate kinase. Pyruvate can be reduced to lactate by lactate dehydrogenase (LDH) or it can be converted to acetyl‐Co A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. Pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by alanine aminotransferase, resulting in the formation of alanine. Lactate either locally formed after reduction of pyruvate or coming from a distant source, can be consumed in the mitochondria by reformation of pyruvate by mitochondrial lactate dehydrogenase (mLDH) after diffusion across membranes via monocarboxylate transporters (MCTs). This concept is better known as the cell‐to‐cell lactate shuttle.
FIGURE 3 Lactate/pyruvate ratio. In aerobic glycolysis, the physiologic ratio of lactate/pyruvate is approximately 10 and is warranted by lactate dehydrogenase (LDH) catalyzing the reduction of pyruvate in lactate. When there is any perturbation of tissular oxygenation, cellular oxygenation is inhibited causing and acceleration of the reduction in pyruvate into lactate by LDH which results in a pathological lactate/pyruvate ratio above 10. The inhibition of the oxidative phosphorylation avoids any proton recycling leading to high anion gap lactic acidosis. Lactate is mostly converted into glucose through neoglucogenesis in the Cori cycle taking place in the liver and the kidneys. In case of insufficient hepatic perfusion or hepatic failure, lactate will be less cleared causing a variable lactate/pyruvate ratio depending on the source of production of lactate. Protons, normally recycled in the Cori cycle, will accumulate causing acidosis. MTC, monocarboxylate transporter.
He underwent intensive inpatient chemotherapy with one cycle of R‐CHP and six cycles of R‐CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride, O = vincristine sulfate, P = prednisone) and 10 prophylactic intrathecal injections of methotrexate. Chemotherapy was complicated with multiple episodes of febrile agranulocytosis, anemia and thrombocytopenia, which resolved after treatment with antibiotics in combination with filgrastim and multiple transfusions. The patient could be discharged with closed outpatient follow‐up after 5 months of admission. A PET‐CT was carried out 2 months after discharge and showed complete regression of all the lesions. A thoraco‐abdominal CT performed 1 year after the diagnosis seemed to be completely normal.
3 DISCUSSION
3.1 Lactate homeostasis
As with the blood levels of any substance, elevated lactate levels can be the result of increased production or reduced clearance, or both. Under physiological conditions, 1500 mmol of lactate or 20 mmol/kg of body weight is produced daily from various organs, including the muscle, intestine, red blood cells, brain, and skin (Kraut & Madias, 2014). Lactate is metabolized by the liver (60%), kidneys (30%), and other organs. The normal arterial blood lactate level is approximately 1 mmol/L (Kraut & Madias, 2014; Vincent et al., 2016).
3.2 Lactate production
Lactate formation is closely related to glycolysis. Glycolysis takes place in ten steps, five of which are in the preparatory phase and five in the payoff phase. Phosphofructokinase (PFK) is the rate‐limiting enzyme. Two net ATP molecules are generated by phosphorylation by high‐energy compounds. The final product of glycolysis is pyruvate and lactate, to which pyruvate can be reduced. LDH catalyzes the reduction of pyruvate into lactate at a well‐defined rate so that in normal homeostasis, the physiological ratio of lactate/pyruvate is approximately 10. In the presence of oxygen, pyruvate can be converted into acetyl‐coenzyme A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. This respiratory chain of reactions results in a net production of 36 ATP molecules per molecule of glucose. The metabolic yield of glycolysis when participating in the aerobic metabolic pathway (i.e., along with the Krebs cycle and oxidative phosphorylation) is superior to fermentation (without O2) into lactate (38 vs. 2 molecules of ATP). Anaerobic fermentation into lactate may be inefficient compared to oxidative phosphorylation, however, the rate of glucose metabolism into lactate is 10–100 times faster than the complete oxidation of glucose in the mitochondria (Liberti & Locasale, 2016). In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is utilized (Liberti & Locasale, 2016). In addition to the better‐known reduction to lactate and the oxidation to acetyl‐coenzyme A, for the completeness of this review, we need to mention that pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by ALT, resulting in the formation of alanine (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
Experiments by Pasteur (Platt, 1988), Meyerhof (1927), and A.V. Hill (Bassett, 2002) led to the widespread understanding of the glycolytic pathway and the notion that only a limitation of oxygen availability leads to fermentation and lactate accumulation. Out of this early work came the idea that lactate is just an anaerobic waste product that must be cleared from the muscles and blood, preferably by being converted to glucose in the liver via the Cori cycle. However, it has been demonstrated that lactate is a potent fuel and signaling molecule and is constantly being produced and circulated throughout the body, even and most often when there is adequate oxygen. Lactate is more than just a “hypoxic waste product.” Lactate as a result of dysoxia is often the exception rather than the rule, even in critically ill patients (Goodwin et al., 2014).
3.3 Lactate metabolism
Any time glycolysis is active, lactate is formed and equilibrates with local lactate gradients. Lactate equilibrates mainly by diffusing across membranes via monocarboxylate transporters (MCTs). In lactate‐producing tissues, this means exporting lactate into the circulation where both local and distant tissues can take it up and use it.
Lactate is metabolized by the liver (60%), kidneys (30%) and other organs. Lactate can be used for gluconeogenesis by reformation of pyruvate and glucose in the Cori cycle, which takes place in the liver and kidneys. In addition, lactate can readily replace glucose as a fuel for almost all cells of the body (any cell with mitochondria) by reformation and subsequent oxidation of pyruvate in the mitochondria. Lactate clearance occurs in the heart, liver, skeletal muscle and even brain. This observation that lactate is constantly being produced and consumed formed the basis of the cell‐to‐cell lactate shuttle, an energy exchange hypothesis originally introduced by Brooks in 1984 (Brooks, 1986). Lactate seems to be a key intermediate metabolite in whole body metabolism (Ben‐Hamouda et al., 2013; Goodwin et al., 2014; Kraut & Madias, 2014).
3.4 Hyperlactatemia (Table 1)
3.4.1 Elevated production of lactate
As mentioned earlier, normal lactate production is approximately 1 mmol/min or 1500 mmol/24 h, and the normal lactate level is approximately 1 mmol/L (Ben‐Hamouda et al., 2013; Vincent et al., 2016). Elevated lactate production can be the consequence of either an elevated pyruvate concentration (as seen in accelerated glycolysis, in elevated protein catabolism or through inhibition of PDH) or cellular dysoxia. Dysoxic lactic acidosis is better known as type‐A lactic acidosis, and all other nondysoxic causes of lactic acidosis are classified as type B according to the classification of Woods and Cohen (Ben‐Hamouda et al., 2013). Indeed, if lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics (i.e. normal blood pressure, normal volemia, normal blood oxygen, and oxygen‐carrying capacity), it is traditionally termed Type B lactic acidosis. In the present setting, the physiologic ratio value of lactate/pyruvate is around 10 or higher.
TABLE 1 Classification of hyperlactatemia according to Woods and Cohen
Type A: Hyperlactatemia associated with cellular dysoxia due to insufficient oxygen supply
Stagnant dysoxia Low cardiac output
Redistribution of cardiac output at the expense of certain tissues
Vascular occlusion
Dysoxia caused by elevated demand of oxygen Convulsions
Intensive exercise
Dysoxia caused by low oxygen carrying capacity Anemic dysoxia
Carbon monoxide intoxication
Hypoxic dysoxia (low PaO2)
Cytotoxic dysoxia due to inefficient mitochondrial consumption of oxygen Sepsis
Cyanide intoxication
Type B1: Hyperlactatemia due to an underlying disease
Accelerated glycolysis Hyperglycemia
Sepsis
Endogenous catecholamines
Lactagenic cancer
Elevated protein catabolism Burn victims
Severe septic shock
Acquired inhibition of pyruvate dehydrogenase (PDH) Sepsis
Thiamine deficiency
Lactagenic cancer
Reduced lactate clearance Reduced liver blood flow
Hepatic failure
Type B2: Hyperlactatemia due to drugs and toxins
Exogenous catecholamines (adrenaline, dobutamine, terbutaline) Cocaine, metamphetamines
Propofol Salicylates
Metformine Antiretroviral drugs
Linezolid Toxic alcohols (ethanol, methanol, propylene glycol, ethylene glycol)
Paracetamol
Type B3: Hyperlactatemia due to inborn errors of metabolism (enzymatic deficiencies)
Congenital PDH deficiency
Glucose‐6‐phosphatase deficiency (von Gierke disease)
Pyruvate carboxylase deficiency
Methylmalonic aciduria
Mitochondrial encephalomyopathies
John Wiley & Sons, LtdAccelerated glycolysis
Any cause of an accelerated level of glycolysis causes an expected elevation of pyruvate and thus of lactate, as the physiologic ratio of lactate/pyruvate of approximately 10 or higher is always warranted by LDH. Accelerated glycolysis is the case in hyperglycemia, sepsis, or other situations with elevated endogenous or exogenous catecholamines (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014). Finally, accelerated aerobic glycolysis may partially explain the hyperlactatemia caused by tumoral cells of lactagenic cancers, known as the Warburg effect (San‐Millán & Brooks, 2017), the cause of lactic acidosis in the present case.
Elevated protein catabolism
Elevated protein catabolism can also cause a rise in pyruvate levels. As mentioned earlier, pyruvate can be transaminated into alanine, and the reverse can be witnessed through the activity of the ALT enzyme, forming pyruvate in the liver. This mechanism contributes to hepatic neoglucogenesis. Accelerated protein catabolism is seen as muscle wasting, present in many critically ill patients, most severely in burn victims and in patients with severe septic shock. The elevated alanine supply in the liver contributes to the elevated pyruvate concentration and, ultimately, to hyperlactatemia, as the physiologic lactate/pyruvate ratio is always warranted by LDH (Ben‐Hamouda et al., 2013).
Inhibition of PDH
As discussed earlier, pyruvate is oxidized into acetyl‐coenzyme‐A by PDH. A congenital or an acquired reduction in the enzymatic activity of PDH can cause an accumulation of pyruvate and therefore of lactate. An acquired reduction in PDH can be caused by certain endotoxins and inflammatory cytokines in sepsis. This explains why hemodynamically stable patients with sepsis and normal liver function may have lactic acidosis (Kraut & Madias, 2014). It can also be caused by nucleoside reverse transcriptase inhibitors used to treat patients with HIV or by a thiamine deficiency, as in patients receiving parenteral nutrition or with severe Beri‐beri. Thiamine is an important cofactor in the PDH complex. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead, conversion into lactate takes place (Friedenberg et al., 2007). Finally, certain oncogenes express PDH kinase, which inactivates PDH and inhibits the Krebs cycle (San‐Millán & Brooks, 2017; Swenson, 2016) and partially explains the development of hyperlactatemia caused by tumoral cells.
Cellular dysoxia
Perturbations of tissular oxygenation, termed “cellular dysoxia”, are caused by insufficient oxygen supply. This dysoxia can be either generalized due to a low cardiac output, carbon monoxide intoxication, profound arterial hemoglobin desaturation, and reduced oxygen content or either localized in the context of redistribution of the cardiac output at the expense of certain tissues or due to a vascular occlusion (Swenson, 2016). It can also be caused by mitochondrial enzyme defects and by inhibitors of aerobic metabolism, such as cyanide. Every drop in cellular oxygenation causes an acceleration of the reduction in pyruvate to lactate by LDH, which results in a pathological augmentation of the lactate/pyruvate ratio above 10 (Ben‐Hamouda et al., 2013). Even if the pyruvate dosage is expensive, its use and the finding of a pathological L/P level confirm cellular dysoxia and excludes other causes.
3.4.2 Reduced lactate clearance
Lactate is partly transported to the liver and the kidneys and converted to glucose through gluconeogenesis (the Cori cycle). The hepatic clearance of lactate thus depends on hepatic extraction and hepatic functioning. Hepatic extraction is determined by the liver blood flow, which needs no less than one‐fourth of its normal flow. The capture of lactate by hepatocytes depends on its transportation by a family of MCTs with different isoforms (MCT1‐4). Thus, neoglucogenesis will depend on hepatic functioning. Its activity is decreased in hepatic failure and inhibited in shock states and severe acidosis (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
3.5 Distinction between hyperlactatemia and lactic acidosis
Hyperlactatemia and lactic acidosis are frequently mixed, which may cause confusion. However, the two are governed by a different concept. Glycolysis causes lactate formation without lactic acidosis when there is no net H+ production. The H+ protons may arise following ATP hydrolyzation and are produced through glycolysis. However, those protons are recycled by lactate consumption either through the Krebs cycle or through the hepatic Cori cycle, hence maintaining the internal acid‐base balance (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
In this regard, acquired or congenital inhibition of PDH, inhibition of oxidative phosphorylation due to cellular dysoxia, medication or intoxication and hepatic insufficiency are all causes of reduced proton recycling in either the Krebs or the Cori cycle, therefore causing high anion gap lactic acidosis. Other causes of hyperlactatemia, such as elevated glycolysis in hyperglycemia, arising from beta‐adrenergic stimulation or muscular catabolism, will only cause an elevated production of lactate without proton recycling impairment and without ensuing concomitant lactic acidosis (Kraut & Madias, 2014).
3.6 Lactagenic cancers
3.6.1 Warburg effect
In glycolytic tumors, lactate levels of cancer cells are markedly elevated up to 40‐fold and are highly associated with cancer aggressiveness and poor survival (Brizel et al., 2001; San‐Millán & Brooks, 2017). In fast‐growing malignancies, the rate of tumor metabolism may be great enough to exceed normal muscle and liver lactate clearance and cause systemic type B lactic acidosis (Sillos et al., 2001; Swenson, 2016). The majority of lactic acidosis in malignancies is reported in cases of hematologic malignancies. Only a few cases have been reported for solid tumors presenting with lactic acidosis (Nair & Shah, 2017).
In 1923, Warburg observed in his Nobel Prize winning studies that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions and that tumor cells live and grow in a more acidic milieu as a result of increased lactic acid production not generally tolerated by normal cells (San‐Millán & Brooks, 2017; Swenson, 2016). His discovery was named the “Warburg effect” by Racker in 1972 (San‐Millán & Brooks, 2017). The Warburg effect is a hallmark of cancer, and its significance is still apparent in the common cancer diagnostic test using fluorodeoxyglucose positron emission tomography, which has a high diagnostic accuracy (Potter et al., 2016).
From a contemporary perspective of cell metabolic efficiency, it seems difficult to understand why, despite fully aerobic conditions, cancer cells choose an inefficient pathway producing two ATP molecules per molecule of glucose instead of 38 via coupled mitochondrial respiration. However, as mentioned earlier, the amount of ATP synthesized over any given period of time is comparable in both ways of glucose metabolism because fermentation into lactate is 10–100 times faster than the completion of oxidative phosphorylation (Liberti & Locasale, 2016). Moreover, the stress of lactate production is simply passed on to the host. Then, the cancer cells proliferate, and the tumor grows and metastasizes because of host exploitation, ending in final host expiration (San‐Millán & Brooks, 2017).
3.6.2 Origin of tumoral lactagenesis
Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous and unstoppable glucose utilization to produce lactate involving five major steps: (i) an increase in glucose uptake; (ii) upregulation of PFK, the rate‐limiting enzyme of glycolysis; (iii) a decrease in mitochondrial respiration by upregulation of PDH kinase (PDK) that inhibits pyruvate uptake in mitochondria; (iv) increased lactate production by LDH upregulation; and (v) upregulation of MCT1 and MCT4 expression, the transmembrane transporters of lactate, for higher lactate plus H+ efflux and further lactate shuttling, thus mediating tumor growth and proliferation (Brahimi‐Horn et al., 2011; San‐Millán & Brooks, 2017; Swenson, 2016).
In our case, the Warburg effect was caused by a Burkitt lymphoma, a B‐cell derived malignancy. The main characteristic of a Burkitt lymphoma is an increased production of the MYC oncoprotein caused by chromosomal rearrangements. This translocation results in inappropriately high expression levels of MYC, which gives cells proliferative capacity. Moreover, MYC also activates the transcription of genes encoding glucose transporter, hexokinase, MCT, PDK, PK (pyruvate kinase), and LDH, resulting in the accelerated aerobic glycolysis or the Warburg effect. The MYC protein is the master regulator of the Warburg effect in BL cells (Mushtaq et al., 2015).
3.6.3 Aim of tumoral lactagenesis
The role of the Warburg effect in the pathogenesis of cancer has not yet been completely established. Lactate is the end product of the Warburg effect, but lactate production or lactagenesis is probably the purpose of the Warburg effect as well.
In addition to being a potent oxidative fuel, lactate is also a potent signaling molecule necessary for all the major steps in carcinogenesis, as follows: (i) angiogenesis, (ii) cell migration, (iii) metastasis, (iv) immune escape, and (v) self‐sufficiency of cancer cells (San‐Millán & Brooks, 2017).
Lactate released from tumor cells by MCT4 plays a role in stimulating angiogenesis (i) by increasing the expression of vascular endothelial growth factor protein in endothelial cells (Goodwin et al., 2014; San‐Millán & Brooks, 2017). Cell migration (ii) is another essential step in carcinogenesis and metastasis in which lactate seems to be a key element to increase cell migration. Marked extracellular acidosis appears to promote the migration and metastasis (iii) of cancer cells by disrupting normal cell‐matrix interactions that act to maintain stable growth patterns (Swenson, 2016). Lactate levels are highly associated with a high incidence of distant metastasis. Acidosis reduces host defense against malignant cells and contributes to immune escape (iv) in many different ways: first, by inhibiting the release of the cytokines tumor necrosis factor and interleukin‐6; and second, by inhibiting the activation of T‐cells with a decrease in the cytotoxic activity of T‐cells and inhibition of natural killer cell functioning. Lactate also plays a central role in the self‐sufficiency and sustainability (v) of cancer cells. Cancer cells at the hypoxic core might use glucose and produce lactate, whereas cells on the periphery, close to a robust vascular supply, might take up this lactate and oxidize it as a fuel. The self‐sufficiency depending upon high glycolytic flux also allows cancer cells to produce lactate for carcinogenesis by angiogenesis, immune escape, cell migration, and metastasis. A glucose to lactate shunt occurs in which the host bears the burden of providing a limitless glucose supply as well as a sink for disposal of lactate and hydrogen ions. This may even explain why the actual cause of cachexia and death due to cancer appears to be multifactorial, with organ failure rather than the tumor itself (San‐Millán & Brooks, 2017).
3.6.4 Targeting lactate production and shuttling: Future direction in cancer treatment
Given the profound changes in acid‐base balance in tumors and the role of pH in tumor survival and growth, altering the acid‐base milieu has presented itself as an interesting approach for treating cancer (Swenson, 2016), but the development of these new adjuvant therapies goes way beyond the scope of this article. Nevertheless, after explaining all the pathophysiology, it seems important to shed light on some future possible treatments: on the one hand, medication increasing PDH activity, such as dichloroacetate, seems to halt carcinogenesis by lowering cytosolic lactate production; on the other hand, MCT1 and MCT4 inhibitors seem to have enormous potential in cancer treatment by inhibiting lactate shuttling, even if there is still a lack of specificity (San‐Millán & Brooks, 2017). Furthermore, simpler approaches such as aerobic exercise seem to have beneficial effects by augmenting mitochondrial size and function and thus lactate clearance capacity. Further research is necessary to identify possible targets and create tumor‐specific treatments.
3.6.5 Treatment options in patients with type‐B LA due to malignancies
Lactic acidosis in association with malignancies carries an extremely poor prognosis with a mortality rate over 90% (Nair & Shah, 2017; Sillos et al., 2001). Moreover, the high mortality associated with lactic acidosis has prompted some oncologists to consider this an oncological emergency (Nair & Shah, 2017). The best treatment for patients with hematologic malignancies who develop type B lactic acidosis is not yet clear.
Chemotherapy
Initiating aggressive chemotherapy has been effective in correcting acute acidosis (Friedenberg et al., 2007). It is actually the only treatment modality that consistently leads to remission. Resolution of lactic acidosis was reported to occur as early as 15 h and up to 3 days after starting chemotherapy. This treatment would not be effective in patients whose tumors are unresponsive to chemotherapy. Lactic acidosis improves with chemotherapy, and resolution of the lactic acidosis could be a surrogate marker of inducing remission (Chan et al., 2009).
Intravenous bicarbonate
The use of IV bicarbonate as a treatment for profound acidosis has never shown a meaningful clinical benefit, even in the worst cases (Swenson, 2016). As severe acidosis can cause respiratory fatigue and hemodynamic instability, intravenous bicarbonate is often used to attenuate systemic acidosis and increase the responsiveness to catecholamines. However, it would appear that the benefits of sodium bicarbonate are outweighed by its disadvantages, such as hypernatremia and hyperosmolality (Swenson, 2016). Acidemia leads to unloading oxygen from hemoglobin by shifting the hemoglobin‐oxygen dissociation curve to the right, and reducing acidosis will hinder oxygen release. Studies have shown that intracellular acidosis tends to slow lactate production (Madias, 1986; Sillos et al., 2001). Alkalinization has been shown to potentiate lactate production in patients with malignancy‐induced chronic lactic acidosis (Fields et al., 1981; Fraley et al., 1980). The effect of IV bicarbonate on mortality or lactate concentration in the setting of malignancy‐induced type B lactic acidosis has not been studied directly, as the incidence is very low. In a case report by Fraley et al. (1980), administration of bicarbonate improved pH but not the serum bicarbonate level. Intravenous bicarbonate corrected the extracellular pH but did not affect the significant intracellular acid production due to high tumor cell turnover. The use of sodium bicarbonate may not be recommended in these patient groups.
Renal replacement therapy
Renal replacement therapy, continuous or intermittent, in patients with renal dysfunction may be useful in addition to chemotherapy to correct metabolic acidosis. Here, once again, since the prognosis of type B lactic acidosis related to malignancies is grim, the only chance for remission is starting cytoreductive chemotherapy. Intravenous bicarbonate and hemodialysis will no longer act as a bridge to stabilize the patient enough so that the underlying cause can be treated (Chan et al., 2009).
Intravenous insulin
Lactic acidosis has also been treated with intravenous administration of insulin, which increases the conversion of pyruvate to acetyl‐coenzyme A and consequently facilitates oxidation of lactate to pyruvate (Sillos et al., 2001). Administration of glucose can actually induce lactic acidosis by increasing the availability of glucose and thus increasing the production of lactate by the tumor. Returning to the case presented in this manuscript, the patient was severely hypoglycemic, which is the reason why we substituted for intravenous glucose to maintain the patient's euglycemia. However, in a provocative hypothesis in 2009, Nijsten & van Dam (2009) presented a hypothetical treatment whereby glucose might be systemically lowered. If tumors are glucose consumers and lactate producers and all other tissues in the body can actively take up and use lactate as a fuel, why not systemically induce hypoglycemia to starve tumor cells? In this configuration, lactate would provide salvage fuel for the other tissues (Goodwin et al., 2014). Work to investigate this concept should be pursued.
4 CONCLUSION
Lactic acidosis is a commonly encountered problem in intensive care units and is most commonly associated with dysoxia, better known as type A lactic acidosis. Type B is more uncommon and can be life‐threatening and sometimes even a lethal complication in patients with malignancies. Due to its rareness, it is likely to be under recognized and therefore underdiagnosed. If oncological patients develop high anion gap lactic acidosis without hemodynamic compromise associated with acute respiratory distress without a pulmonary source, the possibility for tumor‐induced type B lactic acidosis through the “Warburg effect” should be considered. Awareness about this condition is important in the clinical practice of intensive care physicians since it will allow a timely diagnosis and the implementation of subsequent therapy. Currently, effective chemotherapy seems to be the only hope for survival.
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
Carole Looyens, and Karim Bendjelid designed the present review. Carole Looyens, and Karim Bendjelid analyzed data and references. Carole Looyens, Raphael Giraud, Ivo Neto Silva, and Karim Bendjelid wrote the manuscript. All authors read and approved the final manuscript.
DATA AVAILABILITY STATEMENT
The data that support these findings are available upon reasonable request from the corresponding author. | Intrathecal | DrugAdministrationRoute | CC BY | 33611854 | 19,126,628 | 2021-02 |
What was the administration route of drug 'METHOTREXATE'? | Burkitt lymphoma and lactic acidosis: A case report and review of the literature.
Type A lactic acidosis is a potentially life-threatening complication in critically ill patients and is the hallmark of a shock state as a result of tissue hypoperfusion and dysoxia. Type B lactic acidosis results from mechanisms other than dysoxia and is a rare condition in patients with solid tumors or hematological malignancies. We present a case of a 60-year-old man with lactic acidosis who was found to have a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Lactagenic cancers are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Warburg in 1923 that is correlated with cancer aggressiveness and poor survival. There is increased glucose utilization with the purpose of lactagenesis under fully oxygenated conditions, as lactate seems to be a potent signaling molecule for angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, which are five essential steps of carcinogenesis. Type B lactic acidosis in association with malignancies carries an extremely poor prognosis. Currently, effective chemotherapy seems to be the only hope for survival.
1 INTRODUCTION
A high arterial lactate level in critically ill patients has been associated with significant morbidity and mortality ever since the first description two centuries ago (Kompanje et al., 2007). Hyperlactatemia in the critically ill is the hallmark of shock states (Kraut & Madias, 2014; Levy, 2006; Nichol et al., 2010; Vincent & De Backer, 2013; Vincent et al., 2016), and the degree of increase in arterial lactate concentrations is directly related to the severity of the shock state (Haas et al., 2016; Nichol et al., 2011; Vincent et al., 2016). In this regard, the prognostic value of arterial lactate levels seems to be independent of the underlying critical illness (Jansen et al., 2010). Serial lactate measurements are widely used in intensive care medicine in the evaluation of the progression of a shock state and the response to intensive and urgent therapy (Levy et al., 2018; Vincent et al., 2016).
Although high lactate levels have been widely used as a marker of altered tissue perfusion in critically ill patients, this condition does not always simply reflect the development of anaerobic metabolism and cellular dysoxia better known as Type A lactic acidosis (Kraut & Madias, 2014; Vincent et al., 2016). While a lack of oxygen forbids the continuation of oxidative phosphorylation in the Krebs cycle, a normal oxygen supply does not impose a complete cessation of anaerobic metabolism. Type B lactic acidosis results from mechanisms other than dysoxia, including inborn errors of metabolism, drugs and toxins, systemic diseases (i.e., diabetes and sepsis), and less commonly malignancy. In this case report, we try to emphasize the pathophysiology leading to hyperlactatemia, and we will focus on the hyperlactatemia caused by lactagenic cancers and the Warburg effect.
2 CASE SUMMARY
A 60‐year‐old‐male patient presented at the emergency department with increasing abdominal girth, abdominal discomfort, severe asthenia, malaise, and profuse diaphoresis without fever. His medical history highlighted chronic renal failure (stage G3bA1) and a cardiac transplant 4 years ago due to terminal ischemic cardiomyopathy. His recent cardiac biopsy was free from any signs of rejection. He was taking immunosuppression with cyclosporine and mycophenolic acid. On admission, the clinical examination revealed a tense and distended abdomen with abdominal ascites. Initial vital signs were stable except for tachycardia at 110 beat per minute. The respiratory rate was 22 breath per minute, and the temperature was within the normal range. Physical exam was otherwise normal.
Laboratory analysis showed leukocytosis with a left shift, signs of hepatocellular injury without cholestasis, and chronic renal failure. His white blood count count was 14.8 G/L, C‐reactive protein was 45 mg/L (normal <10 mg/L), aspartate aminotransferase (AST) was 144 IU/L (normal, 14–50 IU/L), alanine aminotransferase (ALT) was 79 IU/L (normal, 12–50 IU/L), lactate dehydrogenase (LDH) was 1082 IU/L (normal, 87–210 IU/L), total bilirubin was 4 μmol/L (normal, 7–25 μmol/L), alkaline phosphatase was 82 IU/L (normal, 25–102 IU/L), gamma‐glutamyl transferase was 41 IU/L (normal, 9–40 IU/L), creatinine was 198 µmol/L (normal, 62–106 µmol/L), with an estimated glomerular filtration rate of 31 ml/min/1.73 m2. An ultrasound assessment confirmed the presence of moderate ascites in all four abdominal quadrants. Ascites liquid puncture showed leukocytosis, but the liquid culture remained sterile. Abdominal CT was then performed following a rapid clinical deterioration for abdominal sepsis, showing signs of diffuse peritonitis with a pelvic abscess located adjacent to the small intestine. The patient was therefore immediately started on broad‐spectrum antibiotics and antifungal treatment. In addition, a median laparotomy was performed to remove the pelvic abscess. The resected mass (suspect for any neoplasm) was sent for an extemporaneous analysis that elicited a high‐grade lymphoma. Later pathology testing confirmed a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Following emergency department admission and immediate surgery, the patient was admitted to the intensive care unit for high anion gap lactic acidosis, with a pH of 7.29 and a lactate level of 7.4 mmol/L on the arterial blood gas analysis. However, the patient's vital signs remained stable, and he could be extubated on the same day. Signs of hypoxia or circulatory failure were absent, capillary refill time was within normal limits and there was no skin mottling. Moreover, lactate/pyruvate ratio value was 19.0. In contrast, he simultaneously developed profuse hypoglycemia necessitating continuous high‐dose intravenous glucose supplementation. Cardiac output measured with bedside echocardiography appeared to be within the normal ranges. A new postoperative abdominal CT angiography was performed to exclude abdominal ischemia. The lactic acidosis (mean pH 7.3) remained for several days with lactate levels fluctuating around approximately 7 mmol/L. A concomitant thiamine deficiency was excluded by intravenous supplementation. Lactic acidosis started to decrease once chemotherapy with cyclophosphamide and vincristine, initiated 5 days after surgical resection, began to have an effect.
The interpretation of an initial positron emission tomography–computed tomography (PET‐CT) (Figures 1, 2, 3) 6 days after surgery was not clear due to the difficult differentiation between an infectious versus an oncological process. In addition to diffuse hypermetabolism in the peritoneal cavity associated with retroperitoneal adenopathies, it revealed supradiaphragmatic invasion of the lymphoma with a mass located in the right cardiophrenic recess, left mammary adenopathies, and pleural and pericardial nodules. There were also two hypermetabolic, osseous spots, suspected of metastasis, one in the second cervical vertebrae and one in the left scapula.
FIGURE 1 Left: Transversal image from patient's abdominal positron emission tomography–computed tomography (PET‐CT) post tumoral resection revealing diffuse peritoneal hypermetabolism with difficult differentiation between an infectious versus an oncological process. Middle: Transversal image from patients thoracic PET‐CT revealing supradiafragmatic invasion of the lymphoma with a mass and a nodule located in the right cardiophrenic recess with diffuse bilateral pleural nodular thickening. Right: Transversal image from patient's abdominal PET‐CT showing retroperitoneal adenopathies.
FIGURE 2 Lactate production and destination. Glycolysis takes place in the cellular cytosol. The preparatory phase consists of the generation of 1–3 diphosphoglycerate by hekoxinase and phosphofructokinase (PFK), the rate‐limiting enzyme. The pay off phase consists of the generation of pyruvate by pyruvate kinase. Pyruvate can be reduced to lactate by lactate dehydrogenase (LDH) or it can be converted to acetyl‐Co A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. Pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by alanine aminotransferase, resulting in the formation of alanine. Lactate either locally formed after reduction of pyruvate or coming from a distant source, can be consumed in the mitochondria by reformation of pyruvate by mitochondrial lactate dehydrogenase (mLDH) after diffusion across membranes via monocarboxylate transporters (MCTs). This concept is better known as the cell‐to‐cell lactate shuttle.
FIGURE 3 Lactate/pyruvate ratio. In aerobic glycolysis, the physiologic ratio of lactate/pyruvate is approximately 10 and is warranted by lactate dehydrogenase (LDH) catalyzing the reduction of pyruvate in lactate. When there is any perturbation of tissular oxygenation, cellular oxygenation is inhibited causing and acceleration of the reduction in pyruvate into lactate by LDH which results in a pathological lactate/pyruvate ratio above 10. The inhibition of the oxidative phosphorylation avoids any proton recycling leading to high anion gap lactic acidosis. Lactate is mostly converted into glucose through neoglucogenesis in the Cori cycle taking place in the liver and the kidneys. In case of insufficient hepatic perfusion or hepatic failure, lactate will be less cleared causing a variable lactate/pyruvate ratio depending on the source of production of lactate. Protons, normally recycled in the Cori cycle, will accumulate causing acidosis. MTC, monocarboxylate transporter.
He underwent intensive inpatient chemotherapy with one cycle of R‐CHP and six cycles of R‐CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride, O = vincristine sulfate, P = prednisone) and 10 prophylactic intrathecal injections of methotrexate. Chemotherapy was complicated with multiple episodes of febrile agranulocytosis, anemia and thrombocytopenia, which resolved after treatment with antibiotics in combination with filgrastim and multiple transfusions. The patient could be discharged with closed outpatient follow‐up after 5 months of admission. A PET‐CT was carried out 2 months after discharge and showed complete regression of all the lesions. A thoraco‐abdominal CT performed 1 year after the diagnosis seemed to be completely normal.
3 DISCUSSION
3.1 Lactate homeostasis
As with the blood levels of any substance, elevated lactate levels can be the result of increased production or reduced clearance, or both. Under physiological conditions, 1500 mmol of lactate or 20 mmol/kg of body weight is produced daily from various organs, including the muscle, intestine, red blood cells, brain, and skin (Kraut & Madias, 2014). Lactate is metabolized by the liver (60%), kidneys (30%), and other organs. The normal arterial blood lactate level is approximately 1 mmol/L (Kraut & Madias, 2014; Vincent et al., 2016).
3.2 Lactate production
Lactate formation is closely related to glycolysis. Glycolysis takes place in ten steps, five of which are in the preparatory phase and five in the payoff phase. Phosphofructokinase (PFK) is the rate‐limiting enzyme. Two net ATP molecules are generated by phosphorylation by high‐energy compounds. The final product of glycolysis is pyruvate and lactate, to which pyruvate can be reduced. LDH catalyzes the reduction of pyruvate into lactate at a well‐defined rate so that in normal homeostasis, the physiological ratio of lactate/pyruvate is approximately 10. In the presence of oxygen, pyruvate can be converted into acetyl‐coenzyme A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. This respiratory chain of reactions results in a net production of 36 ATP molecules per molecule of glucose. The metabolic yield of glycolysis when participating in the aerobic metabolic pathway (i.e., along with the Krebs cycle and oxidative phosphorylation) is superior to fermentation (without O2) into lactate (38 vs. 2 molecules of ATP). Anaerobic fermentation into lactate may be inefficient compared to oxidative phosphorylation, however, the rate of glucose metabolism into lactate is 10–100 times faster than the complete oxidation of glucose in the mitochondria (Liberti & Locasale, 2016). In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is utilized (Liberti & Locasale, 2016). In addition to the better‐known reduction to lactate and the oxidation to acetyl‐coenzyme A, for the completeness of this review, we need to mention that pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by ALT, resulting in the formation of alanine (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
Experiments by Pasteur (Platt, 1988), Meyerhof (1927), and A.V. Hill (Bassett, 2002) led to the widespread understanding of the glycolytic pathway and the notion that only a limitation of oxygen availability leads to fermentation and lactate accumulation. Out of this early work came the idea that lactate is just an anaerobic waste product that must be cleared from the muscles and blood, preferably by being converted to glucose in the liver via the Cori cycle. However, it has been demonstrated that lactate is a potent fuel and signaling molecule and is constantly being produced and circulated throughout the body, even and most often when there is adequate oxygen. Lactate is more than just a “hypoxic waste product.” Lactate as a result of dysoxia is often the exception rather than the rule, even in critically ill patients (Goodwin et al., 2014).
3.3 Lactate metabolism
Any time glycolysis is active, lactate is formed and equilibrates with local lactate gradients. Lactate equilibrates mainly by diffusing across membranes via monocarboxylate transporters (MCTs). In lactate‐producing tissues, this means exporting lactate into the circulation where both local and distant tissues can take it up and use it.
Lactate is metabolized by the liver (60%), kidneys (30%) and other organs. Lactate can be used for gluconeogenesis by reformation of pyruvate and glucose in the Cori cycle, which takes place in the liver and kidneys. In addition, lactate can readily replace glucose as a fuel for almost all cells of the body (any cell with mitochondria) by reformation and subsequent oxidation of pyruvate in the mitochondria. Lactate clearance occurs in the heart, liver, skeletal muscle and even brain. This observation that lactate is constantly being produced and consumed formed the basis of the cell‐to‐cell lactate shuttle, an energy exchange hypothesis originally introduced by Brooks in 1984 (Brooks, 1986). Lactate seems to be a key intermediate metabolite in whole body metabolism (Ben‐Hamouda et al., 2013; Goodwin et al., 2014; Kraut & Madias, 2014).
3.4 Hyperlactatemia (Table 1)
3.4.1 Elevated production of lactate
As mentioned earlier, normal lactate production is approximately 1 mmol/min or 1500 mmol/24 h, and the normal lactate level is approximately 1 mmol/L (Ben‐Hamouda et al., 2013; Vincent et al., 2016). Elevated lactate production can be the consequence of either an elevated pyruvate concentration (as seen in accelerated glycolysis, in elevated protein catabolism or through inhibition of PDH) or cellular dysoxia. Dysoxic lactic acidosis is better known as type‐A lactic acidosis, and all other nondysoxic causes of lactic acidosis are classified as type B according to the classification of Woods and Cohen (Ben‐Hamouda et al., 2013). Indeed, if lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics (i.e. normal blood pressure, normal volemia, normal blood oxygen, and oxygen‐carrying capacity), it is traditionally termed Type B lactic acidosis. In the present setting, the physiologic ratio value of lactate/pyruvate is around 10 or higher.
TABLE 1 Classification of hyperlactatemia according to Woods and Cohen
Type A: Hyperlactatemia associated with cellular dysoxia due to insufficient oxygen supply
Stagnant dysoxia Low cardiac output
Redistribution of cardiac output at the expense of certain tissues
Vascular occlusion
Dysoxia caused by elevated demand of oxygen Convulsions
Intensive exercise
Dysoxia caused by low oxygen carrying capacity Anemic dysoxia
Carbon monoxide intoxication
Hypoxic dysoxia (low PaO2)
Cytotoxic dysoxia due to inefficient mitochondrial consumption of oxygen Sepsis
Cyanide intoxication
Type B1: Hyperlactatemia due to an underlying disease
Accelerated glycolysis Hyperglycemia
Sepsis
Endogenous catecholamines
Lactagenic cancer
Elevated protein catabolism Burn victims
Severe septic shock
Acquired inhibition of pyruvate dehydrogenase (PDH) Sepsis
Thiamine deficiency
Lactagenic cancer
Reduced lactate clearance Reduced liver blood flow
Hepatic failure
Type B2: Hyperlactatemia due to drugs and toxins
Exogenous catecholamines (adrenaline, dobutamine, terbutaline) Cocaine, metamphetamines
Propofol Salicylates
Metformine Antiretroviral drugs
Linezolid Toxic alcohols (ethanol, methanol, propylene glycol, ethylene glycol)
Paracetamol
Type B3: Hyperlactatemia due to inborn errors of metabolism (enzymatic deficiencies)
Congenital PDH deficiency
Glucose‐6‐phosphatase deficiency (von Gierke disease)
Pyruvate carboxylase deficiency
Methylmalonic aciduria
Mitochondrial encephalomyopathies
John Wiley & Sons, LtdAccelerated glycolysis
Any cause of an accelerated level of glycolysis causes an expected elevation of pyruvate and thus of lactate, as the physiologic ratio of lactate/pyruvate of approximately 10 or higher is always warranted by LDH. Accelerated glycolysis is the case in hyperglycemia, sepsis, or other situations with elevated endogenous or exogenous catecholamines (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014). Finally, accelerated aerobic glycolysis may partially explain the hyperlactatemia caused by tumoral cells of lactagenic cancers, known as the Warburg effect (San‐Millán & Brooks, 2017), the cause of lactic acidosis in the present case.
Elevated protein catabolism
Elevated protein catabolism can also cause a rise in pyruvate levels. As mentioned earlier, pyruvate can be transaminated into alanine, and the reverse can be witnessed through the activity of the ALT enzyme, forming pyruvate in the liver. This mechanism contributes to hepatic neoglucogenesis. Accelerated protein catabolism is seen as muscle wasting, present in many critically ill patients, most severely in burn victims and in patients with severe septic shock. The elevated alanine supply in the liver contributes to the elevated pyruvate concentration and, ultimately, to hyperlactatemia, as the physiologic lactate/pyruvate ratio is always warranted by LDH (Ben‐Hamouda et al., 2013).
Inhibition of PDH
As discussed earlier, pyruvate is oxidized into acetyl‐coenzyme‐A by PDH. A congenital or an acquired reduction in the enzymatic activity of PDH can cause an accumulation of pyruvate and therefore of lactate. An acquired reduction in PDH can be caused by certain endotoxins and inflammatory cytokines in sepsis. This explains why hemodynamically stable patients with sepsis and normal liver function may have lactic acidosis (Kraut & Madias, 2014). It can also be caused by nucleoside reverse transcriptase inhibitors used to treat patients with HIV or by a thiamine deficiency, as in patients receiving parenteral nutrition or with severe Beri‐beri. Thiamine is an important cofactor in the PDH complex. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead, conversion into lactate takes place (Friedenberg et al., 2007). Finally, certain oncogenes express PDH kinase, which inactivates PDH and inhibits the Krebs cycle (San‐Millán & Brooks, 2017; Swenson, 2016) and partially explains the development of hyperlactatemia caused by tumoral cells.
Cellular dysoxia
Perturbations of tissular oxygenation, termed “cellular dysoxia”, are caused by insufficient oxygen supply. This dysoxia can be either generalized due to a low cardiac output, carbon monoxide intoxication, profound arterial hemoglobin desaturation, and reduced oxygen content or either localized in the context of redistribution of the cardiac output at the expense of certain tissues or due to a vascular occlusion (Swenson, 2016). It can also be caused by mitochondrial enzyme defects and by inhibitors of aerobic metabolism, such as cyanide. Every drop in cellular oxygenation causes an acceleration of the reduction in pyruvate to lactate by LDH, which results in a pathological augmentation of the lactate/pyruvate ratio above 10 (Ben‐Hamouda et al., 2013). Even if the pyruvate dosage is expensive, its use and the finding of a pathological L/P level confirm cellular dysoxia and excludes other causes.
3.4.2 Reduced lactate clearance
Lactate is partly transported to the liver and the kidneys and converted to glucose through gluconeogenesis (the Cori cycle). The hepatic clearance of lactate thus depends on hepatic extraction and hepatic functioning. Hepatic extraction is determined by the liver blood flow, which needs no less than one‐fourth of its normal flow. The capture of lactate by hepatocytes depends on its transportation by a family of MCTs with different isoforms (MCT1‐4). Thus, neoglucogenesis will depend on hepatic functioning. Its activity is decreased in hepatic failure and inhibited in shock states and severe acidosis (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
3.5 Distinction between hyperlactatemia and lactic acidosis
Hyperlactatemia and lactic acidosis are frequently mixed, which may cause confusion. However, the two are governed by a different concept. Glycolysis causes lactate formation without lactic acidosis when there is no net H+ production. The H+ protons may arise following ATP hydrolyzation and are produced through glycolysis. However, those protons are recycled by lactate consumption either through the Krebs cycle or through the hepatic Cori cycle, hence maintaining the internal acid‐base balance (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
In this regard, acquired or congenital inhibition of PDH, inhibition of oxidative phosphorylation due to cellular dysoxia, medication or intoxication and hepatic insufficiency are all causes of reduced proton recycling in either the Krebs or the Cori cycle, therefore causing high anion gap lactic acidosis. Other causes of hyperlactatemia, such as elevated glycolysis in hyperglycemia, arising from beta‐adrenergic stimulation or muscular catabolism, will only cause an elevated production of lactate without proton recycling impairment and without ensuing concomitant lactic acidosis (Kraut & Madias, 2014).
3.6 Lactagenic cancers
3.6.1 Warburg effect
In glycolytic tumors, lactate levels of cancer cells are markedly elevated up to 40‐fold and are highly associated with cancer aggressiveness and poor survival (Brizel et al., 2001; San‐Millán & Brooks, 2017). In fast‐growing malignancies, the rate of tumor metabolism may be great enough to exceed normal muscle and liver lactate clearance and cause systemic type B lactic acidosis (Sillos et al., 2001; Swenson, 2016). The majority of lactic acidosis in malignancies is reported in cases of hematologic malignancies. Only a few cases have been reported for solid tumors presenting with lactic acidosis (Nair & Shah, 2017).
In 1923, Warburg observed in his Nobel Prize winning studies that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions and that tumor cells live and grow in a more acidic milieu as a result of increased lactic acid production not generally tolerated by normal cells (San‐Millán & Brooks, 2017; Swenson, 2016). His discovery was named the “Warburg effect” by Racker in 1972 (San‐Millán & Brooks, 2017). The Warburg effect is a hallmark of cancer, and its significance is still apparent in the common cancer diagnostic test using fluorodeoxyglucose positron emission tomography, which has a high diagnostic accuracy (Potter et al., 2016).
From a contemporary perspective of cell metabolic efficiency, it seems difficult to understand why, despite fully aerobic conditions, cancer cells choose an inefficient pathway producing two ATP molecules per molecule of glucose instead of 38 via coupled mitochondrial respiration. However, as mentioned earlier, the amount of ATP synthesized over any given period of time is comparable in both ways of glucose metabolism because fermentation into lactate is 10–100 times faster than the completion of oxidative phosphorylation (Liberti & Locasale, 2016). Moreover, the stress of lactate production is simply passed on to the host. Then, the cancer cells proliferate, and the tumor grows and metastasizes because of host exploitation, ending in final host expiration (San‐Millán & Brooks, 2017).
3.6.2 Origin of tumoral lactagenesis
Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous and unstoppable glucose utilization to produce lactate involving five major steps: (i) an increase in glucose uptake; (ii) upregulation of PFK, the rate‐limiting enzyme of glycolysis; (iii) a decrease in mitochondrial respiration by upregulation of PDH kinase (PDK) that inhibits pyruvate uptake in mitochondria; (iv) increased lactate production by LDH upregulation; and (v) upregulation of MCT1 and MCT4 expression, the transmembrane transporters of lactate, for higher lactate plus H+ efflux and further lactate shuttling, thus mediating tumor growth and proliferation (Brahimi‐Horn et al., 2011; San‐Millán & Brooks, 2017; Swenson, 2016).
In our case, the Warburg effect was caused by a Burkitt lymphoma, a B‐cell derived malignancy. The main characteristic of a Burkitt lymphoma is an increased production of the MYC oncoprotein caused by chromosomal rearrangements. This translocation results in inappropriately high expression levels of MYC, which gives cells proliferative capacity. Moreover, MYC also activates the transcription of genes encoding glucose transporter, hexokinase, MCT, PDK, PK (pyruvate kinase), and LDH, resulting in the accelerated aerobic glycolysis or the Warburg effect. The MYC protein is the master regulator of the Warburg effect in BL cells (Mushtaq et al., 2015).
3.6.3 Aim of tumoral lactagenesis
The role of the Warburg effect in the pathogenesis of cancer has not yet been completely established. Lactate is the end product of the Warburg effect, but lactate production or lactagenesis is probably the purpose of the Warburg effect as well.
In addition to being a potent oxidative fuel, lactate is also a potent signaling molecule necessary for all the major steps in carcinogenesis, as follows: (i) angiogenesis, (ii) cell migration, (iii) metastasis, (iv) immune escape, and (v) self‐sufficiency of cancer cells (San‐Millán & Brooks, 2017).
Lactate released from tumor cells by MCT4 plays a role in stimulating angiogenesis (i) by increasing the expression of vascular endothelial growth factor protein in endothelial cells (Goodwin et al., 2014; San‐Millán & Brooks, 2017). Cell migration (ii) is another essential step in carcinogenesis and metastasis in which lactate seems to be a key element to increase cell migration. Marked extracellular acidosis appears to promote the migration and metastasis (iii) of cancer cells by disrupting normal cell‐matrix interactions that act to maintain stable growth patterns (Swenson, 2016). Lactate levels are highly associated with a high incidence of distant metastasis. Acidosis reduces host defense against malignant cells and contributes to immune escape (iv) in many different ways: first, by inhibiting the release of the cytokines tumor necrosis factor and interleukin‐6; and second, by inhibiting the activation of T‐cells with a decrease in the cytotoxic activity of T‐cells and inhibition of natural killer cell functioning. Lactate also plays a central role in the self‐sufficiency and sustainability (v) of cancer cells. Cancer cells at the hypoxic core might use glucose and produce lactate, whereas cells on the periphery, close to a robust vascular supply, might take up this lactate and oxidize it as a fuel. The self‐sufficiency depending upon high glycolytic flux also allows cancer cells to produce lactate for carcinogenesis by angiogenesis, immune escape, cell migration, and metastasis. A glucose to lactate shunt occurs in which the host bears the burden of providing a limitless glucose supply as well as a sink for disposal of lactate and hydrogen ions. This may even explain why the actual cause of cachexia and death due to cancer appears to be multifactorial, with organ failure rather than the tumor itself (San‐Millán & Brooks, 2017).
3.6.4 Targeting lactate production and shuttling: Future direction in cancer treatment
Given the profound changes in acid‐base balance in tumors and the role of pH in tumor survival and growth, altering the acid‐base milieu has presented itself as an interesting approach for treating cancer (Swenson, 2016), but the development of these new adjuvant therapies goes way beyond the scope of this article. Nevertheless, after explaining all the pathophysiology, it seems important to shed light on some future possible treatments: on the one hand, medication increasing PDH activity, such as dichloroacetate, seems to halt carcinogenesis by lowering cytosolic lactate production; on the other hand, MCT1 and MCT4 inhibitors seem to have enormous potential in cancer treatment by inhibiting lactate shuttling, even if there is still a lack of specificity (San‐Millán & Brooks, 2017). Furthermore, simpler approaches such as aerobic exercise seem to have beneficial effects by augmenting mitochondrial size and function and thus lactate clearance capacity. Further research is necessary to identify possible targets and create tumor‐specific treatments.
3.6.5 Treatment options in patients with type‐B LA due to malignancies
Lactic acidosis in association with malignancies carries an extremely poor prognosis with a mortality rate over 90% (Nair & Shah, 2017; Sillos et al., 2001). Moreover, the high mortality associated with lactic acidosis has prompted some oncologists to consider this an oncological emergency (Nair & Shah, 2017). The best treatment for patients with hematologic malignancies who develop type B lactic acidosis is not yet clear.
Chemotherapy
Initiating aggressive chemotherapy has been effective in correcting acute acidosis (Friedenberg et al., 2007). It is actually the only treatment modality that consistently leads to remission. Resolution of lactic acidosis was reported to occur as early as 15 h and up to 3 days after starting chemotherapy. This treatment would not be effective in patients whose tumors are unresponsive to chemotherapy. Lactic acidosis improves with chemotherapy, and resolution of the lactic acidosis could be a surrogate marker of inducing remission (Chan et al., 2009).
Intravenous bicarbonate
The use of IV bicarbonate as a treatment for profound acidosis has never shown a meaningful clinical benefit, even in the worst cases (Swenson, 2016). As severe acidosis can cause respiratory fatigue and hemodynamic instability, intravenous bicarbonate is often used to attenuate systemic acidosis and increase the responsiveness to catecholamines. However, it would appear that the benefits of sodium bicarbonate are outweighed by its disadvantages, such as hypernatremia and hyperosmolality (Swenson, 2016). Acidemia leads to unloading oxygen from hemoglobin by shifting the hemoglobin‐oxygen dissociation curve to the right, and reducing acidosis will hinder oxygen release. Studies have shown that intracellular acidosis tends to slow lactate production (Madias, 1986; Sillos et al., 2001). Alkalinization has been shown to potentiate lactate production in patients with malignancy‐induced chronic lactic acidosis (Fields et al., 1981; Fraley et al., 1980). The effect of IV bicarbonate on mortality or lactate concentration in the setting of malignancy‐induced type B lactic acidosis has not been studied directly, as the incidence is very low. In a case report by Fraley et al. (1980), administration of bicarbonate improved pH but not the serum bicarbonate level. Intravenous bicarbonate corrected the extracellular pH but did not affect the significant intracellular acid production due to high tumor cell turnover. The use of sodium bicarbonate may not be recommended in these patient groups.
Renal replacement therapy
Renal replacement therapy, continuous or intermittent, in patients with renal dysfunction may be useful in addition to chemotherapy to correct metabolic acidosis. Here, once again, since the prognosis of type B lactic acidosis related to malignancies is grim, the only chance for remission is starting cytoreductive chemotherapy. Intravenous bicarbonate and hemodialysis will no longer act as a bridge to stabilize the patient enough so that the underlying cause can be treated (Chan et al., 2009).
Intravenous insulin
Lactic acidosis has also been treated with intravenous administration of insulin, which increases the conversion of pyruvate to acetyl‐coenzyme A and consequently facilitates oxidation of lactate to pyruvate (Sillos et al., 2001). Administration of glucose can actually induce lactic acidosis by increasing the availability of glucose and thus increasing the production of lactate by the tumor. Returning to the case presented in this manuscript, the patient was severely hypoglycemic, which is the reason why we substituted for intravenous glucose to maintain the patient's euglycemia. However, in a provocative hypothesis in 2009, Nijsten & van Dam (2009) presented a hypothetical treatment whereby glucose might be systemically lowered. If tumors are glucose consumers and lactate producers and all other tissues in the body can actively take up and use lactate as a fuel, why not systemically induce hypoglycemia to starve tumor cells? In this configuration, lactate would provide salvage fuel for the other tissues (Goodwin et al., 2014). Work to investigate this concept should be pursued.
4 CONCLUSION
Lactic acidosis is a commonly encountered problem in intensive care units and is most commonly associated with dysoxia, better known as type A lactic acidosis. Type B is more uncommon and can be life‐threatening and sometimes even a lethal complication in patients with malignancies. Due to its rareness, it is likely to be under recognized and therefore underdiagnosed. If oncological patients develop high anion gap lactic acidosis without hemodynamic compromise associated with acute respiratory distress without a pulmonary source, the possibility for tumor‐induced type B lactic acidosis through the “Warburg effect” should be considered. Awareness about this condition is important in the clinical practice of intensive care physicians since it will allow a timely diagnosis and the implementation of subsequent therapy. Currently, effective chemotherapy seems to be the only hope for survival.
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
Carole Looyens, and Karim Bendjelid designed the present review. Carole Looyens, and Karim Bendjelid analyzed data and references. Carole Looyens, Raphael Giraud, Ivo Neto Silva, and Karim Bendjelid wrote the manuscript. All authors read and approved the final manuscript.
DATA AVAILABILITY STATEMENT
The data that support these findings are available upon reasonable request from the corresponding author. | Intrathecal | DrugAdministrationRoute | CC BY | 33611854 | 19,163,699 | 2021-02 |
What was the dosage of drug 'DOXORUBICIN'? | Burkitt lymphoma and lactic acidosis: A case report and review of the literature.
Type A lactic acidosis is a potentially life-threatening complication in critically ill patients and is the hallmark of a shock state as a result of tissue hypoperfusion and dysoxia. Type B lactic acidosis results from mechanisms other than dysoxia and is a rare condition in patients with solid tumors or hematological malignancies. We present a case of a 60-year-old man with lactic acidosis who was found to have a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Lactagenic cancers are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Warburg in 1923 that is correlated with cancer aggressiveness and poor survival. There is increased glucose utilization with the purpose of lactagenesis under fully oxygenated conditions, as lactate seems to be a potent signaling molecule for angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, which are five essential steps of carcinogenesis. Type B lactic acidosis in association with malignancies carries an extremely poor prognosis. Currently, effective chemotherapy seems to be the only hope for survival.
1 INTRODUCTION
A high arterial lactate level in critically ill patients has been associated with significant morbidity and mortality ever since the first description two centuries ago (Kompanje et al., 2007). Hyperlactatemia in the critically ill is the hallmark of shock states (Kraut & Madias, 2014; Levy, 2006; Nichol et al., 2010; Vincent & De Backer, 2013; Vincent et al., 2016), and the degree of increase in arterial lactate concentrations is directly related to the severity of the shock state (Haas et al., 2016; Nichol et al., 2011; Vincent et al., 2016). In this regard, the prognostic value of arterial lactate levels seems to be independent of the underlying critical illness (Jansen et al., 2010). Serial lactate measurements are widely used in intensive care medicine in the evaluation of the progression of a shock state and the response to intensive and urgent therapy (Levy et al., 2018; Vincent et al., 2016).
Although high lactate levels have been widely used as a marker of altered tissue perfusion in critically ill patients, this condition does not always simply reflect the development of anaerobic metabolism and cellular dysoxia better known as Type A lactic acidosis (Kraut & Madias, 2014; Vincent et al., 2016). While a lack of oxygen forbids the continuation of oxidative phosphorylation in the Krebs cycle, a normal oxygen supply does not impose a complete cessation of anaerobic metabolism. Type B lactic acidosis results from mechanisms other than dysoxia, including inborn errors of metabolism, drugs and toxins, systemic diseases (i.e., diabetes and sepsis), and less commonly malignancy. In this case report, we try to emphasize the pathophysiology leading to hyperlactatemia, and we will focus on the hyperlactatemia caused by lactagenic cancers and the Warburg effect.
2 CASE SUMMARY
A 60‐year‐old‐male patient presented at the emergency department with increasing abdominal girth, abdominal discomfort, severe asthenia, malaise, and profuse diaphoresis without fever. His medical history highlighted chronic renal failure (stage G3bA1) and a cardiac transplant 4 years ago due to terminal ischemic cardiomyopathy. His recent cardiac biopsy was free from any signs of rejection. He was taking immunosuppression with cyclosporine and mycophenolic acid. On admission, the clinical examination revealed a tense and distended abdomen with abdominal ascites. Initial vital signs were stable except for tachycardia at 110 beat per minute. The respiratory rate was 22 breath per minute, and the temperature was within the normal range. Physical exam was otherwise normal.
Laboratory analysis showed leukocytosis with a left shift, signs of hepatocellular injury without cholestasis, and chronic renal failure. His white blood count count was 14.8 G/L, C‐reactive protein was 45 mg/L (normal <10 mg/L), aspartate aminotransferase (AST) was 144 IU/L (normal, 14–50 IU/L), alanine aminotransferase (ALT) was 79 IU/L (normal, 12–50 IU/L), lactate dehydrogenase (LDH) was 1082 IU/L (normal, 87–210 IU/L), total bilirubin was 4 μmol/L (normal, 7–25 μmol/L), alkaline phosphatase was 82 IU/L (normal, 25–102 IU/L), gamma‐glutamyl transferase was 41 IU/L (normal, 9–40 IU/L), creatinine was 198 µmol/L (normal, 62–106 µmol/L), with an estimated glomerular filtration rate of 31 ml/min/1.73 m2. An ultrasound assessment confirmed the presence of moderate ascites in all four abdominal quadrants. Ascites liquid puncture showed leukocytosis, but the liquid culture remained sterile. Abdominal CT was then performed following a rapid clinical deterioration for abdominal sepsis, showing signs of diffuse peritonitis with a pelvic abscess located adjacent to the small intestine. The patient was therefore immediately started on broad‐spectrum antibiotics and antifungal treatment. In addition, a median laparotomy was performed to remove the pelvic abscess. The resected mass (suspect for any neoplasm) was sent for an extemporaneous analysis that elicited a high‐grade lymphoma. Later pathology testing confirmed a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Following emergency department admission and immediate surgery, the patient was admitted to the intensive care unit for high anion gap lactic acidosis, with a pH of 7.29 and a lactate level of 7.4 mmol/L on the arterial blood gas analysis. However, the patient's vital signs remained stable, and he could be extubated on the same day. Signs of hypoxia or circulatory failure were absent, capillary refill time was within normal limits and there was no skin mottling. Moreover, lactate/pyruvate ratio value was 19.0. In contrast, he simultaneously developed profuse hypoglycemia necessitating continuous high‐dose intravenous glucose supplementation. Cardiac output measured with bedside echocardiography appeared to be within the normal ranges. A new postoperative abdominal CT angiography was performed to exclude abdominal ischemia. The lactic acidosis (mean pH 7.3) remained for several days with lactate levels fluctuating around approximately 7 mmol/L. A concomitant thiamine deficiency was excluded by intravenous supplementation. Lactic acidosis started to decrease once chemotherapy with cyclophosphamide and vincristine, initiated 5 days after surgical resection, began to have an effect.
The interpretation of an initial positron emission tomography–computed tomography (PET‐CT) (Figures 1, 2, 3) 6 days after surgery was not clear due to the difficult differentiation between an infectious versus an oncological process. In addition to diffuse hypermetabolism in the peritoneal cavity associated with retroperitoneal adenopathies, it revealed supradiaphragmatic invasion of the lymphoma with a mass located in the right cardiophrenic recess, left mammary adenopathies, and pleural and pericardial nodules. There were also two hypermetabolic, osseous spots, suspected of metastasis, one in the second cervical vertebrae and one in the left scapula.
FIGURE 1 Left: Transversal image from patient's abdominal positron emission tomography–computed tomography (PET‐CT) post tumoral resection revealing diffuse peritoneal hypermetabolism with difficult differentiation between an infectious versus an oncological process. Middle: Transversal image from patients thoracic PET‐CT revealing supradiafragmatic invasion of the lymphoma with a mass and a nodule located in the right cardiophrenic recess with diffuse bilateral pleural nodular thickening. Right: Transversal image from patient's abdominal PET‐CT showing retroperitoneal adenopathies.
FIGURE 2 Lactate production and destination. Glycolysis takes place in the cellular cytosol. The preparatory phase consists of the generation of 1–3 diphosphoglycerate by hekoxinase and phosphofructokinase (PFK), the rate‐limiting enzyme. The pay off phase consists of the generation of pyruvate by pyruvate kinase. Pyruvate can be reduced to lactate by lactate dehydrogenase (LDH) or it can be converted to acetyl‐Co A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. Pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by alanine aminotransferase, resulting in the formation of alanine. Lactate either locally formed after reduction of pyruvate or coming from a distant source, can be consumed in the mitochondria by reformation of pyruvate by mitochondrial lactate dehydrogenase (mLDH) after diffusion across membranes via monocarboxylate transporters (MCTs). This concept is better known as the cell‐to‐cell lactate shuttle.
FIGURE 3 Lactate/pyruvate ratio. In aerobic glycolysis, the physiologic ratio of lactate/pyruvate is approximately 10 and is warranted by lactate dehydrogenase (LDH) catalyzing the reduction of pyruvate in lactate. When there is any perturbation of tissular oxygenation, cellular oxygenation is inhibited causing and acceleration of the reduction in pyruvate into lactate by LDH which results in a pathological lactate/pyruvate ratio above 10. The inhibition of the oxidative phosphorylation avoids any proton recycling leading to high anion gap lactic acidosis. Lactate is mostly converted into glucose through neoglucogenesis in the Cori cycle taking place in the liver and the kidneys. In case of insufficient hepatic perfusion or hepatic failure, lactate will be less cleared causing a variable lactate/pyruvate ratio depending on the source of production of lactate. Protons, normally recycled in the Cori cycle, will accumulate causing acidosis. MTC, monocarboxylate transporter.
He underwent intensive inpatient chemotherapy with one cycle of R‐CHP and six cycles of R‐CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride, O = vincristine sulfate, P = prednisone) and 10 prophylactic intrathecal injections of methotrexate. Chemotherapy was complicated with multiple episodes of febrile agranulocytosis, anemia and thrombocytopenia, which resolved after treatment with antibiotics in combination with filgrastim and multiple transfusions. The patient could be discharged with closed outpatient follow‐up after 5 months of admission. A PET‐CT was carried out 2 months after discharge and showed complete regression of all the lesions. A thoraco‐abdominal CT performed 1 year after the diagnosis seemed to be completely normal.
3 DISCUSSION
3.1 Lactate homeostasis
As with the blood levels of any substance, elevated lactate levels can be the result of increased production or reduced clearance, or both. Under physiological conditions, 1500 mmol of lactate or 20 mmol/kg of body weight is produced daily from various organs, including the muscle, intestine, red blood cells, brain, and skin (Kraut & Madias, 2014). Lactate is metabolized by the liver (60%), kidneys (30%), and other organs. The normal arterial blood lactate level is approximately 1 mmol/L (Kraut & Madias, 2014; Vincent et al., 2016).
3.2 Lactate production
Lactate formation is closely related to glycolysis. Glycolysis takes place in ten steps, five of which are in the preparatory phase and five in the payoff phase. Phosphofructokinase (PFK) is the rate‐limiting enzyme. Two net ATP molecules are generated by phosphorylation by high‐energy compounds. The final product of glycolysis is pyruvate and lactate, to which pyruvate can be reduced. LDH catalyzes the reduction of pyruvate into lactate at a well‐defined rate so that in normal homeostasis, the physiological ratio of lactate/pyruvate is approximately 10. In the presence of oxygen, pyruvate can be converted into acetyl‐coenzyme A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. This respiratory chain of reactions results in a net production of 36 ATP molecules per molecule of glucose. The metabolic yield of glycolysis when participating in the aerobic metabolic pathway (i.e., along with the Krebs cycle and oxidative phosphorylation) is superior to fermentation (without O2) into lactate (38 vs. 2 molecules of ATP). Anaerobic fermentation into lactate may be inefficient compared to oxidative phosphorylation, however, the rate of glucose metabolism into lactate is 10–100 times faster than the complete oxidation of glucose in the mitochondria (Liberti & Locasale, 2016). In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is utilized (Liberti & Locasale, 2016). In addition to the better‐known reduction to lactate and the oxidation to acetyl‐coenzyme A, for the completeness of this review, we need to mention that pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by ALT, resulting in the formation of alanine (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
Experiments by Pasteur (Platt, 1988), Meyerhof (1927), and A.V. Hill (Bassett, 2002) led to the widespread understanding of the glycolytic pathway and the notion that only a limitation of oxygen availability leads to fermentation and lactate accumulation. Out of this early work came the idea that lactate is just an anaerobic waste product that must be cleared from the muscles and blood, preferably by being converted to glucose in the liver via the Cori cycle. However, it has been demonstrated that lactate is a potent fuel and signaling molecule and is constantly being produced and circulated throughout the body, even and most often when there is adequate oxygen. Lactate is more than just a “hypoxic waste product.” Lactate as a result of dysoxia is often the exception rather than the rule, even in critically ill patients (Goodwin et al., 2014).
3.3 Lactate metabolism
Any time glycolysis is active, lactate is formed and equilibrates with local lactate gradients. Lactate equilibrates mainly by diffusing across membranes via monocarboxylate transporters (MCTs). In lactate‐producing tissues, this means exporting lactate into the circulation where both local and distant tissues can take it up and use it.
Lactate is metabolized by the liver (60%), kidneys (30%) and other organs. Lactate can be used for gluconeogenesis by reformation of pyruvate and glucose in the Cori cycle, which takes place in the liver and kidneys. In addition, lactate can readily replace glucose as a fuel for almost all cells of the body (any cell with mitochondria) by reformation and subsequent oxidation of pyruvate in the mitochondria. Lactate clearance occurs in the heart, liver, skeletal muscle and even brain. This observation that lactate is constantly being produced and consumed formed the basis of the cell‐to‐cell lactate shuttle, an energy exchange hypothesis originally introduced by Brooks in 1984 (Brooks, 1986). Lactate seems to be a key intermediate metabolite in whole body metabolism (Ben‐Hamouda et al., 2013; Goodwin et al., 2014; Kraut & Madias, 2014).
3.4 Hyperlactatemia (Table 1)
3.4.1 Elevated production of lactate
As mentioned earlier, normal lactate production is approximately 1 mmol/min or 1500 mmol/24 h, and the normal lactate level is approximately 1 mmol/L (Ben‐Hamouda et al., 2013; Vincent et al., 2016). Elevated lactate production can be the consequence of either an elevated pyruvate concentration (as seen in accelerated glycolysis, in elevated protein catabolism or through inhibition of PDH) or cellular dysoxia. Dysoxic lactic acidosis is better known as type‐A lactic acidosis, and all other nondysoxic causes of lactic acidosis are classified as type B according to the classification of Woods and Cohen (Ben‐Hamouda et al., 2013). Indeed, if lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics (i.e. normal blood pressure, normal volemia, normal blood oxygen, and oxygen‐carrying capacity), it is traditionally termed Type B lactic acidosis. In the present setting, the physiologic ratio value of lactate/pyruvate is around 10 or higher.
TABLE 1 Classification of hyperlactatemia according to Woods and Cohen
Type A: Hyperlactatemia associated with cellular dysoxia due to insufficient oxygen supply
Stagnant dysoxia Low cardiac output
Redistribution of cardiac output at the expense of certain tissues
Vascular occlusion
Dysoxia caused by elevated demand of oxygen Convulsions
Intensive exercise
Dysoxia caused by low oxygen carrying capacity Anemic dysoxia
Carbon monoxide intoxication
Hypoxic dysoxia (low PaO2)
Cytotoxic dysoxia due to inefficient mitochondrial consumption of oxygen Sepsis
Cyanide intoxication
Type B1: Hyperlactatemia due to an underlying disease
Accelerated glycolysis Hyperglycemia
Sepsis
Endogenous catecholamines
Lactagenic cancer
Elevated protein catabolism Burn victims
Severe septic shock
Acquired inhibition of pyruvate dehydrogenase (PDH) Sepsis
Thiamine deficiency
Lactagenic cancer
Reduced lactate clearance Reduced liver blood flow
Hepatic failure
Type B2: Hyperlactatemia due to drugs and toxins
Exogenous catecholamines (adrenaline, dobutamine, terbutaline) Cocaine, metamphetamines
Propofol Salicylates
Metformine Antiretroviral drugs
Linezolid Toxic alcohols (ethanol, methanol, propylene glycol, ethylene glycol)
Paracetamol
Type B3: Hyperlactatemia due to inborn errors of metabolism (enzymatic deficiencies)
Congenital PDH deficiency
Glucose‐6‐phosphatase deficiency (von Gierke disease)
Pyruvate carboxylase deficiency
Methylmalonic aciduria
Mitochondrial encephalomyopathies
John Wiley & Sons, LtdAccelerated glycolysis
Any cause of an accelerated level of glycolysis causes an expected elevation of pyruvate and thus of lactate, as the physiologic ratio of lactate/pyruvate of approximately 10 or higher is always warranted by LDH. Accelerated glycolysis is the case in hyperglycemia, sepsis, or other situations with elevated endogenous or exogenous catecholamines (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014). Finally, accelerated aerobic glycolysis may partially explain the hyperlactatemia caused by tumoral cells of lactagenic cancers, known as the Warburg effect (San‐Millán & Brooks, 2017), the cause of lactic acidosis in the present case.
Elevated protein catabolism
Elevated protein catabolism can also cause a rise in pyruvate levels. As mentioned earlier, pyruvate can be transaminated into alanine, and the reverse can be witnessed through the activity of the ALT enzyme, forming pyruvate in the liver. This mechanism contributes to hepatic neoglucogenesis. Accelerated protein catabolism is seen as muscle wasting, present in many critically ill patients, most severely in burn victims and in patients with severe septic shock. The elevated alanine supply in the liver contributes to the elevated pyruvate concentration and, ultimately, to hyperlactatemia, as the physiologic lactate/pyruvate ratio is always warranted by LDH (Ben‐Hamouda et al., 2013).
Inhibition of PDH
As discussed earlier, pyruvate is oxidized into acetyl‐coenzyme‐A by PDH. A congenital or an acquired reduction in the enzymatic activity of PDH can cause an accumulation of pyruvate and therefore of lactate. An acquired reduction in PDH can be caused by certain endotoxins and inflammatory cytokines in sepsis. This explains why hemodynamically stable patients with sepsis and normal liver function may have lactic acidosis (Kraut & Madias, 2014). It can also be caused by nucleoside reverse transcriptase inhibitors used to treat patients with HIV or by a thiamine deficiency, as in patients receiving parenteral nutrition or with severe Beri‐beri. Thiamine is an important cofactor in the PDH complex. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead, conversion into lactate takes place (Friedenberg et al., 2007). Finally, certain oncogenes express PDH kinase, which inactivates PDH and inhibits the Krebs cycle (San‐Millán & Brooks, 2017; Swenson, 2016) and partially explains the development of hyperlactatemia caused by tumoral cells.
Cellular dysoxia
Perturbations of tissular oxygenation, termed “cellular dysoxia”, are caused by insufficient oxygen supply. This dysoxia can be either generalized due to a low cardiac output, carbon monoxide intoxication, profound arterial hemoglobin desaturation, and reduced oxygen content or either localized in the context of redistribution of the cardiac output at the expense of certain tissues or due to a vascular occlusion (Swenson, 2016). It can also be caused by mitochondrial enzyme defects and by inhibitors of aerobic metabolism, such as cyanide. Every drop in cellular oxygenation causes an acceleration of the reduction in pyruvate to lactate by LDH, which results in a pathological augmentation of the lactate/pyruvate ratio above 10 (Ben‐Hamouda et al., 2013). Even if the pyruvate dosage is expensive, its use and the finding of a pathological L/P level confirm cellular dysoxia and excludes other causes.
3.4.2 Reduced lactate clearance
Lactate is partly transported to the liver and the kidneys and converted to glucose through gluconeogenesis (the Cori cycle). The hepatic clearance of lactate thus depends on hepatic extraction and hepatic functioning. Hepatic extraction is determined by the liver blood flow, which needs no less than one‐fourth of its normal flow. The capture of lactate by hepatocytes depends on its transportation by a family of MCTs with different isoforms (MCT1‐4). Thus, neoglucogenesis will depend on hepatic functioning. Its activity is decreased in hepatic failure and inhibited in shock states and severe acidosis (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
3.5 Distinction between hyperlactatemia and lactic acidosis
Hyperlactatemia and lactic acidosis are frequently mixed, which may cause confusion. However, the two are governed by a different concept. Glycolysis causes lactate formation without lactic acidosis when there is no net H+ production. The H+ protons may arise following ATP hydrolyzation and are produced through glycolysis. However, those protons are recycled by lactate consumption either through the Krebs cycle or through the hepatic Cori cycle, hence maintaining the internal acid‐base balance (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
In this regard, acquired or congenital inhibition of PDH, inhibition of oxidative phosphorylation due to cellular dysoxia, medication or intoxication and hepatic insufficiency are all causes of reduced proton recycling in either the Krebs or the Cori cycle, therefore causing high anion gap lactic acidosis. Other causes of hyperlactatemia, such as elevated glycolysis in hyperglycemia, arising from beta‐adrenergic stimulation or muscular catabolism, will only cause an elevated production of lactate without proton recycling impairment and without ensuing concomitant lactic acidosis (Kraut & Madias, 2014).
3.6 Lactagenic cancers
3.6.1 Warburg effect
In glycolytic tumors, lactate levels of cancer cells are markedly elevated up to 40‐fold and are highly associated with cancer aggressiveness and poor survival (Brizel et al., 2001; San‐Millán & Brooks, 2017). In fast‐growing malignancies, the rate of tumor metabolism may be great enough to exceed normal muscle and liver lactate clearance and cause systemic type B lactic acidosis (Sillos et al., 2001; Swenson, 2016). The majority of lactic acidosis in malignancies is reported in cases of hematologic malignancies. Only a few cases have been reported for solid tumors presenting with lactic acidosis (Nair & Shah, 2017).
In 1923, Warburg observed in his Nobel Prize winning studies that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions and that tumor cells live and grow in a more acidic milieu as a result of increased lactic acid production not generally tolerated by normal cells (San‐Millán & Brooks, 2017; Swenson, 2016). His discovery was named the “Warburg effect” by Racker in 1972 (San‐Millán & Brooks, 2017). The Warburg effect is a hallmark of cancer, and its significance is still apparent in the common cancer diagnostic test using fluorodeoxyglucose positron emission tomography, which has a high diagnostic accuracy (Potter et al., 2016).
From a contemporary perspective of cell metabolic efficiency, it seems difficult to understand why, despite fully aerobic conditions, cancer cells choose an inefficient pathway producing two ATP molecules per molecule of glucose instead of 38 via coupled mitochondrial respiration. However, as mentioned earlier, the amount of ATP synthesized over any given period of time is comparable in both ways of glucose metabolism because fermentation into lactate is 10–100 times faster than the completion of oxidative phosphorylation (Liberti & Locasale, 2016). Moreover, the stress of lactate production is simply passed on to the host. Then, the cancer cells proliferate, and the tumor grows and metastasizes because of host exploitation, ending in final host expiration (San‐Millán & Brooks, 2017).
3.6.2 Origin of tumoral lactagenesis
Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous and unstoppable glucose utilization to produce lactate involving five major steps: (i) an increase in glucose uptake; (ii) upregulation of PFK, the rate‐limiting enzyme of glycolysis; (iii) a decrease in mitochondrial respiration by upregulation of PDH kinase (PDK) that inhibits pyruvate uptake in mitochondria; (iv) increased lactate production by LDH upregulation; and (v) upregulation of MCT1 and MCT4 expression, the transmembrane transporters of lactate, for higher lactate plus H+ efflux and further lactate shuttling, thus mediating tumor growth and proliferation (Brahimi‐Horn et al., 2011; San‐Millán & Brooks, 2017; Swenson, 2016).
In our case, the Warburg effect was caused by a Burkitt lymphoma, a B‐cell derived malignancy. The main characteristic of a Burkitt lymphoma is an increased production of the MYC oncoprotein caused by chromosomal rearrangements. This translocation results in inappropriately high expression levels of MYC, which gives cells proliferative capacity. Moreover, MYC also activates the transcription of genes encoding glucose transporter, hexokinase, MCT, PDK, PK (pyruvate kinase), and LDH, resulting in the accelerated aerobic glycolysis or the Warburg effect. The MYC protein is the master regulator of the Warburg effect in BL cells (Mushtaq et al., 2015).
3.6.3 Aim of tumoral lactagenesis
The role of the Warburg effect in the pathogenesis of cancer has not yet been completely established. Lactate is the end product of the Warburg effect, but lactate production or lactagenesis is probably the purpose of the Warburg effect as well.
In addition to being a potent oxidative fuel, lactate is also a potent signaling molecule necessary for all the major steps in carcinogenesis, as follows: (i) angiogenesis, (ii) cell migration, (iii) metastasis, (iv) immune escape, and (v) self‐sufficiency of cancer cells (San‐Millán & Brooks, 2017).
Lactate released from tumor cells by MCT4 plays a role in stimulating angiogenesis (i) by increasing the expression of vascular endothelial growth factor protein in endothelial cells (Goodwin et al., 2014; San‐Millán & Brooks, 2017). Cell migration (ii) is another essential step in carcinogenesis and metastasis in which lactate seems to be a key element to increase cell migration. Marked extracellular acidosis appears to promote the migration and metastasis (iii) of cancer cells by disrupting normal cell‐matrix interactions that act to maintain stable growth patterns (Swenson, 2016). Lactate levels are highly associated with a high incidence of distant metastasis. Acidosis reduces host defense against malignant cells and contributes to immune escape (iv) in many different ways: first, by inhibiting the release of the cytokines tumor necrosis factor and interleukin‐6; and second, by inhibiting the activation of T‐cells with a decrease in the cytotoxic activity of T‐cells and inhibition of natural killer cell functioning. Lactate also plays a central role in the self‐sufficiency and sustainability (v) of cancer cells. Cancer cells at the hypoxic core might use glucose and produce lactate, whereas cells on the periphery, close to a robust vascular supply, might take up this lactate and oxidize it as a fuel. The self‐sufficiency depending upon high glycolytic flux also allows cancer cells to produce lactate for carcinogenesis by angiogenesis, immune escape, cell migration, and metastasis. A glucose to lactate shunt occurs in which the host bears the burden of providing a limitless glucose supply as well as a sink for disposal of lactate and hydrogen ions. This may even explain why the actual cause of cachexia and death due to cancer appears to be multifactorial, with organ failure rather than the tumor itself (San‐Millán & Brooks, 2017).
3.6.4 Targeting lactate production and shuttling: Future direction in cancer treatment
Given the profound changes in acid‐base balance in tumors and the role of pH in tumor survival and growth, altering the acid‐base milieu has presented itself as an interesting approach for treating cancer (Swenson, 2016), but the development of these new adjuvant therapies goes way beyond the scope of this article. Nevertheless, after explaining all the pathophysiology, it seems important to shed light on some future possible treatments: on the one hand, medication increasing PDH activity, such as dichloroacetate, seems to halt carcinogenesis by lowering cytosolic lactate production; on the other hand, MCT1 and MCT4 inhibitors seem to have enormous potential in cancer treatment by inhibiting lactate shuttling, even if there is still a lack of specificity (San‐Millán & Brooks, 2017). Furthermore, simpler approaches such as aerobic exercise seem to have beneficial effects by augmenting mitochondrial size and function and thus lactate clearance capacity. Further research is necessary to identify possible targets and create tumor‐specific treatments.
3.6.5 Treatment options in patients with type‐B LA due to malignancies
Lactic acidosis in association with malignancies carries an extremely poor prognosis with a mortality rate over 90% (Nair & Shah, 2017; Sillos et al., 2001). Moreover, the high mortality associated with lactic acidosis has prompted some oncologists to consider this an oncological emergency (Nair & Shah, 2017). The best treatment for patients with hematologic malignancies who develop type B lactic acidosis is not yet clear.
Chemotherapy
Initiating aggressive chemotherapy has been effective in correcting acute acidosis (Friedenberg et al., 2007). It is actually the only treatment modality that consistently leads to remission. Resolution of lactic acidosis was reported to occur as early as 15 h and up to 3 days after starting chemotherapy. This treatment would not be effective in patients whose tumors are unresponsive to chemotherapy. Lactic acidosis improves with chemotherapy, and resolution of the lactic acidosis could be a surrogate marker of inducing remission (Chan et al., 2009).
Intravenous bicarbonate
The use of IV bicarbonate as a treatment for profound acidosis has never shown a meaningful clinical benefit, even in the worst cases (Swenson, 2016). As severe acidosis can cause respiratory fatigue and hemodynamic instability, intravenous bicarbonate is often used to attenuate systemic acidosis and increase the responsiveness to catecholamines. However, it would appear that the benefits of sodium bicarbonate are outweighed by its disadvantages, such as hypernatremia and hyperosmolality (Swenson, 2016). Acidemia leads to unloading oxygen from hemoglobin by shifting the hemoglobin‐oxygen dissociation curve to the right, and reducing acidosis will hinder oxygen release. Studies have shown that intracellular acidosis tends to slow lactate production (Madias, 1986; Sillos et al., 2001). Alkalinization has been shown to potentiate lactate production in patients with malignancy‐induced chronic lactic acidosis (Fields et al., 1981; Fraley et al., 1980). The effect of IV bicarbonate on mortality or lactate concentration in the setting of malignancy‐induced type B lactic acidosis has not been studied directly, as the incidence is very low. In a case report by Fraley et al. (1980), administration of bicarbonate improved pH but not the serum bicarbonate level. Intravenous bicarbonate corrected the extracellular pH but did not affect the significant intracellular acid production due to high tumor cell turnover. The use of sodium bicarbonate may not be recommended in these patient groups.
Renal replacement therapy
Renal replacement therapy, continuous or intermittent, in patients with renal dysfunction may be useful in addition to chemotherapy to correct metabolic acidosis. Here, once again, since the prognosis of type B lactic acidosis related to malignancies is grim, the only chance for remission is starting cytoreductive chemotherapy. Intravenous bicarbonate and hemodialysis will no longer act as a bridge to stabilize the patient enough so that the underlying cause can be treated (Chan et al., 2009).
Intravenous insulin
Lactic acidosis has also been treated with intravenous administration of insulin, which increases the conversion of pyruvate to acetyl‐coenzyme A and consequently facilitates oxidation of lactate to pyruvate (Sillos et al., 2001). Administration of glucose can actually induce lactic acidosis by increasing the availability of glucose and thus increasing the production of lactate by the tumor. Returning to the case presented in this manuscript, the patient was severely hypoglycemic, which is the reason why we substituted for intravenous glucose to maintain the patient's euglycemia. However, in a provocative hypothesis in 2009, Nijsten & van Dam (2009) presented a hypothetical treatment whereby glucose might be systemically lowered. If tumors are glucose consumers and lactate producers and all other tissues in the body can actively take up and use lactate as a fuel, why not systemically induce hypoglycemia to starve tumor cells? In this configuration, lactate would provide salvage fuel for the other tissues (Goodwin et al., 2014). Work to investigate this concept should be pursued.
4 CONCLUSION
Lactic acidosis is a commonly encountered problem in intensive care units and is most commonly associated with dysoxia, better known as type A lactic acidosis. Type B is more uncommon and can be life‐threatening and sometimes even a lethal complication in patients with malignancies. Due to its rareness, it is likely to be under recognized and therefore underdiagnosed. If oncological patients develop high anion gap lactic acidosis without hemodynamic compromise associated with acute respiratory distress without a pulmonary source, the possibility for tumor‐induced type B lactic acidosis through the “Warburg effect” should be considered. Awareness about this condition is important in the clinical practice of intensive care physicians since it will allow a timely diagnosis and the implementation of subsequent therapy. Currently, effective chemotherapy seems to be the only hope for survival.
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
Carole Looyens, and Karim Bendjelid designed the present review. Carole Looyens, and Karim Bendjelid analyzed data and references. Carole Looyens, Raphael Giraud, Ivo Neto Silva, and Karim Bendjelid wrote the manuscript. All authors read and approved the final manuscript.
DATA AVAILABILITY STATEMENT
The data that support these findings are available upon reasonable request from the corresponding author. | UNK, CYCLICAL | DrugDosageText | CC BY | 33611854 | 19,163,699 | 2021-02 |
What was the dosage of drug 'METHOTREXATE SODIUM'? | Burkitt lymphoma and lactic acidosis: A case report and review of the literature.
Type A lactic acidosis is a potentially life-threatening complication in critically ill patients and is the hallmark of a shock state as a result of tissue hypoperfusion and dysoxia. Type B lactic acidosis results from mechanisms other than dysoxia and is a rare condition in patients with solid tumors or hematological malignancies. We present a case of a 60-year-old man with lactic acidosis who was found to have a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Lactagenic cancers are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Warburg in 1923 that is correlated with cancer aggressiveness and poor survival. There is increased glucose utilization with the purpose of lactagenesis under fully oxygenated conditions, as lactate seems to be a potent signaling molecule for angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, which are five essential steps of carcinogenesis. Type B lactic acidosis in association with malignancies carries an extremely poor prognosis. Currently, effective chemotherapy seems to be the only hope for survival.
1 INTRODUCTION
A high arterial lactate level in critically ill patients has been associated with significant morbidity and mortality ever since the first description two centuries ago (Kompanje et al., 2007). Hyperlactatemia in the critically ill is the hallmark of shock states (Kraut & Madias, 2014; Levy, 2006; Nichol et al., 2010; Vincent & De Backer, 2013; Vincent et al., 2016), and the degree of increase in arterial lactate concentrations is directly related to the severity of the shock state (Haas et al., 2016; Nichol et al., 2011; Vincent et al., 2016). In this regard, the prognostic value of arterial lactate levels seems to be independent of the underlying critical illness (Jansen et al., 2010). Serial lactate measurements are widely used in intensive care medicine in the evaluation of the progression of a shock state and the response to intensive and urgent therapy (Levy et al., 2018; Vincent et al., 2016).
Although high lactate levels have been widely used as a marker of altered tissue perfusion in critically ill patients, this condition does not always simply reflect the development of anaerobic metabolism and cellular dysoxia better known as Type A lactic acidosis (Kraut & Madias, 2014; Vincent et al., 2016). While a lack of oxygen forbids the continuation of oxidative phosphorylation in the Krebs cycle, a normal oxygen supply does not impose a complete cessation of anaerobic metabolism. Type B lactic acidosis results from mechanisms other than dysoxia, including inborn errors of metabolism, drugs and toxins, systemic diseases (i.e., diabetes and sepsis), and less commonly malignancy. In this case report, we try to emphasize the pathophysiology leading to hyperlactatemia, and we will focus on the hyperlactatemia caused by lactagenic cancers and the Warburg effect.
2 CASE SUMMARY
A 60‐year‐old‐male patient presented at the emergency department with increasing abdominal girth, abdominal discomfort, severe asthenia, malaise, and profuse diaphoresis without fever. His medical history highlighted chronic renal failure (stage G3bA1) and a cardiac transplant 4 years ago due to terminal ischemic cardiomyopathy. His recent cardiac biopsy was free from any signs of rejection. He was taking immunosuppression with cyclosporine and mycophenolic acid. On admission, the clinical examination revealed a tense and distended abdomen with abdominal ascites. Initial vital signs were stable except for tachycardia at 110 beat per minute. The respiratory rate was 22 breath per minute, and the temperature was within the normal range. Physical exam was otherwise normal.
Laboratory analysis showed leukocytosis with a left shift, signs of hepatocellular injury without cholestasis, and chronic renal failure. His white blood count count was 14.8 G/L, C‐reactive protein was 45 mg/L (normal <10 mg/L), aspartate aminotransferase (AST) was 144 IU/L (normal, 14–50 IU/L), alanine aminotransferase (ALT) was 79 IU/L (normal, 12–50 IU/L), lactate dehydrogenase (LDH) was 1082 IU/L (normal, 87–210 IU/L), total bilirubin was 4 μmol/L (normal, 7–25 μmol/L), alkaline phosphatase was 82 IU/L (normal, 25–102 IU/L), gamma‐glutamyl transferase was 41 IU/L (normal, 9–40 IU/L), creatinine was 198 µmol/L (normal, 62–106 µmol/L), with an estimated glomerular filtration rate of 31 ml/min/1.73 m2. An ultrasound assessment confirmed the presence of moderate ascites in all four abdominal quadrants. Ascites liquid puncture showed leukocytosis, but the liquid culture remained sterile. Abdominal CT was then performed following a rapid clinical deterioration for abdominal sepsis, showing signs of diffuse peritonitis with a pelvic abscess located adjacent to the small intestine. The patient was therefore immediately started on broad‐spectrum antibiotics and antifungal treatment. In addition, a median laparotomy was performed to remove the pelvic abscess. The resected mass (suspect for any neoplasm) was sent for an extemporaneous analysis that elicited a high‐grade lymphoma. Later pathology testing confirmed a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Following emergency department admission and immediate surgery, the patient was admitted to the intensive care unit for high anion gap lactic acidosis, with a pH of 7.29 and a lactate level of 7.4 mmol/L on the arterial blood gas analysis. However, the patient's vital signs remained stable, and he could be extubated on the same day. Signs of hypoxia or circulatory failure were absent, capillary refill time was within normal limits and there was no skin mottling. Moreover, lactate/pyruvate ratio value was 19.0. In contrast, he simultaneously developed profuse hypoglycemia necessitating continuous high‐dose intravenous glucose supplementation. Cardiac output measured with bedside echocardiography appeared to be within the normal ranges. A new postoperative abdominal CT angiography was performed to exclude abdominal ischemia. The lactic acidosis (mean pH 7.3) remained for several days with lactate levels fluctuating around approximately 7 mmol/L. A concomitant thiamine deficiency was excluded by intravenous supplementation. Lactic acidosis started to decrease once chemotherapy with cyclophosphamide and vincristine, initiated 5 days after surgical resection, began to have an effect.
The interpretation of an initial positron emission tomography–computed tomography (PET‐CT) (Figures 1, 2, 3) 6 days after surgery was not clear due to the difficult differentiation between an infectious versus an oncological process. In addition to diffuse hypermetabolism in the peritoneal cavity associated with retroperitoneal adenopathies, it revealed supradiaphragmatic invasion of the lymphoma with a mass located in the right cardiophrenic recess, left mammary adenopathies, and pleural and pericardial nodules. There were also two hypermetabolic, osseous spots, suspected of metastasis, one in the second cervical vertebrae and one in the left scapula.
FIGURE 1 Left: Transversal image from patient's abdominal positron emission tomography–computed tomography (PET‐CT) post tumoral resection revealing diffuse peritoneal hypermetabolism with difficult differentiation between an infectious versus an oncological process. Middle: Transversal image from patients thoracic PET‐CT revealing supradiafragmatic invasion of the lymphoma with a mass and a nodule located in the right cardiophrenic recess with diffuse bilateral pleural nodular thickening. Right: Transversal image from patient's abdominal PET‐CT showing retroperitoneal adenopathies.
FIGURE 2 Lactate production and destination. Glycolysis takes place in the cellular cytosol. The preparatory phase consists of the generation of 1–3 diphosphoglycerate by hekoxinase and phosphofructokinase (PFK), the rate‐limiting enzyme. The pay off phase consists of the generation of pyruvate by pyruvate kinase. Pyruvate can be reduced to lactate by lactate dehydrogenase (LDH) or it can be converted to acetyl‐Co A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. Pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by alanine aminotransferase, resulting in the formation of alanine. Lactate either locally formed after reduction of pyruvate or coming from a distant source, can be consumed in the mitochondria by reformation of pyruvate by mitochondrial lactate dehydrogenase (mLDH) after diffusion across membranes via monocarboxylate transporters (MCTs). This concept is better known as the cell‐to‐cell lactate shuttle.
FIGURE 3 Lactate/pyruvate ratio. In aerobic glycolysis, the physiologic ratio of lactate/pyruvate is approximately 10 and is warranted by lactate dehydrogenase (LDH) catalyzing the reduction of pyruvate in lactate. When there is any perturbation of tissular oxygenation, cellular oxygenation is inhibited causing and acceleration of the reduction in pyruvate into lactate by LDH which results in a pathological lactate/pyruvate ratio above 10. The inhibition of the oxidative phosphorylation avoids any proton recycling leading to high anion gap lactic acidosis. Lactate is mostly converted into glucose through neoglucogenesis in the Cori cycle taking place in the liver and the kidneys. In case of insufficient hepatic perfusion or hepatic failure, lactate will be less cleared causing a variable lactate/pyruvate ratio depending on the source of production of lactate. Protons, normally recycled in the Cori cycle, will accumulate causing acidosis. MTC, monocarboxylate transporter.
He underwent intensive inpatient chemotherapy with one cycle of R‐CHP and six cycles of R‐CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride, O = vincristine sulfate, P = prednisone) and 10 prophylactic intrathecal injections of methotrexate. Chemotherapy was complicated with multiple episodes of febrile agranulocytosis, anemia and thrombocytopenia, which resolved after treatment with antibiotics in combination with filgrastim and multiple transfusions. The patient could be discharged with closed outpatient follow‐up after 5 months of admission. A PET‐CT was carried out 2 months after discharge and showed complete regression of all the lesions. A thoraco‐abdominal CT performed 1 year after the diagnosis seemed to be completely normal.
3 DISCUSSION
3.1 Lactate homeostasis
As with the blood levels of any substance, elevated lactate levels can be the result of increased production or reduced clearance, or both. Under physiological conditions, 1500 mmol of lactate or 20 mmol/kg of body weight is produced daily from various organs, including the muscle, intestine, red blood cells, brain, and skin (Kraut & Madias, 2014). Lactate is metabolized by the liver (60%), kidneys (30%), and other organs. The normal arterial blood lactate level is approximately 1 mmol/L (Kraut & Madias, 2014; Vincent et al., 2016).
3.2 Lactate production
Lactate formation is closely related to glycolysis. Glycolysis takes place in ten steps, five of which are in the preparatory phase and five in the payoff phase. Phosphofructokinase (PFK) is the rate‐limiting enzyme. Two net ATP molecules are generated by phosphorylation by high‐energy compounds. The final product of glycolysis is pyruvate and lactate, to which pyruvate can be reduced. LDH catalyzes the reduction of pyruvate into lactate at a well‐defined rate so that in normal homeostasis, the physiological ratio of lactate/pyruvate is approximately 10. In the presence of oxygen, pyruvate can be converted into acetyl‐coenzyme A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. This respiratory chain of reactions results in a net production of 36 ATP molecules per molecule of glucose. The metabolic yield of glycolysis when participating in the aerobic metabolic pathway (i.e., along with the Krebs cycle and oxidative phosphorylation) is superior to fermentation (without O2) into lactate (38 vs. 2 molecules of ATP). Anaerobic fermentation into lactate may be inefficient compared to oxidative phosphorylation, however, the rate of glucose metabolism into lactate is 10–100 times faster than the complete oxidation of glucose in the mitochondria (Liberti & Locasale, 2016). In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is utilized (Liberti & Locasale, 2016). In addition to the better‐known reduction to lactate and the oxidation to acetyl‐coenzyme A, for the completeness of this review, we need to mention that pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by ALT, resulting in the formation of alanine (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
Experiments by Pasteur (Platt, 1988), Meyerhof (1927), and A.V. Hill (Bassett, 2002) led to the widespread understanding of the glycolytic pathway and the notion that only a limitation of oxygen availability leads to fermentation and lactate accumulation. Out of this early work came the idea that lactate is just an anaerobic waste product that must be cleared from the muscles and blood, preferably by being converted to glucose in the liver via the Cori cycle. However, it has been demonstrated that lactate is a potent fuel and signaling molecule and is constantly being produced and circulated throughout the body, even and most often when there is adequate oxygen. Lactate is more than just a “hypoxic waste product.” Lactate as a result of dysoxia is often the exception rather than the rule, even in critically ill patients (Goodwin et al., 2014).
3.3 Lactate metabolism
Any time glycolysis is active, lactate is formed and equilibrates with local lactate gradients. Lactate equilibrates mainly by diffusing across membranes via monocarboxylate transporters (MCTs). In lactate‐producing tissues, this means exporting lactate into the circulation where both local and distant tissues can take it up and use it.
Lactate is metabolized by the liver (60%), kidneys (30%) and other organs. Lactate can be used for gluconeogenesis by reformation of pyruvate and glucose in the Cori cycle, which takes place in the liver and kidneys. In addition, lactate can readily replace glucose as a fuel for almost all cells of the body (any cell with mitochondria) by reformation and subsequent oxidation of pyruvate in the mitochondria. Lactate clearance occurs in the heart, liver, skeletal muscle and even brain. This observation that lactate is constantly being produced and consumed formed the basis of the cell‐to‐cell lactate shuttle, an energy exchange hypothesis originally introduced by Brooks in 1984 (Brooks, 1986). Lactate seems to be a key intermediate metabolite in whole body metabolism (Ben‐Hamouda et al., 2013; Goodwin et al., 2014; Kraut & Madias, 2014).
3.4 Hyperlactatemia (Table 1)
3.4.1 Elevated production of lactate
As mentioned earlier, normal lactate production is approximately 1 mmol/min or 1500 mmol/24 h, and the normal lactate level is approximately 1 mmol/L (Ben‐Hamouda et al., 2013; Vincent et al., 2016). Elevated lactate production can be the consequence of either an elevated pyruvate concentration (as seen in accelerated glycolysis, in elevated protein catabolism or through inhibition of PDH) or cellular dysoxia. Dysoxic lactic acidosis is better known as type‐A lactic acidosis, and all other nondysoxic causes of lactic acidosis are classified as type B according to the classification of Woods and Cohen (Ben‐Hamouda et al., 2013). Indeed, if lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics (i.e. normal blood pressure, normal volemia, normal blood oxygen, and oxygen‐carrying capacity), it is traditionally termed Type B lactic acidosis. In the present setting, the physiologic ratio value of lactate/pyruvate is around 10 or higher.
TABLE 1 Classification of hyperlactatemia according to Woods and Cohen
Type A: Hyperlactatemia associated with cellular dysoxia due to insufficient oxygen supply
Stagnant dysoxia Low cardiac output
Redistribution of cardiac output at the expense of certain tissues
Vascular occlusion
Dysoxia caused by elevated demand of oxygen Convulsions
Intensive exercise
Dysoxia caused by low oxygen carrying capacity Anemic dysoxia
Carbon monoxide intoxication
Hypoxic dysoxia (low PaO2)
Cytotoxic dysoxia due to inefficient mitochondrial consumption of oxygen Sepsis
Cyanide intoxication
Type B1: Hyperlactatemia due to an underlying disease
Accelerated glycolysis Hyperglycemia
Sepsis
Endogenous catecholamines
Lactagenic cancer
Elevated protein catabolism Burn victims
Severe septic shock
Acquired inhibition of pyruvate dehydrogenase (PDH) Sepsis
Thiamine deficiency
Lactagenic cancer
Reduced lactate clearance Reduced liver blood flow
Hepatic failure
Type B2: Hyperlactatemia due to drugs and toxins
Exogenous catecholamines (adrenaline, dobutamine, terbutaline) Cocaine, metamphetamines
Propofol Salicylates
Metformine Antiretroviral drugs
Linezolid Toxic alcohols (ethanol, methanol, propylene glycol, ethylene glycol)
Paracetamol
Type B3: Hyperlactatemia due to inborn errors of metabolism (enzymatic deficiencies)
Congenital PDH deficiency
Glucose‐6‐phosphatase deficiency (von Gierke disease)
Pyruvate carboxylase deficiency
Methylmalonic aciduria
Mitochondrial encephalomyopathies
John Wiley & Sons, LtdAccelerated glycolysis
Any cause of an accelerated level of glycolysis causes an expected elevation of pyruvate and thus of lactate, as the physiologic ratio of lactate/pyruvate of approximately 10 or higher is always warranted by LDH. Accelerated glycolysis is the case in hyperglycemia, sepsis, or other situations with elevated endogenous or exogenous catecholamines (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014). Finally, accelerated aerobic glycolysis may partially explain the hyperlactatemia caused by tumoral cells of lactagenic cancers, known as the Warburg effect (San‐Millán & Brooks, 2017), the cause of lactic acidosis in the present case.
Elevated protein catabolism
Elevated protein catabolism can also cause a rise in pyruvate levels. As mentioned earlier, pyruvate can be transaminated into alanine, and the reverse can be witnessed through the activity of the ALT enzyme, forming pyruvate in the liver. This mechanism contributes to hepatic neoglucogenesis. Accelerated protein catabolism is seen as muscle wasting, present in many critically ill patients, most severely in burn victims and in patients with severe septic shock. The elevated alanine supply in the liver contributes to the elevated pyruvate concentration and, ultimately, to hyperlactatemia, as the physiologic lactate/pyruvate ratio is always warranted by LDH (Ben‐Hamouda et al., 2013).
Inhibition of PDH
As discussed earlier, pyruvate is oxidized into acetyl‐coenzyme‐A by PDH. A congenital or an acquired reduction in the enzymatic activity of PDH can cause an accumulation of pyruvate and therefore of lactate. An acquired reduction in PDH can be caused by certain endotoxins and inflammatory cytokines in sepsis. This explains why hemodynamically stable patients with sepsis and normal liver function may have lactic acidosis (Kraut & Madias, 2014). It can also be caused by nucleoside reverse transcriptase inhibitors used to treat patients with HIV or by a thiamine deficiency, as in patients receiving parenteral nutrition or with severe Beri‐beri. Thiamine is an important cofactor in the PDH complex. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead, conversion into lactate takes place (Friedenberg et al., 2007). Finally, certain oncogenes express PDH kinase, which inactivates PDH and inhibits the Krebs cycle (San‐Millán & Brooks, 2017; Swenson, 2016) and partially explains the development of hyperlactatemia caused by tumoral cells.
Cellular dysoxia
Perturbations of tissular oxygenation, termed “cellular dysoxia”, are caused by insufficient oxygen supply. This dysoxia can be either generalized due to a low cardiac output, carbon monoxide intoxication, profound arterial hemoglobin desaturation, and reduced oxygen content or either localized in the context of redistribution of the cardiac output at the expense of certain tissues or due to a vascular occlusion (Swenson, 2016). It can also be caused by mitochondrial enzyme defects and by inhibitors of aerobic metabolism, such as cyanide. Every drop in cellular oxygenation causes an acceleration of the reduction in pyruvate to lactate by LDH, which results in a pathological augmentation of the lactate/pyruvate ratio above 10 (Ben‐Hamouda et al., 2013). Even if the pyruvate dosage is expensive, its use and the finding of a pathological L/P level confirm cellular dysoxia and excludes other causes.
3.4.2 Reduced lactate clearance
Lactate is partly transported to the liver and the kidneys and converted to glucose through gluconeogenesis (the Cori cycle). The hepatic clearance of lactate thus depends on hepatic extraction and hepatic functioning. Hepatic extraction is determined by the liver blood flow, which needs no less than one‐fourth of its normal flow. The capture of lactate by hepatocytes depends on its transportation by a family of MCTs with different isoforms (MCT1‐4). Thus, neoglucogenesis will depend on hepatic functioning. Its activity is decreased in hepatic failure and inhibited in shock states and severe acidosis (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
3.5 Distinction between hyperlactatemia and lactic acidosis
Hyperlactatemia and lactic acidosis are frequently mixed, which may cause confusion. However, the two are governed by a different concept. Glycolysis causes lactate formation without lactic acidosis when there is no net H+ production. The H+ protons may arise following ATP hydrolyzation and are produced through glycolysis. However, those protons are recycled by lactate consumption either through the Krebs cycle or through the hepatic Cori cycle, hence maintaining the internal acid‐base balance (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
In this regard, acquired or congenital inhibition of PDH, inhibition of oxidative phosphorylation due to cellular dysoxia, medication or intoxication and hepatic insufficiency are all causes of reduced proton recycling in either the Krebs or the Cori cycle, therefore causing high anion gap lactic acidosis. Other causes of hyperlactatemia, such as elevated glycolysis in hyperglycemia, arising from beta‐adrenergic stimulation or muscular catabolism, will only cause an elevated production of lactate without proton recycling impairment and without ensuing concomitant lactic acidosis (Kraut & Madias, 2014).
3.6 Lactagenic cancers
3.6.1 Warburg effect
In glycolytic tumors, lactate levels of cancer cells are markedly elevated up to 40‐fold and are highly associated with cancer aggressiveness and poor survival (Brizel et al., 2001; San‐Millán & Brooks, 2017). In fast‐growing malignancies, the rate of tumor metabolism may be great enough to exceed normal muscle and liver lactate clearance and cause systemic type B lactic acidosis (Sillos et al., 2001; Swenson, 2016). The majority of lactic acidosis in malignancies is reported in cases of hematologic malignancies. Only a few cases have been reported for solid tumors presenting with lactic acidosis (Nair & Shah, 2017).
In 1923, Warburg observed in his Nobel Prize winning studies that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions and that tumor cells live and grow in a more acidic milieu as a result of increased lactic acid production not generally tolerated by normal cells (San‐Millán & Brooks, 2017; Swenson, 2016). His discovery was named the “Warburg effect” by Racker in 1972 (San‐Millán & Brooks, 2017). The Warburg effect is a hallmark of cancer, and its significance is still apparent in the common cancer diagnostic test using fluorodeoxyglucose positron emission tomography, which has a high diagnostic accuracy (Potter et al., 2016).
From a contemporary perspective of cell metabolic efficiency, it seems difficult to understand why, despite fully aerobic conditions, cancer cells choose an inefficient pathway producing two ATP molecules per molecule of glucose instead of 38 via coupled mitochondrial respiration. However, as mentioned earlier, the amount of ATP synthesized over any given period of time is comparable in both ways of glucose metabolism because fermentation into lactate is 10–100 times faster than the completion of oxidative phosphorylation (Liberti & Locasale, 2016). Moreover, the stress of lactate production is simply passed on to the host. Then, the cancer cells proliferate, and the tumor grows and metastasizes because of host exploitation, ending in final host expiration (San‐Millán & Brooks, 2017).
3.6.2 Origin of tumoral lactagenesis
Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous and unstoppable glucose utilization to produce lactate involving five major steps: (i) an increase in glucose uptake; (ii) upregulation of PFK, the rate‐limiting enzyme of glycolysis; (iii) a decrease in mitochondrial respiration by upregulation of PDH kinase (PDK) that inhibits pyruvate uptake in mitochondria; (iv) increased lactate production by LDH upregulation; and (v) upregulation of MCT1 and MCT4 expression, the transmembrane transporters of lactate, for higher lactate plus H+ efflux and further lactate shuttling, thus mediating tumor growth and proliferation (Brahimi‐Horn et al., 2011; San‐Millán & Brooks, 2017; Swenson, 2016).
In our case, the Warburg effect was caused by a Burkitt lymphoma, a B‐cell derived malignancy. The main characteristic of a Burkitt lymphoma is an increased production of the MYC oncoprotein caused by chromosomal rearrangements. This translocation results in inappropriately high expression levels of MYC, which gives cells proliferative capacity. Moreover, MYC also activates the transcription of genes encoding glucose transporter, hexokinase, MCT, PDK, PK (pyruvate kinase), and LDH, resulting in the accelerated aerobic glycolysis or the Warburg effect. The MYC protein is the master regulator of the Warburg effect in BL cells (Mushtaq et al., 2015).
3.6.3 Aim of tumoral lactagenesis
The role of the Warburg effect in the pathogenesis of cancer has not yet been completely established. Lactate is the end product of the Warburg effect, but lactate production or lactagenesis is probably the purpose of the Warburg effect as well.
In addition to being a potent oxidative fuel, lactate is also a potent signaling molecule necessary for all the major steps in carcinogenesis, as follows: (i) angiogenesis, (ii) cell migration, (iii) metastasis, (iv) immune escape, and (v) self‐sufficiency of cancer cells (San‐Millán & Brooks, 2017).
Lactate released from tumor cells by MCT4 plays a role in stimulating angiogenesis (i) by increasing the expression of vascular endothelial growth factor protein in endothelial cells (Goodwin et al., 2014; San‐Millán & Brooks, 2017). Cell migration (ii) is another essential step in carcinogenesis and metastasis in which lactate seems to be a key element to increase cell migration. Marked extracellular acidosis appears to promote the migration and metastasis (iii) of cancer cells by disrupting normal cell‐matrix interactions that act to maintain stable growth patterns (Swenson, 2016). Lactate levels are highly associated with a high incidence of distant metastasis. Acidosis reduces host defense against malignant cells and contributes to immune escape (iv) in many different ways: first, by inhibiting the release of the cytokines tumor necrosis factor and interleukin‐6; and second, by inhibiting the activation of T‐cells with a decrease in the cytotoxic activity of T‐cells and inhibition of natural killer cell functioning. Lactate also plays a central role in the self‐sufficiency and sustainability (v) of cancer cells. Cancer cells at the hypoxic core might use glucose and produce lactate, whereas cells on the periphery, close to a robust vascular supply, might take up this lactate and oxidize it as a fuel. The self‐sufficiency depending upon high glycolytic flux also allows cancer cells to produce lactate for carcinogenesis by angiogenesis, immune escape, cell migration, and metastasis. A glucose to lactate shunt occurs in which the host bears the burden of providing a limitless glucose supply as well as a sink for disposal of lactate and hydrogen ions. This may even explain why the actual cause of cachexia and death due to cancer appears to be multifactorial, with organ failure rather than the tumor itself (San‐Millán & Brooks, 2017).
3.6.4 Targeting lactate production and shuttling: Future direction in cancer treatment
Given the profound changes in acid‐base balance in tumors and the role of pH in tumor survival and growth, altering the acid‐base milieu has presented itself as an interesting approach for treating cancer (Swenson, 2016), but the development of these new adjuvant therapies goes way beyond the scope of this article. Nevertheless, after explaining all the pathophysiology, it seems important to shed light on some future possible treatments: on the one hand, medication increasing PDH activity, such as dichloroacetate, seems to halt carcinogenesis by lowering cytosolic lactate production; on the other hand, MCT1 and MCT4 inhibitors seem to have enormous potential in cancer treatment by inhibiting lactate shuttling, even if there is still a lack of specificity (San‐Millán & Brooks, 2017). Furthermore, simpler approaches such as aerobic exercise seem to have beneficial effects by augmenting mitochondrial size and function and thus lactate clearance capacity. Further research is necessary to identify possible targets and create tumor‐specific treatments.
3.6.5 Treatment options in patients with type‐B LA due to malignancies
Lactic acidosis in association with malignancies carries an extremely poor prognosis with a mortality rate over 90% (Nair & Shah, 2017; Sillos et al., 2001). Moreover, the high mortality associated with lactic acidosis has prompted some oncologists to consider this an oncological emergency (Nair & Shah, 2017). The best treatment for patients with hematologic malignancies who develop type B lactic acidosis is not yet clear.
Chemotherapy
Initiating aggressive chemotherapy has been effective in correcting acute acidosis (Friedenberg et al., 2007). It is actually the only treatment modality that consistently leads to remission. Resolution of lactic acidosis was reported to occur as early as 15 h and up to 3 days after starting chemotherapy. This treatment would not be effective in patients whose tumors are unresponsive to chemotherapy. Lactic acidosis improves with chemotherapy, and resolution of the lactic acidosis could be a surrogate marker of inducing remission (Chan et al., 2009).
Intravenous bicarbonate
The use of IV bicarbonate as a treatment for profound acidosis has never shown a meaningful clinical benefit, even in the worst cases (Swenson, 2016). As severe acidosis can cause respiratory fatigue and hemodynamic instability, intravenous bicarbonate is often used to attenuate systemic acidosis and increase the responsiveness to catecholamines. However, it would appear that the benefits of sodium bicarbonate are outweighed by its disadvantages, such as hypernatremia and hyperosmolality (Swenson, 2016). Acidemia leads to unloading oxygen from hemoglobin by shifting the hemoglobin‐oxygen dissociation curve to the right, and reducing acidosis will hinder oxygen release. Studies have shown that intracellular acidosis tends to slow lactate production (Madias, 1986; Sillos et al., 2001). Alkalinization has been shown to potentiate lactate production in patients with malignancy‐induced chronic lactic acidosis (Fields et al., 1981; Fraley et al., 1980). The effect of IV bicarbonate on mortality or lactate concentration in the setting of malignancy‐induced type B lactic acidosis has not been studied directly, as the incidence is very low. In a case report by Fraley et al. (1980), administration of bicarbonate improved pH but not the serum bicarbonate level. Intravenous bicarbonate corrected the extracellular pH but did not affect the significant intracellular acid production due to high tumor cell turnover. The use of sodium bicarbonate may not be recommended in these patient groups.
Renal replacement therapy
Renal replacement therapy, continuous or intermittent, in patients with renal dysfunction may be useful in addition to chemotherapy to correct metabolic acidosis. Here, once again, since the prognosis of type B lactic acidosis related to malignancies is grim, the only chance for remission is starting cytoreductive chemotherapy. Intravenous bicarbonate and hemodialysis will no longer act as a bridge to stabilize the patient enough so that the underlying cause can be treated (Chan et al., 2009).
Intravenous insulin
Lactic acidosis has also been treated with intravenous administration of insulin, which increases the conversion of pyruvate to acetyl‐coenzyme A and consequently facilitates oxidation of lactate to pyruvate (Sillos et al., 2001). Administration of glucose can actually induce lactic acidosis by increasing the availability of glucose and thus increasing the production of lactate by the tumor. Returning to the case presented in this manuscript, the patient was severely hypoglycemic, which is the reason why we substituted for intravenous glucose to maintain the patient's euglycemia. However, in a provocative hypothesis in 2009, Nijsten & van Dam (2009) presented a hypothetical treatment whereby glucose might be systemically lowered. If tumors are glucose consumers and lactate producers and all other tissues in the body can actively take up and use lactate as a fuel, why not systemically induce hypoglycemia to starve tumor cells? In this configuration, lactate would provide salvage fuel for the other tissues (Goodwin et al., 2014). Work to investigate this concept should be pursued.
4 CONCLUSION
Lactic acidosis is a commonly encountered problem in intensive care units and is most commonly associated with dysoxia, better known as type A lactic acidosis. Type B is more uncommon and can be life‐threatening and sometimes even a lethal complication in patients with malignancies. Due to its rareness, it is likely to be under recognized and therefore underdiagnosed. If oncological patients develop high anion gap lactic acidosis without hemodynamic compromise associated with acute respiratory distress without a pulmonary source, the possibility for tumor‐induced type B lactic acidosis through the “Warburg effect” should be considered. Awareness about this condition is important in the clinical practice of intensive care physicians since it will allow a timely diagnosis and the implementation of subsequent therapy. Currently, effective chemotherapy seems to be the only hope for survival.
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
Carole Looyens, and Karim Bendjelid designed the present review. Carole Looyens, and Karim Bendjelid analyzed data and references. Carole Looyens, Raphael Giraud, Ivo Neto Silva, and Karim Bendjelid wrote the manuscript. All authors read and approved the final manuscript.
DATA AVAILABILITY STATEMENT
The data that support these findings are available upon reasonable request from the corresponding author. | 10 DF | DrugDosageText | CC BY | 33611854 | 19,126,628 | 2021-02 |
What was the dosage of drug 'PREDNISOLONE'? | Burkitt lymphoma and lactic acidosis: A case report and review of the literature.
Type A lactic acidosis is a potentially life-threatening complication in critically ill patients and is the hallmark of a shock state as a result of tissue hypoperfusion and dysoxia. Type B lactic acidosis results from mechanisms other than dysoxia and is a rare condition in patients with solid tumors or hematological malignancies. We present a case of a 60-year-old man with lactic acidosis who was found to have a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Lactagenic cancers are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Warburg in 1923 that is correlated with cancer aggressiveness and poor survival. There is increased glucose utilization with the purpose of lactagenesis under fully oxygenated conditions, as lactate seems to be a potent signaling molecule for angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, which are five essential steps of carcinogenesis. Type B lactic acidosis in association with malignancies carries an extremely poor prognosis. Currently, effective chemotherapy seems to be the only hope for survival.
1 INTRODUCTION
A high arterial lactate level in critically ill patients has been associated with significant morbidity and mortality ever since the first description two centuries ago (Kompanje et al., 2007). Hyperlactatemia in the critically ill is the hallmark of shock states (Kraut & Madias, 2014; Levy, 2006; Nichol et al., 2010; Vincent & De Backer, 2013; Vincent et al., 2016), and the degree of increase in arterial lactate concentrations is directly related to the severity of the shock state (Haas et al., 2016; Nichol et al., 2011; Vincent et al., 2016). In this regard, the prognostic value of arterial lactate levels seems to be independent of the underlying critical illness (Jansen et al., 2010). Serial lactate measurements are widely used in intensive care medicine in the evaluation of the progression of a shock state and the response to intensive and urgent therapy (Levy et al., 2018; Vincent et al., 2016).
Although high lactate levels have been widely used as a marker of altered tissue perfusion in critically ill patients, this condition does not always simply reflect the development of anaerobic metabolism and cellular dysoxia better known as Type A lactic acidosis (Kraut & Madias, 2014; Vincent et al., 2016). While a lack of oxygen forbids the continuation of oxidative phosphorylation in the Krebs cycle, a normal oxygen supply does not impose a complete cessation of anaerobic metabolism. Type B lactic acidosis results from mechanisms other than dysoxia, including inborn errors of metabolism, drugs and toxins, systemic diseases (i.e., diabetes and sepsis), and less commonly malignancy. In this case report, we try to emphasize the pathophysiology leading to hyperlactatemia, and we will focus on the hyperlactatemia caused by lactagenic cancers and the Warburg effect.
2 CASE SUMMARY
A 60‐year‐old‐male patient presented at the emergency department with increasing abdominal girth, abdominal discomfort, severe asthenia, malaise, and profuse diaphoresis without fever. His medical history highlighted chronic renal failure (stage G3bA1) and a cardiac transplant 4 years ago due to terminal ischemic cardiomyopathy. His recent cardiac biopsy was free from any signs of rejection. He was taking immunosuppression with cyclosporine and mycophenolic acid. On admission, the clinical examination revealed a tense and distended abdomen with abdominal ascites. Initial vital signs were stable except for tachycardia at 110 beat per minute. The respiratory rate was 22 breath per minute, and the temperature was within the normal range. Physical exam was otherwise normal.
Laboratory analysis showed leukocytosis with a left shift, signs of hepatocellular injury without cholestasis, and chronic renal failure. His white blood count count was 14.8 G/L, C‐reactive protein was 45 mg/L (normal <10 mg/L), aspartate aminotransferase (AST) was 144 IU/L (normal, 14–50 IU/L), alanine aminotransferase (ALT) was 79 IU/L (normal, 12–50 IU/L), lactate dehydrogenase (LDH) was 1082 IU/L (normal, 87–210 IU/L), total bilirubin was 4 μmol/L (normal, 7–25 μmol/L), alkaline phosphatase was 82 IU/L (normal, 25–102 IU/L), gamma‐glutamyl transferase was 41 IU/L (normal, 9–40 IU/L), creatinine was 198 µmol/L (normal, 62–106 µmol/L), with an estimated glomerular filtration rate of 31 ml/min/1.73 m2. An ultrasound assessment confirmed the presence of moderate ascites in all four abdominal quadrants. Ascites liquid puncture showed leukocytosis, but the liquid culture remained sterile. Abdominal CT was then performed following a rapid clinical deterioration for abdominal sepsis, showing signs of diffuse peritonitis with a pelvic abscess located adjacent to the small intestine. The patient was therefore immediately started on broad‐spectrum antibiotics and antifungal treatment. In addition, a median laparotomy was performed to remove the pelvic abscess. The resected mass (suspect for any neoplasm) was sent for an extemporaneous analysis that elicited a high‐grade lymphoma. Later pathology testing confirmed a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Following emergency department admission and immediate surgery, the patient was admitted to the intensive care unit for high anion gap lactic acidosis, with a pH of 7.29 and a lactate level of 7.4 mmol/L on the arterial blood gas analysis. However, the patient's vital signs remained stable, and he could be extubated on the same day. Signs of hypoxia or circulatory failure were absent, capillary refill time was within normal limits and there was no skin mottling. Moreover, lactate/pyruvate ratio value was 19.0. In contrast, he simultaneously developed profuse hypoglycemia necessitating continuous high‐dose intravenous glucose supplementation. Cardiac output measured with bedside echocardiography appeared to be within the normal ranges. A new postoperative abdominal CT angiography was performed to exclude abdominal ischemia. The lactic acidosis (mean pH 7.3) remained for several days with lactate levels fluctuating around approximately 7 mmol/L. A concomitant thiamine deficiency was excluded by intravenous supplementation. Lactic acidosis started to decrease once chemotherapy with cyclophosphamide and vincristine, initiated 5 days after surgical resection, began to have an effect.
The interpretation of an initial positron emission tomography–computed tomography (PET‐CT) (Figures 1, 2, 3) 6 days after surgery was not clear due to the difficult differentiation between an infectious versus an oncological process. In addition to diffuse hypermetabolism in the peritoneal cavity associated with retroperitoneal adenopathies, it revealed supradiaphragmatic invasion of the lymphoma with a mass located in the right cardiophrenic recess, left mammary adenopathies, and pleural and pericardial nodules. There were also two hypermetabolic, osseous spots, suspected of metastasis, one in the second cervical vertebrae and one in the left scapula.
FIGURE 1 Left: Transversal image from patient's abdominal positron emission tomography–computed tomography (PET‐CT) post tumoral resection revealing diffuse peritoneal hypermetabolism with difficult differentiation between an infectious versus an oncological process. Middle: Transversal image from patients thoracic PET‐CT revealing supradiafragmatic invasion of the lymphoma with a mass and a nodule located in the right cardiophrenic recess with diffuse bilateral pleural nodular thickening. Right: Transversal image from patient's abdominal PET‐CT showing retroperitoneal adenopathies.
FIGURE 2 Lactate production and destination. Glycolysis takes place in the cellular cytosol. The preparatory phase consists of the generation of 1–3 diphosphoglycerate by hekoxinase and phosphofructokinase (PFK), the rate‐limiting enzyme. The pay off phase consists of the generation of pyruvate by pyruvate kinase. Pyruvate can be reduced to lactate by lactate dehydrogenase (LDH) or it can be converted to acetyl‐Co A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. Pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by alanine aminotransferase, resulting in the formation of alanine. Lactate either locally formed after reduction of pyruvate or coming from a distant source, can be consumed in the mitochondria by reformation of pyruvate by mitochondrial lactate dehydrogenase (mLDH) after diffusion across membranes via monocarboxylate transporters (MCTs). This concept is better known as the cell‐to‐cell lactate shuttle.
FIGURE 3 Lactate/pyruvate ratio. In aerobic glycolysis, the physiologic ratio of lactate/pyruvate is approximately 10 and is warranted by lactate dehydrogenase (LDH) catalyzing the reduction of pyruvate in lactate. When there is any perturbation of tissular oxygenation, cellular oxygenation is inhibited causing and acceleration of the reduction in pyruvate into lactate by LDH which results in a pathological lactate/pyruvate ratio above 10. The inhibition of the oxidative phosphorylation avoids any proton recycling leading to high anion gap lactic acidosis. Lactate is mostly converted into glucose through neoglucogenesis in the Cori cycle taking place in the liver and the kidneys. In case of insufficient hepatic perfusion or hepatic failure, lactate will be less cleared causing a variable lactate/pyruvate ratio depending on the source of production of lactate. Protons, normally recycled in the Cori cycle, will accumulate causing acidosis. MTC, monocarboxylate transporter.
He underwent intensive inpatient chemotherapy with one cycle of R‐CHP and six cycles of R‐CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride, O = vincristine sulfate, P = prednisone) and 10 prophylactic intrathecal injections of methotrexate. Chemotherapy was complicated with multiple episodes of febrile agranulocytosis, anemia and thrombocytopenia, which resolved after treatment with antibiotics in combination with filgrastim and multiple transfusions. The patient could be discharged with closed outpatient follow‐up after 5 months of admission. A PET‐CT was carried out 2 months after discharge and showed complete regression of all the lesions. A thoraco‐abdominal CT performed 1 year after the diagnosis seemed to be completely normal.
3 DISCUSSION
3.1 Lactate homeostasis
As with the blood levels of any substance, elevated lactate levels can be the result of increased production or reduced clearance, or both. Under physiological conditions, 1500 mmol of lactate or 20 mmol/kg of body weight is produced daily from various organs, including the muscle, intestine, red blood cells, brain, and skin (Kraut & Madias, 2014). Lactate is metabolized by the liver (60%), kidneys (30%), and other organs. The normal arterial blood lactate level is approximately 1 mmol/L (Kraut & Madias, 2014; Vincent et al., 2016).
3.2 Lactate production
Lactate formation is closely related to glycolysis. Glycolysis takes place in ten steps, five of which are in the preparatory phase and five in the payoff phase. Phosphofructokinase (PFK) is the rate‐limiting enzyme. Two net ATP molecules are generated by phosphorylation by high‐energy compounds. The final product of glycolysis is pyruvate and lactate, to which pyruvate can be reduced. LDH catalyzes the reduction of pyruvate into lactate at a well‐defined rate so that in normal homeostasis, the physiological ratio of lactate/pyruvate is approximately 10. In the presence of oxygen, pyruvate can be converted into acetyl‐coenzyme A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. This respiratory chain of reactions results in a net production of 36 ATP molecules per molecule of glucose. The metabolic yield of glycolysis when participating in the aerobic metabolic pathway (i.e., along with the Krebs cycle and oxidative phosphorylation) is superior to fermentation (without O2) into lactate (38 vs. 2 molecules of ATP). Anaerobic fermentation into lactate may be inefficient compared to oxidative phosphorylation, however, the rate of glucose metabolism into lactate is 10–100 times faster than the complete oxidation of glucose in the mitochondria (Liberti & Locasale, 2016). In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is utilized (Liberti & Locasale, 2016). In addition to the better‐known reduction to lactate and the oxidation to acetyl‐coenzyme A, for the completeness of this review, we need to mention that pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by ALT, resulting in the formation of alanine (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
Experiments by Pasteur (Platt, 1988), Meyerhof (1927), and A.V. Hill (Bassett, 2002) led to the widespread understanding of the glycolytic pathway and the notion that only a limitation of oxygen availability leads to fermentation and lactate accumulation. Out of this early work came the idea that lactate is just an anaerobic waste product that must be cleared from the muscles and blood, preferably by being converted to glucose in the liver via the Cori cycle. However, it has been demonstrated that lactate is a potent fuel and signaling molecule and is constantly being produced and circulated throughout the body, even and most often when there is adequate oxygen. Lactate is more than just a “hypoxic waste product.” Lactate as a result of dysoxia is often the exception rather than the rule, even in critically ill patients (Goodwin et al., 2014).
3.3 Lactate metabolism
Any time glycolysis is active, lactate is formed and equilibrates with local lactate gradients. Lactate equilibrates mainly by diffusing across membranes via monocarboxylate transporters (MCTs). In lactate‐producing tissues, this means exporting lactate into the circulation where both local and distant tissues can take it up and use it.
Lactate is metabolized by the liver (60%), kidneys (30%) and other organs. Lactate can be used for gluconeogenesis by reformation of pyruvate and glucose in the Cori cycle, which takes place in the liver and kidneys. In addition, lactate can readily replace glucose as a fuel for almost all cells of the body (any cell with mitochondria) by reformation and subsequent oxidation of pyruvate in the mitochondria. Lactate clearance occurs in the heart, liver, skeletal muscle and even brain. This observation that lactate is constantly being produced and consumed formed the basis of the cell‐to‐cell lactate shuttle, an energy exchange hypothesis originally introduced by Brooks in 1984 (Brooks, 1986). Lactate seems to be a key intermediate metabolite in whole body metabolism (Ben‐Hamouda et al., 2013; Goodwin et al., 2014; Kraut & Madias, 2014).
3.4 Hyperlactatemia (Table 1)
3.4.1 Elevated production of lactate
As mentioned earlier, normal lactate production is approximately 1 mmol/min or 1500 mmol/24 h, and the normal lactate level is approximately 1 mmol/L (Ben‐Hamouda et al., 2013; Vincent et al., 2016). Elevated lactate production can be the consequence of either an elevated pyruvate concentration (as seen in accelerated glycolysis, in elevated protein catabolism or through inhibition of PDH) or cellular dysoxia. Dysoxic lactic acidosis is better known as type‐A lactic acidosis, and all other nondysoxic causes of lactic acidosis are classified as type B according to the classification of Woods and Cohen (Ben‐Hamouda et al., 2013). Indeed, if lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics (i.e. normal blood pressure, normal volemia, normal blood oxygen, and oxygen‐carrying capacity), it is traditionally termed Type B lactic acidosis. In the present setting, the physiologic ratio value of lactate/pyruvate is around 10 or higher.
TABLE 1 Classification of hyperlactatemia according to Woods and Cohen
Type A: Hyperlactatemia associated with cellular dysoxia due to insufficient oxygen supply
Stagnant dysoxia Low cardiac output
Redistribution of cardiac output at the expense of certain tissues
Vascular occlusion
Dysoxia caused by elevated demand of oxygen Convulsions
Intensive exercise
Dysoxia caused by low oxygen carrying capacity Anemic dysoxia
Carbon monoxide intoxication
Hypoxic dysoxia (low PaO2)
Cytotoxic dysoxia due to inefficient mitochondrial consumption of oxygen Sepsis
Cyanide intoxication
Type B1: Hyperlactatemia due to an underlying disease
Accelerated glycolysis Hyperglycemia
Sepsis
Endogenous catecholamines
Lactagenic cancer
Elevated protein catabolism Burn victims
Severe septic shock
Acquired inhibition of pyruvate dehydrogenase (PDH) Sepsis
Thiamine deficiency
Lactagenic cancer
Reduced lactate clearance Reduced liver blood flow
Hepatic failure
Type B2: Hyperlactatemia due to drugs and toxins
Exogenous catecholamines (adrenaline, dobutamine, terbutaline) Cocaine, metamphetamines
Propofol Salicylates
Metformine Antiretroviral drugs
Linezolid Toxic alcohols (ethanol, methanol, propylene glycol, ethylene glycol)
Paracetamol
Type B3: Hyperlactatemia due to inborn errors of metabolism (enzymatic deficiencies)
Congenital PDH deficiency
Glucose‐6‐phosphatase deficiency (von Gierke disease)
Pyruvate carboxylase deficiency
Methylmalonic aciduria
Mitochondrial encephalomyopathies
John Wiley & Sons, LtdAccelerated glycolysis
Any cause of an accelerated level of glycolysis causes an expected elevation of pyruvate and thus of lactate, as the physiologic ratio of lactate/pyruvate of approximately 10 or higher is always warranted by LDH. Accelerated glycolysis is the case in hyperglycemia, sepsis, or other situations with elevated endogenous or exogenous catecholamines (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014). Finally, accelerated aerobic glycolysis may partially explain the hyperlactatemia caused by tumoral cells of lactagenic cancers, known as the Warburg effect (San‐Millán & Brooks, 2017), the cause of lactic acidosis in the present case.
Elevated protein catabolism
Elevated protein catabolism can also cause a rise in pyruvate levels. As mentioned earlier, pyruvate can be transaminated into alanine, and the reverse can be witnessed through the activity of the ALT enzyme, forming pyruvate in the liver. This mechanism contributes to hepatic neoglucogenesis. Accelerated protein catabolism is seen as muscle wasting, present in many critically ill patients, most severely in burn victims and in patients with severe septic shock. The elevated alanine supply in the liver contributes to the elevated pyruvate concentration and, ultimately, to hyperlactatemia, as the physiologic lactate/pyruvate ratio is always warranted by LDH (Ben‐Hamouda et al., 2013).
Inhibition of PDH
As discussed earlier, pyruvate is oxidized into acetyl‐coenzyme‐A by PDH. A congenital or an acquired reduction in the enzymatic activity of PDH can cause an accumulation of pyruvate and therefore of lactate. An acquired reduction in PDH can be caused by certain endotoxins and inflammatory cytokines in sepsis. This explains why hemodynamically stable patients with sepsis and normal liver function may have lactic acidosis (Kraut & Madias, 2014). It can also be caused by nucleoside reverse transcriptase inhibitors used to treat patients with HIV or by a thiamine deficiency, as in patients receiving parenteral nutrition or with severe Beri‐beri. Thiamine is an important cofactor in the PDH complex. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead, conversion into lactate takes place (Friedenberg et al., 2007). Finally, certain oncogenes express PDH kinase, which inactivates PDH and inhibits the Krebs cycle (San‐Millán & Brooks, 2017; Swenson, 2016) and partially explains the development of hyperlactatemia caused by tumoral cells.
Cellular dysoxia
Perturbations of tissular oxygenation, termed “cellular dysoxia”, are caused by insufficient oxygen supply. This dysoxia can be either generalized due to a low cardiac output, carbon monoxide intoxication, profound arterial hemoglobin desaturation, and reduced oxygen content or either localized in the context of redistribution of the cardiac output at the expense of certain tissues or due to a vascular occlusion (Swenson, 2016). It can also be caused by mitochondrial enzyme defects and by inhibitors of aerobic metabolism, such as cyanide. Every drop in cellular oxygenation causes an acceleration of the reduction in pyruvate to lactate by LDH, which results in a pathological augmentation of the lactate/pyruvate ratio above 10 (Ben‐Hamouda et al., 2013). Even if the pyruvate dosage is expensive, its use and the finding of a pathological L/P level confirm cellular dysoxia and excludes other causes.
3.4.2 Reduced lactate clearance
Lactate is partly transported to the liver and the kidneys and converted to glucose through gluconeogenesis (the Cori cycle). The hepatic clearance of lactate thus depends on hepatic extraction and hepatic functioning. Hepatic extraction is determined by the liver blood flow, which needs no less than one‐fourth of its normal flow. The capture of lactate by hepatocytes depends on its transportation by a family of MCTs with different isoforms (MCT1‐4). Thus, neoglucogenesis will depend on hepatic functioning. Its activity is decreased in hepatic failure and inhibited in shock states and severe acidosis (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
3.5 Distinction between hyperlactatemia and lactic acidosis
Hyperlactatemia and lactic acidosis are frequently mixed, which may cause confusion. However, the two are governed by a different concept. Glycolysis causes lactate formation without lactic acidosis when there is no net H+ production. The H+ protons may arise following ATP hydrolyzation and are produced through glycolysis. However, those protons are recycled by lactate consumption either through the Krebs cycle or through the hepatic Cori cycle, hence maintaining the internal acid‐base balance (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
In this regard, acquired or congenital inhibition of PDH, inhibition of oxidative phosphorylation due to cellular dysoxia, medication or intoxication and hepatic insufficiency are all causes of reduced proton recycling in either the Krebs or the Cori cycle, therefore causing high anion gap lactic acidosis. Other causes of hyperlactatemia, such as elevated glycolysis in hyperglycemia, arising from beta‐adrenergic stimulation or muscular catabolism, will only cause an elevated production of lactate without proton recycling impairment and without ensuing concomitant lactic acidosis (Kraut & Madias, 2014).
3.6 Lactagenic cancers
3.6.1 Warburg effect
In glycolytic tumors, lactate levels of cancer cells are markedly elevated up to 40‐fold and are highly associated with cancer aggressiveness and poor survival (Brizel et al., 2001; San‐Millán & Brooks, 2017). In fast‐growing malignancies, the rate of tumor metabolism may be great enough to exceed normal muscle and liver lactate clearance and cause systemic type B lactic acidosis (Sillos et al., 2001; Swenson, 2016). The majority of lactic acidosis in malignancies is reported in cases of hematologic malignancies. Only a few cases have been reported for solid tumors presenting with lactic acidosis (Nair & Shah, 2017).
In 1923, Warburg observed in his Nobel Prize winning studies that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions and that tumor cells live and grow in a more acidic milieu as a result of increased lactic acid production not generally tolerated by normal cells (San‐Millán & Brooks, 2017; Swenson, 2016). His discovery was named the “Warburg effect” by Racker in 1972 (San‐Millán & Brooks, 2017). The Warburg effect is a hallmark of cancer, and its significance is still apparent in the common cancer diagnostic test using fluorodeoxyglucose positron emission tomography, which has a high diagnostic accuracy (Potter et al., 2016).
From a contemporary perspective of cell metabolic efficiency, it seems difficult to understand why, despite fully aerobic conditions, cancer cells choose an inefficient pathway producing two ATP molecules per molecule of glucose instead of 38 via coupled mitochondrial respiration. However, as mentioned earlier, the amount of ATP synthesized over any given period of time is comparable in both ways of glucose metabolism because fermentation into lactate is 10–100 times faster than the completion of oxidative phosphorylation (Liberti & Locasale, 2016). Moreover, the stress of lactate production is simply passed on to the host. Then, the cancer cells proliferate, and the tumor grows and metastasizes because of host exploitation, ending in final host expiration (San‐Millán & Brooks, 2017).
3.6.2 Origin of tumoral lactagenesis
Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous and unstoppable glucose utilization to produce lactate involving five major steps: (i) an increase in glucose uptake; (ii) upregulation of PFK, the rate‐limiting enzyme of glycolysis; (iii) a decrease in mitochondrial respiration by upregulation of PDH kinase (PDK) that inhibits pyruvate uptake in mitochondria; (iv) increased lactate production by LDH upregulation; and (v) upregulation of MCT1 and MCT4 expression, the transmembrane transporters of lactate, for higher lactate plus H+ efflux and further lactate shuttling, thus mediating tumor growth and proliferation (Brahimi‐Horn et al., 2011; San‐Millán & Brooks, 2017; Swenson, 2016).
In our case, the Warburg effect was caused by a Burkitt lymphoma, a B‐cell derived malignancy. The main characteristic of a Burkitt lymphoma is an increased production of the MYC oncoprotein caused by chromosomal rearrangements. This translocation results in inappropriately high expression levels of MYC, which gives cells proliferative capacity. Moreover, MYC also activates the transcription of genes encoding glucose transporter, hexokinase, MCT, PDK, PK (pyruvate kinase), and LDH, resulting in the accelerated aerobic glycolysis or the Warburg effect. The MYC protein is the master regulator of the Warburg effect in BL cells (Mushtaq et al., 2015).
3.6.3 Aim of tumoral lactagenesis
The role of the Warburg effect in the pathogenesis of cancer has not yet been completely established. Lactate is the end product of the Warburg effect, but lactate production or lactagenesis is probably the purpose of the Warburg effect as well.
In addition to being a potent oxidative fuel, lactate is also a potent signaling molecule necessary for all the major steps in carcinogenesis, as follows: (i) angiogenesis, (ii) cell migration, (iii) metastasis, (iv) immune escape, and (v) self‐sufficiency of cancer cells (San‐Millán & Brooks, 2017).
Lactate released from tumor cells by MCT4 plays a role in stimulating angiogenesis (i) by increasing the expression of vascular endothelial growth factor protein in endothelial cells (Goodwin et al., 2014; San‐Millán & Brooks, 2017). Cell migration (ii) is another essential step in carcinogenesis and metastasis in which lactate seems to be a key element to increase cell migration. Marked extracellular acidosis appears to promote the migration and metastasis (iii) of cancer cells by disrupting normal cell‐matrix interactions that act to maintain stable growth patterns (Swenson, 2016). Lactate levels are highly associated with a high incidence of distant metastasis. Acidosis reduces host defense against malignant cells and contributes to immune escape (iv) in many different ways: first, by inhibiting the release of the cytokines tumor necrosis factor and interleukin‐6; and second, by inhibiting the activation of T‐cells with a decrease in the cytotoxic activity of T‐cells and inhibition of natural killer cell functioning. Lactate also plays a central role in the self‐sufficiency and sustainability (v) of cancer cells. Cancer cells at the hypoxic core might use glucose and produce lactate, whereas cells on the periphery, close to a robust vascular supply, might take up this lactate and oxidize it as a fuel. The self‐sufficiency depending upon high glycolytic flux also allows cancer cells to produce lactate for carcinogenesis by angiogenesis, immune escape, cell migration, and metastasis. A glucose to lactate shunt occurs in which the host bears the burden of providing a limitless glucose supply as well as a sink for disposal of lactate and hydrogen ions. This may even explain why the actual cause of cachexia and death due to cancer appears to be multifactorial, with organ failure rather than the tumor itself (San‐Millán & Brooks, 2017).
3.6.4 Targeting lactate production and shuttling: Future direction in cancer treatment
Given the profound changes in acid‐base balance in tumors and the role of pH in tumor survival and growth, altering the acid‐base milieu has presented itself as an interesting approach for treating cancer (Swenson, 2016), but the development of these new adjuvant therapies goes way beyond the scope of this article. Nevertheless, after explaining all the pathophysiology, it seems important to shed light on some future possible treatments: on the one hand, medication increasing PDH activity, such as dichloroacetate, seems to halt carcinogenesis by lowering cytosolic lactate production; on the other hand, MCT1 and MCT4 inhibitors seem to have enormous potential in cancer treatment by inhibiting lactate shuttling, even if there is still a lack of specificity (San‐Millán & Brooks, 2017). Furthermore, simpler approaches such as aerobic exercise seem to have beneficial effects by augmenting mitochondrial size and function and thus lactate clearance capacity. Further research is necessary to identify possible targets and create tumor‐specific treatments.
3.6.5 Treatment options in patients with type‐B LA due to malignancies
Lactic acidosis in association with malignancies carries an extremely poor prognosis with a mortality rate over 90% (Nair & Shah, 2017; Sillos et al., 2001). Moreover, the high mortality associated with lactic acidosis has prompted some oncologists to consider this an oncological emergency (Nair & Shah, 2017). The best treatment for patients with hematologic malignancies who develop type B lactic acidosis is not yet clear.
Chemotherapy
Initiating aggressive chemotherapy has been effective in correcting acute acidosis (Friedenberg et al., 2007). It is actually the only treatment modality that consistently leads to remission. Resolution of lactic acidosis was reported to occur as early as 15 h and up to 3 days after starting chemotherapy. This treatment would not be effective in patients whose tumors are unresponsive to chemotherapy. Lactic acidosis improves with chemotherapy, and resolution of the lactic acidosis could be a surrogate marker of inducing remission (Chan et al., 2009).
Intravenous bicarbonate
The use of IV bicarbonate as a treatment for profound acidosis has never shown a meaningful clinical benefit, even in the worst cases (Swenson, 2016). As severe acidosis can cause respiratory fatigue and hemodynamic instability, intravenous bicarbonate is often used to attenuate systemic acidosis and increase the responsiveness to catecholamines. However, it would appear that the benefits of sodium bicarbonate are outweighed by its disadvantages, such as hypernatremia and hyperosmolality (Swenson, 2016). Acidemia leads to unloading oxygen from hemoglobin by shifting the hemoglobin‐oxygen dissociation curve to the right, and reducing acidosis will hinder oxygen release. Studies have shown that intracellular acidosis tends to slow lactate production (Madias, 1986; Sillos et al., 2001). Alkalinization has been shown to potentiate lactate production in patients with malignancy‐induced chronic lactic acidosis (Fields et al., 1981; Fraley et al., 1980). The effect of IV bicarbonate on mortality or lactate concentration in the setting of malignancy‐induced type B lactic acidosis has not been studied directly, as the incidence is very low. In a case report by Fraley et al. (1980), administration of bicarbonate improved pH but not the serum bicarbonate level. Intravenous bicarbonate corrected the extracellular pH but did not affect the significant intracellular acid production due to high tumor cell turnover. The use of sodium bicarbonate may not be recommended in these patient groups.
Renal replacement therapy
Renal replacement therapy, continuous or intermittent, in patients with renal dysfunction may be useful in addition to chemotherapy to correct metabolic acidosis. Here, once again, since the prognosis of type B lactic acidosis related to malignancies is grim, the only chance for remission is starting cytoreductive chemotherapy. Intravenous bicarbonate and hemodialysis will no longer act as a bridge to stabilize the patient enough so that the underlying cause can be treated (Chan et al., 2009).
Intravenous insulin
Lactic acidosis has also been treated with intravenous administration of insulin, which increases the conversion of pyruvate to acetyl‐coenzyme A and consequently facilitates oxidation of lactate to pyruvate (Sillos et al., 2001). Administration of glucose can actually induce lactic acidosis by increasing the availability of glucose and thus increasing the production of lactate by the tumor. Returning to the case presented in this manuscript, the patient was severely hypoglycemic, which is the reason why we substituted for intravenous glucose to maintain the patient's euglycemia. However, in a provocative hypothesis in 2009, Nijsten & van Dam (2009) presented a hypothetical treatment whereby glucose might be systemically lowered. If tumors are glucose consumers and lactate producers and all other tissues in the body can actively take up and use lactate as a fuel, why not systemically induce hypoglycemia to starve tumor cells? In this configuration, lactate would provide salvage fuel for the other tissues (Goodwin et al., 2014). Work to investigate this concept should be pursued.
4 CONCLUSION
Lactic acidosis is a commonly encountered problem in intensive care units and is most commonly associated with dysoxia, better known as type A lactic acidosis. Type B is more uncommon and can be life‐threatening and sometimes even a lethal complication in patients with malignancies. Due to its rareness, it is likely to be under recognized and therefore underdiagnosed. If oncological patients develop high anion gap lactic acidosis without hemodynamic compromise associated with acute respiratory distress without a pulmonary source, the possibility for tumor‐induced type B lactic acidosis through the “Warburg effect” should be considered. Awareness about this condition is important in the clinical practice of intensive care physicians since it will allow a timely diagnosis and the implementation of subsequent therapy. Currently, effective chemotherapy seems to be the only hope for survival.
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
Carole Looyens, and Karim Bendjelid designed the present review. Carole Looyens, and Karim Bendjelid analyzed data and references. Carole Looyens, Raphael Giraud, Ivo Neto Silva, and Karim Bendjelid wrote the manuscript. All authors read and approved the final manuscript.
DATA AVAILABILITY STATEMENT
The data that support these findings are available upon reasonable request from the corresponding author. | UNK, CYCLICAL | DrugDosageText | CC BY | 33611854 | 19,163,699 | 2021-02 |
What was the outcome of reaction 'Agranulocytosis'? | Burkitt lymphoma and lactic acidosis: A case report and review of the literature.
Type A lactic acidosis is a potentially life-threatening complication in critically ill patients and is the hallmark of a shock state as a result of tissue hypoperfusion and dysoxia. Type B lactic acidosis results from mechanisms other than dysoxia and is a rare condition in patients with solid tumors or hematological malignancies. We present a case of a 60-year-old man with lactic acidosis who was found to have a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Lactagenic cancers are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Warburg in 1923 that is correlated with cancer aggressiveness and poor survival. There is increased glucose utilization with the purpose of lactagenesis under fully oxygenated conditions, as lactate seems to be a potent signaling molecule for angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, which are five essential steps of carcinogenesis. Type B lactic acidosis in association with malignancies carries an extremely poor prognosis. Currently, effective chemotherapy seems to be the only hope for survival.
1 INTRODUCTION
A high arterial lactate level in critically ill patients has been associated with significant morbidity and mortality ever since the first description two centuries ago (Kompanje et al., 2007). Hyperlactatemia in the critically ill is the hallmark of shock states (Kraut & Madias, 2014; Levy, 2006; Nichol et al., 2010; Vincent & De Backer, 2013; Vincent et al., 2016), and the degree of increase in arterial lactate concentrations is directly related to the severity of the shock state (Haas et al., 2016; Nichol et al., 2011; Vincent et al., 2016). In this regard, the prognostic value of arterial lactate levels seems to be independent of the underlying critical illness (Jansen et al., 2010). Serial lactate measurements are widely used in intensive care medicine in the evaluation of the progression of a shock state and the response to intensive and urgent therapy (Levy et al., 2018; Vincent et al., 2016).
Although high lactate levels have been widely used as a marker of altered tissue perfusion in critically ill patients, this condition does not always simply reflect the development of anaerobic metabolism and cellular dysoxia better known as Type A lactic acidosis (Kraut & Madias, 2014; Vincent et al., 2016). While a lack of oxygen forbids the continuation of oxidative phosphorylation in the Krebs cycle, a normal oxygen supply does not impose a complete cessation of anaerobic metabolism. Type B lactic acidosis results from mechanisms other than dysoxia, including inborn errors of metabolism, drugs and toxins, systemic diseases (i.e., diabetes and sepsis), and less commonly malignancy. In this case report, we try to emphasize the pathophysiology leading to hyperlactatemia, and we will focus on the hyperlactatemia caused by lactagenic cancers and the Warburg effect.
2 CASE SUMMARY
A 60‐year‐old‐male patient presented at the emergency department with increasing abdominal girth, abdominal discomfort, severe asthenia, malaise, and profuse diaphoresis without fever. His medical history highlighted chronic renal failure (stage G3bA1) and a cardiac transplant 4 years ago due to terminal ischemic cardiomyopathy. His recent cardiac biopsy was free from any signs of rejection. He was taking immunosuppression with cyclosporine and mycophenolic acid. On admission, the clinical examination revealed a tense and distended abdomen with abdominal ascites. Initial vital signs were stable except for tachycardia at 110 beat per minute. The respiratory rate was 22 breath per minute, and the temperature was within the normal range. Physical exam was otherwise normal.
Laboratory analysis showed leukocytosis with a left shift, signs of hepatocellular injury without cholestasis, and chronic renal failure. His white blood count count was 14.8 G/L, C‐reactive protein was 45 mg/L (normal <10 mg/L), aspartate aminotransferase (AST) was 144 IU/L (normal, 14–50 IU/L), alanine aminotransferase (ALT) was 79 IU/L (normal, 12–50 IU/L), lactate dehydrogenase (LDH) was 1082 IU/L (normal, 87–210 IU/L), total bilirubin was 4 μmol/L (normal, 7–25 μmol/L), alkaline phosphatase was 82 IU/L (normal, 25–102 IU/L), gamma‐glutamyl transferase was 41 IU/L (normal, 9–40 IU/L), creatinine was 198 µmol/L (normal, 62–106 µmol/L), with an estimated glomerular filtration rate of 31 ml/min/1.73 m2. An ultrasound assessment confirmed the presence of moderate ascites in all four abdominal quadrants. Ascites liquid puncture showed leukocytosis, but the liquid culture remained sterile. Abdominal CT was then performed following a rapid clinical deterioration for abdominal sepsis, showing signs of diffuse peritonitis with a pelvic abscess located adjacent to the small intestine. The patient was therefore immediately started on broad‐spectrum antibiotics and antifungal treatment. In addition, a median laparotomy was performed to remove the pelvic abscess. The resected mass (suspect for any neoplasm) was sent for an extemporaneous analysis that elicited a high‐grade lymphoma. Later pathology testing confirmed a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Following emergency department admission and immediate surgery, the patient was admitted to the intensive care unit for high anion gap lactic acidosis, with a pH of 7.29 and a lactate level of 7.4 mmol/L on the arterial blood gas analysis. However, the patient's vital signs remained stable, and he could be extubated on the same day. Signs of hypoxia or circulatory failure were absent, capillary refill time was within normal limits and there was no skin mottling. Moreover, lactate/pyruvate ratio value was 19.0. In contrast, he simultaneously developed profuse hypoglycemia necessitating continuous high‐dose intravenous glucose supplementation. Cardiac output measured with bedside echocardiography appeared to be within the normal ranges. A new postoperative abdominal CT angiography was performed to exclude abdominal ischemia. The lactic acidosis (mean pH 7.3) remained for several days with lactate levels fluctuating around approximately 7 mmol/L. A concomitant thiamine deficiency was excluded by intravenous supplementation. Lactic acidosis started to decrease once chemotherapy with cyclophosphamide and vincristine, initiated 5 days after surgical resection, began to have an effect.
The interpretation of an initial positron emission tomography–computed tomography (PET‐CT) (Figures 1, 2, 3) 6 days after surgery was not clear due to the difficult differentiation between an infectious versus an oncological process. In addition to diffuse hypermetabolism in the peritoneal cavity associated with retroperitoneal adenopathies, it revealed supradiaphragmatic invasion of the lymphoma with a mass located in the right cardiophrenic recess, left mammary adenopathies, and pleural and pericardial nodules. There were also two hypermetabolic, osseous spots, suspected of metastasis, one in the second cervical vertebrae and one in the left scapula.
FIGURE 1 Left: Transversal image from patient's abdominal positron emission tomography–computed tomography (PET‐CT) post tumoral resection revealing diffuse peritoneal hypermetabolism with difficult differentiation between an infectious versus an oncological process. Middle: Transversal image from patients thoracic PET‐CT revealing supradiafragmatic invasion of the lymphoma with a mass and a nodule located in the right cardiophrenic recess with diffuse bilateral pleural nodular thickening. Right: Transversal image from patient's abdominal PET‐CT showing retroperitoneal adenopathies.
FIGURE 2 Lactate production and destination. Glycolysis takes place in the cellular cytosol. The preparatory phase consists of the generation of 1–3 diphosphoglycerate by hekoxinase and phosphofructokinase (PFK), the rate‐limiting enzyme. The pay off phase consists of the generation of pyruvate by pyruvate kinase. Pyruvate can be reduced to lactate by lactate dehydrogenase (LDH) or it can be converted to acetyl‐Co A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. Pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by alanine aminotransferase, resulting in the formation of alanine. Lactate either locally formed after reduction of pyruvate or coming from a distant source, can be consumed in the mitochondria by reformation of pyruvate by mitochondrial lactate dehydrogenase (mLDH) after diffusion across membranes via monocarboxylate transporters (MCTs). This concept is better known as the cell‐to‐cell lactate shuttle.
FIGURE 3 Lactate/pyruvate ratio. In aerobic glycolysis, the physiologic ratio of lactate/pyruvate is approximately 10 and is warranted by lactate dehydrogenase (LDH) catalyzing the reduction of pyruvate in lactate. When there is any perturbation of tissular oxygenation, cellular oxygenation is inhibited causing and acceleration of the reduction in pyruvate into lactate by LDH which results in a pathological lactate/pyruvate ratio above 10. The inhibition of the oxidative phosphorylation avoids any proton recycling leading to high anion gap lactic acidosis. Lactate is mostly converted into glucose through neoglucogenesis in the Cori cycle taking place in the liver and the kidneys. In case of insufficient hepatic perfusion or hepatic failure, lactate will be less cleared causing a variable lactate/pyruvate ratio depending on the source of production of lactate. Protons, normally recycled in the Cori cycle, will accumulate causing acidosis. MTC, monocarboxylate transporter.
He underwent intensive inpatient chemotherapy with one cycle of R‐CHP and six cycles of R‐CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride, O = vincristine sulfate, P = prednisone) and 10 prophylactic intrathecal injections of methotrexate. Chemotherapy was complicated with multiple episodes of febrile agranulocytosis, anemia and thrombocytopenia, which resolved after treatment with antibiotics in combination with filgrastim and multiple transfusions. The patient could be discharged with closed outpatient follow‐up after 5 months of admission. A PET‐CT was carried out 2 months after discharge and showed complete regression of all the lesions. A thoraco‐abdominal CT performed 1 year after the diagnosis seemed to be completely normal.
3 DISCUSSION
3.1 Lactate homeostasis
As with the blood levels of any substance, elevated lactate levels can be the result of increased production or reduced clearance, or both. Under physiological conditions, 1500 mmol of lactate or 20 mmol/kg of body weight is produced daily from various organs, including the muscle, intestine, red blood cells, brain, and skin (Kraut & Madias, 2014). Lactate is metabolized by the liver (60%), kidneys (30%), and other organs. The normal arterial blood lactate level is approximately 1 mmol/L (Kraut & Madias, 2014; Vincent et al., 2016).
3.2 Lactate production
Lactate formation is closely related to glycolysis. Glycolysis takes place in ten steps, five of which are in the preparatory phase and five in the payoff phase. Phosphofructokinase (PFK) is the rate‐limiting enzyme. Two net ATP molecules are generated by phosphorylation by high‐energy compounds. The final product of glycolysis is pyruvate and lactate, to which pyruvate can be reduced. LDH catalyzes the reduction of pyruvate into lactate at a well‐defined rate so that in normal homeostasis, the physiological ratio of lactate/pyruvate is approximately 10. In the presence of oxygen, pyruvate can be converted into acetyl‐coenzyme A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. This respiratory chain of reactions results in a net production of 36 ATP molecules per molecule of glucose. The metabolic yield of glycolysis when participating in the aerobic metabolic pathway (i.e., along with the Krebs cycle and oxidative phosphorylation) is superior to fermentation (without O2) into lactate (38 vs. 2 molecules of ATP). Anaerobic fermentation into lactate may be inefficient compared to oxidative phosphorylation, however, the rate of glucose metabolism into lactate is 10–100 times faster than the complete oxidation of glucose in the mitochondria (Liberti & Locasale, 2016). In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is utilized (Liberti & Locasale, 2016). In addition to the better‐known reduction to lactate and the oxidation to acetyl‐coenzyme A, for the completeness of this review, we need to mention that pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by ALT, resulting in the formation of alanine (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
Experiments by Pasteur (Platt, 1988), Meyerhof (1927), and A.V. Hill (Bassett, 2002) led to the widespread understanding of the glycolytic pathway and the notion that only a limitation of oxygen availability leads to fermentation and lactate accumulation. Out of this early work came the idea that lactate is just an anaerobic waste product that must be cleared from the muscles and blood, preferably by being converted to glucose in the liver via the Cori cycle. However, it has been demonstrated that lactate is a potent fuel and signaling molecule and is constantly being produced and circulated throughout the body, even and most often when there is adequate oxygen. Lactate is more than just a “hypoxic waste product.” Lactate as a result of dysoxia is often the exception rather than the rule, even in critically ill patients (Goodwin et al., 2014).
3.3 Lactate metabolism
Any time glycolysis is active, lactate is formed and equilibrates with local lactate gradients. Lactate equilibrates mainly by diffusing across membranes via monocarboxylate transporters (MCTs). In lactate‐producing tissues, this means exporting lactate into the circulation where both local and distant tissues can take it up and use it.
Lactate is metabolized by the liver (60%), kidneys (30%) and other organs. Lactate can be used for gluconeogenesis by reformation of pyruvate and glucose in the Cori cycle, which takes place in the liver and kidneys. In addition, lactate can readily replace glucose as a fuel for almost all cells of the body (any cell with mitochondria) by reformation and subsequent oxidation of pyruvate in the mitochondria. Lactate clearance occurs in the heart, liver, skeletal muscle and even brain. This observation that lactate is constantly being produced and consumed formed the basis of the cell‐to‐cell lactate shuttle, an energy exchange hypothesis originally introduced by Brooks in 1984 (Brooks, 1986). Lactate seems to be a key intermediate metabolite in whole body metabolism (Ben‐Hamouda et al., 2013; Goodwin et al., 2014; Kraut & Madias, 2014).
3.4 Hyperlactatemia (Table 1)
3.4.1 Elevated production of lactate
As mentioned earlier, normal lactate production is approximately 1 mmol/min or 1500 mmol/24 h, and the normal lactate level is approximately 1 mmol/L (Ben‐Hamouda et al., 2013; Vincent et al., 2016). Elevated lactate production can be the consequence of either an elevated pyruvate concentration (as seen in accelerated glycolysis, in elevated protein catabolism or through inhibition of PDH) or cellular dysoxia. Dysoxic lactic acidosis is better known as type‐A lactic acidosis, and all other nondysoxic causes of lactic acidosis are classified as type B according to the classification of Woods and Cohen (Ben‐Hamouda et al., 2013). Indeed, if lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics (i.e. normal blood pressure, normal volemia, normal blood oxygen, and oxygen‐carrying capacity), it is traditionally termed Type B lactic acidosis. In the present setting, the physiologic ratio value of lactate/pyruvate is around 10 or higher.
TABLE 1 Classification of hyperlactatemia according to Woods and Cohen
Type A: Hyperlactatemia associated with cellular dysoxia due to insufficient oxygen supply
Stagnant dysoxia Low cardiac output
Redistribution of cardiac output at the expense of certain tissues
Vascular occlusion
Dysoxia caused by elevated demand of oxygen Convulsions
Intensive exercise
Dysoxia caused by low oxygen carrying capacity Anemic dysoxia
Carbon monoxide intoxication
Hypoxic dysoxia (low PaO2)
Cytotoxic dysoxia due to inefficient mitochondrial consumption of oxygen Sepsis
Cyanide intoxication
Type B1: Hyperlactatemia due to an underlying disease
Accelerated glycolysis Hyperglycemia
Sepsis
Endogenous catecholamines
Lactagenic cancer
Elevated protein catabolism Burn victims
Severe septic shock
Acquired inhibition of pyruvate dehydrogenase (PDH) Sepsis
Thiamine deficiency
Lactagenic cancer
Reduced lactate clearance Reduced liver blood flow
Hepatic failure
Type B2: Hyperlactatemia due to drugs and toxins
Exogenous catecholamines (adrenaline, dobutamine, terbutaline) Cocaine, metamphetamines
Propofol Salicylates
Metformine Antiretroviral drugs
Linezolid Toxic alcohols (ethanol, methanol, propylene glycol, ethylene glycol)
Paracetamol
Type B3: Hyperlactatemia due to inborn errors of metabolism (enzymatic deficiencies)
Congenital PDH deficiency
Glucose‐6‐phosphatase deficiency (von Gierke disease)
Pyruvate carboxylase deficiency
Methylmalonic aciduria
Mitochondrial encephalomyopathies
John Wiley & Sons, LtdAccelerated glycolysis
Any cause of an accelerated level of glycolysis causes an expected elevation of pyruvate and thus of lactate, as the physiologic ratio of lactate/pyruvate of approximately 10 or higher is always warranted by LDH. Accelerated glycolysis is the case in hyperglycemia, sepsis, or other situations with elevated endogenous or exogenous catecholamines (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014). Finally, accelerated aerobic glycolysis may partially explain the hyperlactatemia caused by tumoral cells of lactagenic cancers, known as the Warburg effect (San‐Millán & Brooks, 2017), the cause of lactic acidosis in the present case.
Elevated protein catabolism
Elevated protein catabolism can also cause a rise in pyruvate levels. As mentioned earlier, pyruvate can be transaminated into alanine, and the reverse can be witnessed through the activity of the ALT enzyme, forming pyruvate in the liver. This mechanism contributes to hepatic neoglucogenesis. Accelerated protein catabolism is seen as muscle wasting, present in many critically ill patients, most severely in burn victims and in patients with severe septic shock. The elevated alanine supply in the liver contributes to the elevated pyruvate concentration and, ultimately, to hyperlactatemia, as the physiologic lactate/pyruvate ratio is always warranted by LDH (Ben‐Hamouda et al., 2013).
Inhibition of PDH
As discussed earlier, pyruvate is oxidized into acetyl‐coenzyme‐A by PDH. A congenital or an acquired reduction in the enzymatic activity of PDH can cause an accumulation of pyruvate and therefore of lactate. An acquired reduction in PDH can be caused by certain endotoxins and inflammatory cytokines in sepsis. This explains why hemodynamically stable patients with sepsis and normal liver function may have lactic acidosis (Kraut & Madias, 2014). It can also be caused by nucleoside reverse transcriptase inhibitors used to treat patients with HIV or by a thiamine deficiency, as in patients receiving parenteral nutrition or with severe Beri‐beri. Thiamine is an important cofactor in the PDH complex. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead, conversion into lactate takes place (Friedenberg et al., 2007). Finally, certain oncogenes express PDH kinase, which inactivates PDH and inhibits the Krebs cycle (San‐Millán & Brooks, 2017; Swenson, 2016) and partially explains the development of hyperlactatemia caused by tumoral cells.
Cellular dysoxia
Perturbations of tissular oxygenation, termed “cellular dysoxia”, are caused by insufficient oxygen supply. This dysoxia can be either generalized due to a low cardiac output, carbon monoxide intoxication, profound arterial hemoglobin desaturation, and reduced oxygen content or either localized in the context of redistribution of the cardiac output at the expense of certain tissues or due to a vascular occlusion (Swenson, 2016). It can also be caused by mitochondrial enzyme defects and by inhibitors of aerobic metabolism, such as cyanide. Every drop in cellular oxygenation causes an acceleration of the reduction in pyruvate to lactate by LDH, which results in a pathological augmentation of the lactate/pyruvate ratio above 10 (Ben‐Hamouda et al., 2013). Even if the pyruvate dosage is expensive, its use and the finding of a pathological L/P level confirm cellular dysoxia and excludes other causes.
3.4.2 Reduced lactate clearance
Lactate is partly transported to the liver and the kidneys and converted to glucose through gluconeogenesis (the Cori cycle). The hepatic clearance of lactate thus depends on hepatic extraction and hepatic functioning. Hepatic extraction is determined by the liver blood flow, which needs no less than one‐fourth of its normal flow. The capture of lactate by hepatocytes depends on its transportation by a family of MCTs with different isoforms (MCT1‐4). Thus, neoglucogenesis will depend on hepatic functioning. Its activity is decreased in hepatic failure and inhibited in shock states and severe acidosis (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
3.5 Distinction between hyperlactatemia and lactic acidosis
Hyperlactatemia and lactic acidosis are frequently mixed, which may cause confusion. However, the two are governed by a different concept. Glycolysis causes lactate formation without lactic acidosis when there is no net H+ production. The H+ protons may arise following ATP hydrolyzation and are produced through glycolysis. However, those protons are recycled by lactate consumption either through the Krebs cycle or through the hepatic Cori cycle, hence maintaining the internal acid‐base balance (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
In this regard, acquired or congenital inhibition of PDH, inhibition of oxidative phosphorylation due to cellular dysoxia, medication or intoxication and hepatic insufficiency are all causes of reduced proton recycling in either the Krebs or the Cori cycle, therefore causing high anion gap lactic acidosis. Other causes of hyperlactatemia, such as elevated glycolysis in hyperglycemia, arising from beta‐adrenergic stimulation or muscular catabolism, will only cause an elevated production of lactate without proton recycling impairment and without ensuing concomitant lactic acidosis (Kraut & Madias, 2014).
3.6 Lactagenic cancers
3.6.1 Warburg effect
In glycolytic tumors, lactate levels of cancer cells are markedly elevated up to 40‐fold and are highly associated with cancer aggressiveness and poor survival (Brizel et al., 2001; San‐Millán & Brooks, 2017). In fast‐growing malignancies, the rate of tumor metabolism may be great enough to exceed normal muscle and liver lactate clearance and cause systemic type B lactic acidosis (Sillos et al., 2001; Swenson, 2016). The majority of lactic acidosis in malignancies is reported in cases of hematologic malignancies. Only a few cases have been reported for solid tumors presenting with lactic acidosis (Nair & Shah, 2017).
In 1923, Warburg observed in his Nobel Prize winning studies that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions and that tumor cells live and grow in a more acidic milieu as a result of increased lactic acid production not generally tolerated by normal cells (San‐Millán & Brooks, 2017; Swenson, 2016). His discovery was named the “Warburg effect” by Racker in 1972 (San‐Millán & Brooks, 2017). The Warburg effect is a hallmark of cancer, and its significance is still apparent in the common cancer diagnostic test using fluorodeoxyglucose positron emission tomography, which has a high diagnostic accuracy (Potter et al., 2016).
From a contemporary perspective of cell metabolic efficiency, it seems difficult to understand why, despite fully aerobic conditions, cancer cells choose an inefficient pathway producing two ATP molecules per molecule of glucose instead of 38 via coupled mitochondrial respiration. However, as mentioned earlier, the amount of ATP synthesized over any given period of time is comparable in both ways of glucose metabolism because fermentation into lactate is 10–100 times faster than the completion of oxidative phosphorylation (Liberti & Locasale, 2016). Moreover, the stress of lactate production is simply passed on to the host. Then, the cancer cells proliferate, and the tumor grows and metastasizes because of host exploitation, ending in final host expiration (San‐Millán & Brooks, 2017).
3.6.2 Origin of tumoral lactagenesis
Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous and unstoppable glucose utilization to produce lactate involving five major steps: (i) an increase in glucose uptake; (ii) upregulation of PFK, the rate‐limiting enzyme of glycolysis; (iii) a decrease in mitochondrial respiration by upregulation of PDH kinase (PDK) that inhibits pyruvate uptake in mitochondria; (iv) increased lactate production by LDH upregulation; and (v) upregulation of MCT1 and MCT4 expression, the transmembrane transporters of lactate, for higher lactate plus H+ efflux and further lactate shuttling, thus mediating tumor growth and proliferation (Brahimi‐Horn et al., 2011; San‐Millán & Brooks, 2017; Swenson, 2016).
In our case, the Warburg effect was caused by a Burkitt lymphoma, a B‐cell derived malignancy. The main characteristic of a Burkitt lymphoma is an increased production of the MYC oncoprotein caused by chromosomal rearrangements. This translocation results in inappropriately high expression levels of MYC, which gives cells proliferative capacity. Moreover, MYC also activates the transcription of genes encoding glucose transporter, hexokinase, MCT, PDK, PK (pyruvate kinase), and LDH, resulting in the accelerated aerobic glycolysis or the Warburg effect. The MYC protein is the master regulator of the Warburg effect in BL cells (Mushtaq et al., 2015).
3.6.3 Aim of tumoral lactagenesis
The role of the Warburg effect in the pathogenesis of cancer has not yet been completely established. Lactate is the end product of the Warburg effect, but lactate production or lactagenesis is probably the purpose of the Warburg effect as well.
In addition to being a potent oxidative fuel, lactate is also a potent signaling molecule necessary for all the major steps in carcinogenesis, as follows: (i) angiogenesis, (ii) cell migration, (iii) metastasis, (iv) immune escape, and (v) self‐sufficiency of cancer cells (San‐Millán & Brooks, 2017).
Lactate released from tumor cells by MCT4 plays a role in stimulating angiogenesis (i) by increasing the expression of vascular endothelial growth factor protein in endothelial cells (Goodwin et al., 2014; San‐Millán & Brooks, 2017). Cell migration (ii) is another essential step in carcinogenesis and metastasis in which lactate seems to be a key element to increase cell migration. Marked extracellular acidosis appears to promote the migration and metastasis (iii) of cancer cells by disrupting normal cell‐matrix interactions that act to maintain stable growth patterns (Swenson, 2016). Lactate levels are highly associated with a high incidence of distant metastasis. Acidosis reduces host defense against malignant cells and contributes to immune escape (iv) in many different ways: first, by inhibiting the release of the cytokines tumor necrosis factor and interleukin‐6; and second, by inhibiting the activation of T‐cells with a decrease in the cytotoxic activity of T‐cells and inhibition of natural killer cell functioning. Lactate also plays a central role in the self‐sufficiency and sustainability (v) of cancer cells. Cancer cells at the hypoxic core might use glucose and produce lactate, whereas cells on the periphery, close to a robust vascular supply, might take up this lactate and oxidize it as a fuel. The self‐sufficiency depending upon high glycolytic flux also allows cancer cells to produce lactate for carcinogenesis by angiogenesis, immune escape, cell migration, and metastasis. A glucose to lactate shunt occurs in which the host bears the burden of providing a limitless glucose supply as well as a sink for disposal of lactate and hydrogen ions. This may even explain why the actual cause of cachexia and death due to cancer appears to be multifactorial, with organ failure rather than the tumor itself (San‐Millán & Brooks, 2017).
3.6.4 Targeting lactate production and shuttling: Future direction in cancer treatment
Given the profound changes in acid‐base balance in tumors and the role of pH in tumor survival and growth, altering the acid‐base milieu has presented itself as an interesting approach for treating cancer (Swenson, 2016), but the development of these new adjuvant therapies goes way beyond the scope of this article. Nevertheless, after explaining all the pathophysiology, it seems important to shed light on some future possible treatments: on the one hand, medication increasing PDH activity, such as dichloroacetate, seems to halt carcinogenesis by lowering cytosolic lactate production; on the other hand, MCT1 and MCT4 inhibitors seem to have enormous potential in cancer treatment by inhibiting lactate shuttling, even if there is still a lack of specificity (San‐Millán & Brooks, 2017). Furthermore, simpler approaches such as aerobic exercise seem to have beneficial effects by augmenting mitochondrial size and function and thus lactate clearance capacity. Further research is necessary to identify possible targets and create tumor‐specific treatments.
3.6.5 Treatment options in patients with type‐B LA due to malignancies
Lactic acidosis in association with malignancies carries an extremely poor prognosis with a mortality rate over 90% (Nair & Shah, 2017; Sillos et al., 2001). Moreover, the high mortality associated with lactic acidosis has prompted some oncologists to consider this an oncological emergency (Nair & Shah, 2017). The best treatment for patients with hematologic malignancies who develop type B lactic acidosis is not yet clear.
Chemotherapy
Initiating aggressive chemotherapy has been effective in correcting acute acidosis (Friedenberg et al., 2007). It is actually the only treatment modality that consistently leads to remission. Resolution of lactic acidosis was reported to occur as early as 15 h and up to 3 days after starting chemotherapy. This treatment would not be effective in patients whose tumors are unresponsive to chemotherapy. Lactic acidosis improves with chemotherapy, and resolution of the lactic acidosis could be a surrogate marker of inducing remission (Chan et al., 2009).
Intravenous bicarbonate
The use of IV bicarbonate as a treatment for profound acidosis has never shown a meaningful clinical benefit, even in the worst cases (Swenson, 2016). As severe acidosis can cause respiratory fatigue and hemodynamic instability, intravenous bicarbonate is often used to attenuate systemic acidosis and increase the responsiveness to catecholamines. However, it would appear that the benefits of sodium bicarbonate are outweighed by its disadvantages, such as hypernatremia and hyperosmolality (Swenson, 2016). Acidemia leads to unloading oxygen from hemoglobin by shifting the hemoglobin‐oxygen dissociation curve to the right, and reducing acidosis will hinder oxygen release. Studies have shown that intracellular acidosis tends to slow lactate production (Madias, 1986; Sillos et al., 2001). Alkalinization has been shown to potentiate lactate production in patients with malignancy‐induced chronic lactic acidosis (Fields et al., 1981; Fraley et al., 1980). The effect of IV bicarbonate on mortality or lactate concentration in the setting of malignancy‐induced type B lactic acidosis has not been studied directly, as the incidence is very low. In a case report by Fraley et al. (1980), administration of bicarbonate improved pH but not the serum bicarbonate level. Intravenous bicarbonate corrected the extracellular pH but did not affect the significant intracellular acid production due to high tumor cell turnover. The use of sodium bicarbonate may not be recommended in these patient groups.
Renal replacement therapy
Renal replacement therapy, continuous or intermittent, in patients with renal dysfunction may be useful in addition to chemotherapy to correct metabolic acidosis. Here, once again, since the prognosis of type B lactic acidosis related to malignancies is grim, the only chance for remission is starting cytoreductive chemotherapy. Intravenous bicarbonate and hemodialysis will no longer act as a bridge to stabilize the patient enough so that the underlying cause can be treated (Chan et al., 2009).
Intravenous insulin
Lactic acidosis has also been treated with intravenous administration of insulin, which increases the conversion of pyruvate to acetyl‐coenzyme A and consequently facilitates oxidation of lactate to pyruvate (Sillos et al., 2001). Administration of glucose can actually induce lactic acidosis by increasing the availability of glucose and thus increasing the production of lactate by the tumor. Returning to the case presented in this manuscript, the patient was severely hypoglycemic, which is the reason why we substituted for intravenous glucose to maintain the patient's euglycemia. However, in a provocative hypothesis in 2009, Nijsten & van Dam (2009) presented a hypothetical treatment whereby glucose might be systemically lowered. If tumors are glucose consumers and lactate producers and all other tissues in the body can actively take up and use lactate as a fuel, why not systemically induce hypoglycemia to starve tumor cells? In this configuration, lactate would provide salvage fuel for the other tissues (Goodwin et al., 2014). Work to investigate this concept should be pursued.
4 CONCLUSION
Lactic acidosis is a commonly encountered problem in intensive care units and is most commonly associated with dysoxia, better known as type A lactic acidosis. Type B is more uncommon and can be life‐threatening and sometimes even a lethal complication in patients with malignancies. Due to its rareness, it is likely to be under recognized and therefore underdiagnosed. If oncological patients develop high anion gap lactic acidosis without hemodynamic compromise associated with acute respiratory distress without a pulmonary source, the possibility for tumor‐induced type B lactic acidosis through the “Warburg effect” should be considered. Awareness about this condition is important in the clinical practice of intensive care physicians since it will allow a timely diagnosis and the implementation of subsequent therapy. Currently, effective chemotherapy seems to be the only hope for survival.
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
Carole Looyens, and Karim Bendjelid designed the present review. Carole Looyens, and Karim Bendjelid analyzed data and references. Carole Looyens, Raphael Giraud, Ivo Neto Silva, and Karim Bendjelid wrote the manuscript. All authors read and approved the final manuscript.
DATA AVAILABILITY STATEMENT
The data that support these findings are available upon reasonable request from the corresponding author. | Recovered | ReactionOutcome | CC BY | 33611854 | 19,114,934 | 2021-02 |
What was the outcome of reaction 'Anaemia'? | Burkitt lymphoma and lactic acidosis: A case report and review of the literature.
Type A lactic acidosis is a potentially life-threatening complication in critically ill patients and is the hallmark of a shock state as a result of tissue hypoperfusion and dysoxia. Type B lactic acidosis results from mechanisms other than dysoxia and is a rare condition in patients with solid tumors or hematological malignancies. We present a case of a 60-year-old man with lactic acidosis who was found to have a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Lactagenic cancers are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Warburg in 1923 that is correlated with cancer aggressiveness and poor survival. There is increased glucose utilization with the purpose of lactagenesis under fully oxygenated conditions, as lactate seems to be a potent signaling molecule for angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, which are five essential steps of carcinogenesis. Type B lactic acidosis in association with malignancies carries an extremely poor prognosis. Currently, effective chemotherapy seems to be the only hope for survival.
1 INTRODUCTION
A high arterial lactate level in critically ill patients has been associated with significant morbidity and mortality ever since the first description two centuries ago (Kompanje et al., 2007). Hyperlactatemia in the critically ill is the hallmark of shock states (Kraut & Madias, 2014; Levy, 2006; Nichol et al., 2010; Vincent & De Backer, 2013; Vincent et al., 2016), and the degree of increase in arterial lactate concentrations is directly related to the severity of the shock state (Haas et al., 2016; Nichol et al., 2011; Vincent et al., 2016). In this regard, the prognostic value of arterial lactate levels seems to be independent of the underlying critical illness (Jansen et al., 2010). Serial lactate measurements are widely used in intensive care medicine in the evaluation of the progression of a shock state and the response to intensive and urgent therapy (Levy et al., 2018; Vincent et al., 2016).
Although high lactate levels have been widely used as a marker of altered tissue perfusion in critically ill patients, this condition does not always simply reflect the development of anaerobic metabolism and cellular dysoxia better known as Type A lactic acidosis (Kraut & Madias, 2014; Vincent et al., 2016). While a lack of oxygen forbids the continuation of oxidative phosphorylation in the Krebs cycle, a normal oxygen supply does not impose a complete cessation of anaerobic metabolism. Type B lactic acidosis results from mechanisms other than dysoxia, including inborn errors of metabolism, drugs and toxins, systemic diseases (i.e., diabetes and sepsis), and less commonly malignancy. In this case report, we try to emphasize the pathophysiology leading to hyperlactatemia, and we will focus on the hyperlactatemia caused by lactagenic cancers and the Warburg effect.
2 CASE SUMMARY
A 60‐year‐old‐male patient presented at the emergency department with increasing abdominal girth, abdominal discomfort, severe asthenia, malaise, and profuse diaphoresis without fever. His medical history highlighted chronic renal failure (stage G3bA1) and a cardiac transplant 4 years ago due to terminal ischemic cardiomyopathy. His recent cardiac biopsy was free from any signs of rejection. He was taking immunosuppression with cyclosporine and mycophenolic acid. On admission, the clinical examination revealed a tense and distended abdomen with abdominal ascites. Initial vital signs were stable except for tachycardia at 110 beat per minute. The respiratory rate was 22 breath per minute, and the temperature was within the normal range. Physical exam was otherwise normal.
Laboratory analysis showed leukocytosis with a left shift, signs of hepatocellular injury without cholestasis, and chronic renal failure. His white blood count count was 14.8 G/L, C‐reactive protein was 45 mg/L (normal <10 mg/L), aspartate aminotransferase (AST) was 144 IU/L (normal, 14–50 IU/L), alanine aminotransferase (ALT) was 79 IU/L (normal, 12–50 IU/L), lactate dehydrogenase (LDH) was 1082 IU/L (normal, 87–210 IU/L), total bilirubin was 4 μmol/L (normal, 7–25 μmol/L), alkaline phosphatase was 82 IU/L (normal, 25–102 IU/L), gamma‐glutamyl transferase was 41 IU/L (normal, 9–40 IU/L), creatinine was 198 µmol/L (normal, 62–106 µmol/L), with an estimated glomerular filtration rate of 31 ml/min/1.73 m2. An ultrasound assessment confirmed the presence of moderate ascites in all four abdominal quadrants. Ascites liquid puncture showed leukocytosis, but the liquid culture remained sterile. Abdominal CT was then performed following a rapid clinical deterioration for abdominal sepsis, showing signs of diffuse peritonitis with a pelvic abscess located adjacent to the small intestine. The patient was therefore immediately started on broad‐spectrum antibiotics and antifungal treatment. In addition, a median laparotomy was performed to remove the pelvic abscess. The resected mass (suspect for any neoplasm) was sent for an extemporaneous analysis that elicited a high‐grade lymphoma. Later pathology testing confirmed a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Following emergency department admission and immediate surgery, the patient was admitted to the intensive care unit for high anion gap lactic acidosis, with a pH of 7.29 and a lactate level of 7.4 mmol/L on the arterial blood gas analysis. However, the patient's vital signs remained stable, and he could be extubated on the same day. Signs of hypoxia or circulatory failure were absent, capillary refill time was within normal limits and there was no skin mottling. Moreover, lactate/pyruvate ratio value was 19.0. In contrast, he simultaneously developed profuse hypoglycemia necessitating continuous high‐dose intravenous glucose supplementation. Cardiac output measured with bedside echocardiography appeared to be within the normal ranges. A new postoperative abdominal CT angiography was performed to exclude abdominal ischemia. The lactic acidosis (mean pH 7.3) remained for several days with lactate levels fluctuating around approximately 7 mmol/L. A concomitant thiamine deficiency was excluded by intravenous supplementation. Lactic acidosis started to decrease once chemotherapy with cyclophosphamide and vincristine, initiated 5 days after surgical resection, began to have an effect.
The interpretation of an initial positron emission tomography–computed tomography (PET‐CT) (Figures 1, 2, 3) 6 days after surgery was not clear due to the difficult differentiation between an infectious versus an oncological process. In addition to diffuse hypermetabolism in the peritoneal cavity associated with retroperitoneal adenopathies, it revealed supradiaphragmatic invasion of the lymphoma with a mass located in the right cardiophrenic recess, left mammary adenopathies, and pleural and pericardial nodules. There were also two hypermetabolic, osseous spots, suspected of metastasis, one in the second cervical vertebrae and one in the left scapula.
FIGURE 1 Left: Transversal image from patient's abdominal positron emission tomography–computed tomography (PET‐CT) post tumoral resection revealing diffuse peritoneal hypermetabolism with difficult differentiation between an infectious versus an oncological process. Middle: Transversal image from patients thoracic PET‐CT revealing supradiafragmatic invasion of the lymphoma with a mass and a nodule located in the right cardiophrenic recess with diffuse bilateral pleural nodular thickening. Right: Transversal image from patient's abdominal PET‐CT showing retroperitoneal adenopathies.
FIGURE 2 Lactate production and destination. Glycolysis takes place in the cellular cytosol. The preparatory phase consists of the generation of 1–3 diphosphoglycerate by hekoxinase and phosphofructokinase (PFK), the rate‐limiting enzyme. The pay off phase consists of the generation of pyruvate by pyruvate kinase. Pyruvate can be reduced to lactate by lactate dehydrogenase (LDH) or it can be converted to acetyl‐Co A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. Pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by alanine aminotransferase, resulting in the formation of alanine. Lactate either locally formed after reduction of pyruvate or coming from a distant source, can be consumed in the mitochondria by reformation of pyruvate by mitochondrial lactate dehydrogenase (mLDH) after diffusion across membranes via monocarboxylate transporters (MCTs). This concept is better known as the cell‐to‐cell lactate shuttle.
FIGURE 3 Lactate/pyruvate ratio. In aerobic glycolysis, the physiologic ratio of lactate/pyruvate is approximately 10 and is warranted by lactate dehydrogenase (LDH) catalyzing the reduction of pyruvate in lactate. When there is any perturbation of tissular oxygenation, cellular oxygenation is inhibited causing and acceleration of the reduction in pyruvate into lactate by LDH which results in a pathological lactate/pyruvate ratio above 10. The inhibition of the oxidative phosphorylation avoids any proton recycling leading to high anion gap lactic acidosis. Lactate is mostly converted into glucose through neoglucogenesis in the Cori cycle taking place in the liver and the kidneys. In case of insufficient hepatic perfusion or hepatic failure, lactate will be less cleared causing a variable lactate/pyruvate ratio depending on the source of production of lactate. Protons, normally recycled in the Cori cycle, will accumulate causing acidosis. MTC, monocarboxylate transporter.
He underwent intensive inpatient chemotherapy with one cycle of R‐CHP and six cycles of R‐CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride, O = vincristine sulfate, P = prednisone) and 10 prophylactic intrathecal injections of methotrexate. Chemotherapy was complicated with multiple episodes of febrile agranulocytosis, anemia and thrombocytopenia, which resolved after treatment with antibiotics in combination with filgrastim and multiple transfusions. The patient could be discharged with closed outpatient follow‐up after 5 months of admission. A PET‐CT was carried out 2 months after discharge and showed complete regression of all the lesions. A thoraco‐abdominal CT performed 1 year after the diagnosis seemed to be completely normal.
3 DISCUSSION
3.1 Lactate homeostasis
As with the blood levels of any substance, elevated lactate levels can be the result of increased production or reduced clearance, or both. Under physiological conditions, 1500 mmol of lactate or 20 mmol/kg of body weight is produced daily from various organs, including the muscle, intestine, red blood cells, brain, and skin (Kraut & Madias, 2014). Lactate is metabolized by the liver (60%), kidneys (30%), and other organs. The normal arterial blood lactate level is approximately 1 mmol/L (Kraut & Madias, 2014; Vincent et al., 2016).
3.2 Lactate production
Lactate formation is closely related to glycolysis. Glycolysis takes place in ten steps, five of which are in the preparatory phase and five in the payoff phase. Phosphofructokinase (PFK) is the rate‐limiting enzyme. Two net ATP molecules are generated by phosphorylation by high‐energy compounds. The final product of glycolysis is pyruvate and lactate, to which pyruvate can be reduced. LDH catalyzes the reduction of pyruvate into lactate at a well‐defined rate so that in normal homeostasis, the physiological ratio of lactate/pyruvate is approximately 10. In the presence of oxygen, pyruvate can be converted into acetyl‐coenzyme A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. This respiratory chain of reactions results in a net production of 36 ATP molecules per molecule of glucose. The metabolic yield of glycolysis when participating in the aerobic metabolic pathway (i.e., along with the Krebs cycle and oxidative phosphorylation) is superior to fermentation (without O2) into lactate (38 vs. 2 molecules of ATP). Anaerobic fermentation into lactate may be inefficient compared to oxidative phosphorylation, however, the rate of glucose metabolism into lactate is 10–100 times faster than the complete oxidation of glucose in the mitochondria (Liberti & Locasale, 2016). In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is utilized (Liberti & Locasale, 2016). In addition to the better‐known reduction to lactate and the oxidation to acetyl‐coenzyme A, for the completeness of this review, we need to mention that pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by ALT, resulting in the formation of alanine (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
Experiments by Pasteur (Platt, 1988), Meyerhof (1927), and A.V. Hill (Bassett, 2002) led to the widespread understanding of the glycolytic pathway and the notion that only a limitation of oxygen availability leads to fermentation and lactate accumulation. Out of this early work came the idea that lactate is just an anaerobic waste product that must be cleared from the muscles and blood, preferably by being converted to glucose in the liver via the Cori cycle. However, it has been demonstrated that lactate is a potent fuel and signaling molecule and is constantly being produced and circulated throughout the body, even and most often when there is adequate oxygen. Lactate is more than just a “hypoxic waste product.” Lactate as a result of dysoxia is often the exception rather than the rule, even in critically ill patients (Goodwin et al., 2014).
3.3 Lactate metabolism
Any time glycolysis is active, lactate is formed and equilibrates with local lactate gradients. Lactate equilibrates mainly by diffusing across membranes via monocarboxylate transporters (MCTs). In lactate‐producing tissues, this means exporting lactate into the circulation where both local and distant tissues can take it up and use it.
Lactate is metabolized by the liver (60%), kidneys (30%) and other organs. Lactate can be used for gluconeogenesis by reformation of pyruvate and glucose in the Cori cycle, which takes place in the liver and kidneys. In addition, lactate can readily replace glucose as a fuel for almost all cells of the body (any cell with mitochondria) by reformation and subsequent oxidation of pyruvate in the mitochondria. Lactate clearance occurs in the heart, liver, skeletal muscle and even brain. This observation that lactate is constantly being produced and consumed formed the basis of the cell‐to‐cell lactate shuttle, an energy exchange hypothesis originally introduced by Brooks in 1984 (Brooks, 1986). Lactate seems to be a key intermediate metabolite in whole body metabolism (Ben‐Hamouda et al., 2013; Goodwin et al., 2014; Kraut & Madias, 2014).
3.4 Hyperlactatemia (Table 1)
3.4.1 Elevated production of lactate
As mentioned earlier, normal lactate production is approximately 1 mmol/min or 1500 mmol/24 h, and the normal lactate level is approximately 1 mmol/L (Ben‐Hamouda et al., 2013; Vincent et al., 2016). Elevated lactate production can be the consequence of either an elevated pyruvate concentration (as seen in accelerated glycolysis, in elevated protein catabolism or through inhibition of PDH) or cellular dysoxia. Dysoxic lactic acidosis is better known as type‐A lactic acidosis, and all other nondysoxic causes of lactic acidosis are classified as type B according to the classification of Woods and Cohen (Ben‐Hamouda et al., 2013). Indeed, if lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics (i.e. normal blood pressure, normal volemia, normal blood oxygen, and oxygen‐carrying capacity), it is traditionally termed Type B lactic acidosis. In the present setting, the physiologic ratio value of lactate/pyruvate is around 10 or higher.
TABLE 1 Classification of hyperlactatemia according to Woods and Cohen
Type A: Hyperlactatemia associated with cellular dysoxia due to insufficient oxygen supply
Stagnant dysoxia Low cardiac output
Redistribution of cardiac output at the expense of certain tissues
Vascular occlusion
Dysoxia caused by elevated demand of oxygen Convulsions
Intensive exercise
Dysoxia caused by low oxygen carrying capacity Anemic dysoxia
Carbon monoxide intoxication
Hypoxic dysoxia (low PaO2)
Cytotoxic dysoxia due to inefficient mitochondrial consumption of oxygen Sepsis
Cyanide intoxication
Type B1: Hyperlactatemia due to an underlying disease
Accelerated glycolysis Hyperglycemia
Sepsis
Endogenous catecholamines
Lactagenic cancer
Elevated protein catabolism Burn victims
Severe septic shock
Acquired inhibition of pyruvate dehydrogenase (PDH) Sepsis
Thiamine deficiency
Lactagenic cancer
Reduced lactate clearance Reduced liver blood flow
Hepatic failure
Type B2: Hyperlactatemia due to drugs and toxins
Exogenous catecholamines (adrenaline, dobutamine, terbutaline) Cocaine, metamphetamines
Propofol Salicylates
Metformine Antiretroviral drugs
Linezolid Toxic alcohols (ethanol, methanol, propylene glycol, ethylene glycol)
Paracetamol
Type B3: Hyperlactatemia due to inborn errors of metabolism (enzymatic deficiencies)
Congenital PDH deficiency
Glucose‐6‐phosphatase deficiency (von Gierke disease)
Pyruvate carboxylase deficiency
Methylmalonic aciduria
Mitochondrial encephalomyopathies
John Wiley & Sons, LtdAccelerated glycolysis
Any cause of an accelerated level of glycolysis causes an expected elevation of pyruvate and thus of lactate, as the physiologic ratio of lactate/pyruvate of approximately 10 or higher is always warranted by LDH. Accelerated glycolysis is the case in hyperglycemia, sepsis, or other situations with elevated endogenous or exogenous catecholamines (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014). Finally, accelerated aerobic glycolysis may partially explain the hyperlactatemia caused by tumoral cells of lactagenic cancers, known as the Warburg effect (San‐Millán & Brooks, 2017), the cause of lactic acidosis in the present case.
Elevated protein catabolism
Elevated protein catabolism can also cause a rise in pyruvate levels. As mentioned earlier, pyruvate can be transaminated into alanine, and the reverse can be witnessed through the activity of the ALT enzyme, forming pyruvate in the liver. This mechanism contributes to hepatic neoglucogenesis. Accelerated protein catabolism is seen as muscle wasting, present in many critically ill patients, most severely in burn victims and in patients with severe septic shock. The elevated alanine supply in the liver contributes to the elevated pyruvate concentration and, ultimately, to hyperlactatemia, as the physiologic lactate/pyruvate ratio is always warranted by LDH (Ben‐Hamouda et al., 2013).
Inhibition of PDH
As discussed earlier, pyruvate is oxidized into acetyl‐coenzyme‐A by PDH. A congenital or an acquired reduction in the enzymatic activity of PDH can cause an accumulation of pyruvate and therefore of lactate. An acquired reduction in PDH can be caused by certain endotoxins and inflammatory cytokines in sepsis. This explains why hemodynamically stable patients with sepsis and normal liver function may have lactic acidosis (Kraut & Madias, 2014). It can also be caused by nucleoside reverse transcriptase inhibitors used to treat patients with HIV or by a thiamine deficiency, as in patients receiving parenteral nutrition or with severe Beri‐beri. Thiamine is an important cofactor in the PDH complex. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead, conversion into lactate takes place (Friedenberg et al., 2007). Finally, certain oncogenes express PDH kinase, which inactivates PDH and inhibits the Krebs cycle (San‐Millán & Brooks, 2017; Swenson, 2016) and partially explains the development of hyperlactatemia caused by tumoral cells.
Cellular dysoxia
Perturbations of tissular oxygenation, termed “cellular dysoxia”, are caused by insufficient oxygen supply. This dysoxia can be either generalized due to a low cardiac output, carbon monoxide intoxication, profound arterial hemoglobin desaturation, and reduced oxygen content or either localized in the context of redistribution of the cardiac output at the expense of certain tissues or due to a vascular occlusion (Swenson, 2016). It can also be caused by mitochondrial enzyme defects and by inhibitors of aerobic metabolism, such as cyanide. Every drop in cellular oxygenation causes an acceleration of the reduction in pyruvate to lactate by LDH, which results in a pathological augmentation of the lactate/pyruvate ratio above 10 (Ben‐Hamouda et al., 2013). Even if the pyruvate dosage is expensive, its use and the finding of a pathological L/P level confirm cellular dysoxia and excludes other causes.
3.4.2 Reduced lactate clearance
Lactate is partly transported to the liver and the kidneys and converted to glucose through gluconeogenesis (the Cori cycle). The hepatic clearance of lactate thus depends on hepatic extraction and hepatic functioning. Hepatic extraction is determined by the liver blood flow, which needs no less than one‐fourth of its normal flow. The capture of lactate by hepatocytes depends on its transportation by a family of MCTs with different isoforms (MCT1‐4). Thus, neoglucogenesis will depend on hepatic functioning. Its activity is decreased in hepatic failure and inhibited in shock states and severe acidosis (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
3.5 Distinction between hyperlactatemia and lactic acidosis
Hyperlactatemia and lactic acidosis are frequently mixed, which may cause confusion. However, the two are governed by a different concept. Glycolysis causes lactate formation without lactic acidosis when there is no net H+ production. The H+ protons may arise following ATP hydrolyzation and are produced through glycolysis. However, those protons are recycled by lactate consumption either through the Krebs cycle or through the hepatic Cori cycle, hence maintaining the internal acid‐base balance (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
In this regard, acquired or congenital inhibition of PDH, inhibition of oxidative phosphorylation due to cellular dysoxia, medication or intoxication and hepatic insufficiency are all causes of reduced proton recycling in either the Krebs or the Cori cycle, therefore causing high anion gap lactic acidosis. Other causes of hyperlactatemia, such as elevated glycolysis in hyperglycemia, arising from beta‐adrenergic stimulation or muscular catabolism, will only cause an elevated production of lactate without proton recycling impairment and without ensuing concomitant lactic acidosis (Kraut & Madias, 2014).
3.6 Lactagenic cancers
3.6.1 Warburg effect
In glycolytic tumors, lactate levels of cancer cells are markedly elevated up to 40‐fold and are highly associated with cancer aggressiveness and poor survival (Brizel et al., 2001; San‐Millán & Brooks, 2017). In fast‐growing malignancies, the rate of tumor metabolism may be great enough to exceed normal muscle and liver lactate clearance and cause systemic type B lactic acidosis (Sillos et al., 2001; Swenson, 2016). The majority of lactic acidosis in malignancies is reported in cases of hematologic malignancies. Only a few cases have been reported for solid tumors presenting with lactic acidosis (Nair & Shah, 2017).
In 1923, Warburg observed in his Nobel Prize winning studies that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions and that tumor cells live and grow in a more acidic milieu as a result of increased lactic acid production not generally tolerated by normal cells (San‐Millán & Brooks, 2017; Swenson, 2016). His discovery was named the “Warburg effect” by Racker in 1972 (San‐Millán & Brooks, 2017). The Warburg effect is a hallmark of cancer, and its significance is still apparent in the common cancer diagnostic test using fluorodeoxyglucose positron emission tomography, which has a high diagnostic accuracy (Potter et al., 2016).
From a contemporary perspective of cell metabolic efficiency, it seems difficult to understand why, despite fully aerobic conditions, cancer cells choose an inefficient pathway producing two ATP molecules per molecule of glucose instead of 38 via coupled mitochondrial respiration. However, as mentioned earlier, the amount of ATP synthesized over any given period of time is comparable in both ways of glucose metabolism because fermentation into lactate is 10–100 times faster than the completion of oxidative phosphorylation (Liberti & Locasale, 2016). Moreover, the stress of lactate production is simply passed on to the host. Then, the cancer cells proliferate, and the tumor grows and metastasizes because of host exploitation, ending in final host expiration (San‐Millán & Brooks, 2017).
3.6.2 Origin of tumoral lactagenesis
Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous and unstoppable glucose utilization to produce lactate involving five major steps: (i) an increase in glucose uptake; (ii) upregulation of PFK, the rate‐limiting enzyme of glycolysis; (iii) a decrease in mitochondrial respiration by upregulation of PDH kinase (PDK) that inhibits pyruvate uptake in mitochondria; (iv) increased lactate production by LDH upregulation; and (v) upregulation of MCT1 and MCT4 expression, the transmembrane transporters of lactate, for higher lactate plus H+ efflux and further lactate shuttling, thus mediating tumor growth and proliferation (Brahimi‐Horn et al., 2011; San‐Millán & Brooks, 2017; Swenson, 2016).
In our case, the Warburg effect was caused by a Burkitt lymphoma, a B‐cell derived malignancy. The main characteristic of a Burkitt lymphoma is an increased production of the MYC oncoprotein caused by chromosomal rearrangements. This translocation results in inappropriately high expression levels of MYC, which gives cells proliferative capacity. Moreover, MYC also activates the transcription of genes encoding glucose transporter, hexokinase, MCT, PDK, PK (pyruvate kinase), and LDH, resulting in the accelerated aerobic glycolysis or the Warburg effect. The MYC protein is the master regulator of the Warburg effect in BL cells (Mushtaq et al., 2015).
3.6.3 Aim of tumoral lactagenesis
The role of the Warburg effect in the pathogenesis of cancer has not yet been completely established. Lactate is the end product of the Warburg effect, but lactate production or lactagenesis is probably the purpose of the Warburg effect as well.
In addition to being a potent oxidative fuel, lactate is also a potent signaling molecule necessary for all the major steps in carcinogenesis, as follows: (i) angiogenesis, (ii) cell migration, (iii) metastasis, (iv) immune escape, and (v) self‐sufficiency of cancer cells (San‐Millán & Brooks, 2017).
Lactate released from tumor cells by MCT4 plays a role in stimulating angiogenesis (i) by increasing the expression of vascular endothelial growth factor protein in endothelial cells (Goodwin et al., 2014; San‐Millán & Brooks, 2017). Cell migration (ii) is another essential step in carcinogenesis and metastasis in which lactate seems to be a key element to increase cell migration. Marked extracellular acidosis appears to promote the migration and metastasis (iii) of cancer cells by disrupting normal cell‐matrix interactions that act to maintain stable growth patterns (Swenson, 2016). Lactate levels are highly associated with a high incidence of distant metastasis. Acidosis reduces host defense against malignant cells and contributes to immune escape (iv) in many different ways: first, by inhibiting the release of the cytokines tumor necrosis factor and interleukin‐6; and second, by inhibiting the activation of T‐cells with a decrease in the cytotoxic activity of T‐cells and inhibition of natural killer cell functioning. Lactate also plays a central role in the self‐sufficiency and sustainability (v) of cancer cells. Cancer cells at the hypoxic core might use glucose and produce lactate, whereas cells on the periphery, close to a robust vascular supply, might take up this lactate and oxidize it as a fuel. The self‐sufficiency depending upon high glycolytic flux also allows cancer cells to produce lactate for carcinogenesis by angiogenesis, immune escape, cell migration, and metastasis. A glucose to lactate shunt occurs in which the host bears the burden of providing a limitless glucose supply as well as a sink for disposal of lactate and hydrogen ions. This may even explain why the actual cause of cachexia and death due to cancer appears to be multifactorial, with organ failure rather than the tumor itself (San‐Millán & Brooks, 2017).
3.6.4 Targeting lactate production and shuttling: Future direction in cancer treatment
Given the profound changes in acid‐base balance in tumors and the role of pH in tumor survival and growth, altering the acid‐base milieu has presented itself as an interesting approach for treating cancer (Swenson, 2016), but the development of these new adjuvant therapies goes way beyond the scope of this article. Nevertheless, after explaining all the pathophysiology, it seems important to shed light on some future possible treatments: on the one hand, medication increasing PDH activity, such as dichloroacetate, seems to halt carcinogenesis by lowering cytosolic lactate production; on the other hand, MCT1 and MCT4 inhibitors seem to have enormous potential in cancer treatment by inhibiting lactate shuttling, even if there is still a lack of specificity (San‐Millán & Brooks, 2017). Furthermore, simpler approaches such as aerobic exercise seem to have beneficial effects by augmenting mitochondrial size and function and thus lactate clearance capacity. Further research is necessary to identify possible targets and create tumor‐specific treatments.
3.6.5 Treatment options in patients with type‐B LA due to malignancies
Lactic acidosis in association with malignancies carries an extremely poor prognosis with a mortality rate over 90% (Nair & Shah, 2017; Sillos et al., 2001). Moreover, the high mortality associated with lactic acidosis has prompted some oncologists to consider this an oncological emergency (Nair & Shah, 2017). The best treatment for patients with hematologic malignancies who develop type B lactic acidosis is not yet clear.
Chemotherapy
Initiating aggressive chemotherapy has been effective in correcting acute acidosis (Friedenberg et al., 2007). It is actually the only treatment modality that consistently leads to remission. Resolution of lactic acidosis was reported to occur as early as 15 h and up to 3 days after starting chemotherapy. This treatment would not be effective in patients whose tumors are unresponsive to chemotherapy. Lactic acidosis improves with chemotherapy, and resolution of the lactic acidosis could be a surrogate marker of inducing remission (Chan et al., 2009).
Intravenous bicarbonate
The use of IV bicarbonate as a treatment for profound acidosis has never shown a meaningful clinical benefit, even in the worst cases (Swenson, 2016). As severe acidosis can cause respiratory fatigue and hemodynamic instability, intravenous bicarbonate is often used to attenuate systemic acidosis and increase the responsiveness to catecholamines. However, it would appear that the benefits of sodium bicarbonate are outweighed by its disadvantages, such as hypernatremia and hyperosmolality (Swenson, 2016). Acidemia leads to unloading oxygen from hemoglobin by shifting the hemoglobin‐oxygen dissociation curve to the right, and reducing acidosis will hinder oxygen release. Studies have shown that intracellular acidosis tends to slow lactate production (Madias, 1986; Sillos et al., 2001). Alkalinization has been shown to potentiate lactate production in patients with malignancy‐induced chronic lactic acidosis (Fields et al., 1981; Fraley et al., 1980). The effect of IV bicarbonate on mortality or lactate concentration in the setting of malignancy‐induced type B lactic acidosis has not been studied directly, as the incidence is very low. In a case report by Fraley et al. (1980), administration of bicarbonate improved pH but not the serum bicarbonate level. Intravenous bicarbonate corrected the extracellular pH but did not affect the significant intracellular acid production due to high tumor cell turnover. The use of sodium bicarbonate may not be recommended in these patient groups.
Renal replacement therapy
Renal replacement therapy, continuous or intermittent, in patients with renal dysfunction may be useful in addition to chemotherapy to correct metabolic acidosis. Here, once again, since the prognosis of type B lactic acidosis related to malignancies is grim, the only chance for remission is starting cytoreductive chemotherapy. Intravenous bicarbonate and hemodialysis will no longer act as a bridge to stabilize the patient enough so that the underlying cause can be treated (Chan et al., 2009).
Intravenous insulin
Lactic acidosis has also been treated with intravenous administration of insulin, which increases the conversion of pyruvate to acetyl‐coenzyme A and consequently facilitates oxidation of lactate to pyruvate (Sillos et al., 2001). Administration of glucose can actually induce lactic acidosis by increasing the availability of glucose and thus increasing the production of lactate by the tumor. Returning to the case presented in this manuscript, the patient was severely hypoglycemic, which is the reason why we substituted for intravenous glucose to maintain the patient's euglycemia. However, in a provocative hypothesis in 2009, Nijsten & van Dam (2009) presented a hypothetical treatment whereby glucose might be systemically lowered. If tumors are glucose consumers and lactate producers and all other tissues in the body can actively take up and use lactate as a fuel, why not systemically induce hypoglycemia to starve tumor cells? In this configuration, lactate would provide salvage fuel for the other tissues (Goodwin et al., 2014). Work to investigate this concept should be pursued.
4 CONCLUSION
Lactic acidosis is a commonly encountered problem in intensive care units and is most commonly associated with dysoxia, better known as type A lactic acidosis. Type B is more uncommon and can be life‐threatening and sometimes even a lethal complication in patients with malignancies. Due to its rareness, it is likely to be under recognized and therefore underdiagnosed. If oncological patients develop high anion gap lactic acidosis without hemodynamic compromise associated with acute respiratory distress without a pulmonary source, the possibility for tumor‐induced type B lactic acidosis through the “Warburg effect” should be considered. Awareness about this condition is important in the clinical practice of intensive care physicians since it will allow a timely diagnosis and the implementation of subsequent therapy. Currently, effective chemotherapy seems to be the only hope for survival.
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
Carole Looyens, and Karim Bendjelid designed the present review. Carole Looyens, and Karim Bendjelid analyzed data and references. Carole Looyens, Raphael Giraud, Ivo Neto Silva, and Karim Bendjelid wrote the manuscript. All authors read and approved the final manuscript.
DATA AVAILABILITY STATEMENT
The data that support these findings are available upon reasonable request from the corresponding author. | Recovered | ReactionOutcome | CC BY | 33611854 | 19,114,934 | 2021-02 |
What was the outcome of reaction 'Pyrexia'? | Burkitt lymphoma and lactic acidosis: A case report and review of the literature.
Type A lactic acidosis is a potentially life-threatening complication in critically ill patients and is the hallmark of a shock state as a result of tissue hypoperfusion and dysoxia. Type B lactic acidosis results from mechanisms other than dysoxia and is a rare condition in patients with solid tumors or hematological malignancies. We present a case of a 60-year-old man with lactic acidosis who was found to have a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Lactagenic cancers are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Warburg in 1923 that is correlated with cancer aggressiveness and poor survival. There is increased glucose utilization with the purpose of lactagenesis under fully oxygenated conditions, as lactate seems to be a potent signaling molecule for angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, which are five essential steps of carcinogenesis. Type B lactic acidosis in association with malignancies carries an extremely poor prognosis. Currently, effective chemotherapy seems to be the only hope for survival.
1 INTRODUCTION
A high arterial lactate level in critically ill patients has been associated with significant morbidity and mortality ever since the first description two centuries ago (Kompanje et al., 2007). Hyperlactatemia in the critically ill is the hallmark of shock states (Kraut & Madias, 2014; Levy, 2006; Nichol et al., 2010; Vincent & De Backer, 2013; Vincent et al., 2016), and the degree of increase in arterial lactate concentrations is directly related to the severity of the shock state (Haas et al., 2016; Nichol et al., 2011; Vincent et al., 2016). In this regard, the prognostic value of arterial lactate levels seems to be independent of the underlying critical illness (Jansen et al., 2010). Serial lactate measurements are widely used in intensive care medicine in the evaluation of the progression of a shock state and the response to intensive and urgent therapy (Levy et al., 2018; Vincent et al., 2016).
Although high lactate levels have been widely used as a marker of altered tissue perfusion in critically ill patients, this condition does not always simply reflect the development of anaerobic metabolism and cellular dysoxia better known as Type A lactic acidosis (Kraut & Madias, 2014; Vincent et al., 2016). While a lack of oxygen forbids the continuation of oxidative phosphorylation in the Krebs cycle, a normal oxygen supply does not impose a complete cessation of anaerobic metabolism. Type B lactic acidosis results from mechanisms other than dysoxia, including inborn errors of metabolism, drugs and toxins, systemic diseases (i.e., diabetes and sepsis), and less commonly malignancy. In this case report, we try to emphasize the pathophysiology leading to hyperlactatemia, and we will focus on the hyperlactatemia caused by lactagenic cancers and the Warburg effect.
2 CASE SUMMARY
A 60‐year‐old‐male patient presented at the emergency department with increasing abdominal girth, abdominal discomfort, severe asthenia, malaise, and profuse diaphoresis without fever. His medical history highlighted chronic renal failure (stage G3bA1) and a cardiac transplant 4 years ago due to terminal ischemic cardiomyopathy. His recent cardiac biopsy was free from any signs of rejection. He was taking immunosuppression with cyclosporine and mycophenolic acid. On admission, the clinical examination revealed a tense and distended abdomen with abdominal ascites. Initial vital signs were stable except for tachycardia at 110 beat per minute. The respiratory rate was 22 breath per minute, and the temperature was within the normal range. Physical exam was otherwise normal.
Laboratory analysis showed leukocytosis with a left shift, signs of hepatocellular injury without cholestasis, and chronic renal failure. His white blood count count was 14.8 G/L, C‐reactive protein was 45 mg/L (normal <10 mg/L), aspartate aminotransferase (AST) was 144 IU/L (normal, 14–50 IU/L), alanine aminotransferase (ALT) was 79 IU/L (normal, 12–50 IU/L), lactate dehydrogenase (LDH) was 1082 IU/L (normal, 87–210 IU/L), total bilirubin was 4 μmol/L (normal, 7–25 μmol/L), alkaline phosphatase was 82 IU/L (normal, 25–102 IU/L), gamma‐glutamyl transferase was 41 IU/L (normal, 9–40 IU/L), creatinine was 198 µmol/L (normal, 62–106 µmol/L), with an estimated glomerular filtration rate of 31 ml/min/1.73 m2. An ultrasound assessment confirmed the presence of moderate ascites in all four abdominal quadrants. Ascites liquid puncture showed leukocytosis, but the liquid culture remained sterile. Abdominal CT was then performed following a rapid clinical deterioration for abdominal sepsis, showing signs of diffuse peritonitis with a pelvic abscess located adjacent to the small intestine. The patient was therefore immediately started on broad‐spectrum antibiotics and antifungal treatment. In addition, a median laparotomy was performed to remove the pelvic abscess. The resected mass (suspect for any neoplasm) was sent for an extemporaneous analysis that elicited a high‐grade lymphoma. Later pathology testing confirmed a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Following emergency department admission and immediate surgery, the patient was admitted to the intensive care unit for high anion gap lactic acidosis, with a pH of 7.29 and a lactate level of 7.4 mmol/L on the arterial blood gas analysis. However, the patient's vital signs remained stable, and he could be extubated on the same day. Signs of hypoxia or circulatory failure were absent, capillary refill time was within normal limits and there was no skin mottling. Moreover, lactate/pyruvate ratio value was 19.0. In contrast, he simultaneously developed profuse hypoglycemia necessitating continuous high‐dose intravenous glucose supplementation. Cardiac output measured with bedside echocardiography appeared to be within the normal ranges. A new postoperative abdominal CT angiography was performed to exclude abdominal ischemia. The lactic acidosis (mean pH 7.3) remained for several days with lactate levels fluctuating around approximately 7 mmol/L. A concomitant thiamine deficiency was excluded by intravenous supplementation. Lactic acidosis started to decrease once chemotherapy with cyclophosphamide and vincristine, initiated 5 days after surgical resection, began to have an effect.
The interpretation of an initial positron emission tomography–computed tomography (PET‐CT) (Figures 1, 2, 3) 6 days after surgery was not clear due to the difficult differentiation between an infectious versus an oncological process. In addition to diffuse hypermetabolism in the peritoneal cavity associated with retroperitoneal adenopathies, it revealed supradiaphragmatic invasion of the lymphoma with a mass located in the right cardiophrenic recess, left mammary adenopathies, and pleural and pericardial nodules. There were also two hypermetabolic, osseous spots, suspected of metastasis, one in the second cervical vertebrae and one in the left scapula.
FIGURE 1 Left: Transversal image from patient's abdominal positron emission tomography–computed tomography (PET‐CT) post tumoral resection revealing diffuse peritoneal hypermetabolism with difficult differentiation between an infectious versus an oncological process. Middle: Transversal image from patients thoracic PET‐CT revealing supradiafragmatic invasion of the lymphoma with a mass and a nodule located in the right cardiophrenic recess with diffuse bilateral pleural nodular thickening. Right: Transversal image from patient's abdominal PET‐CT showing retroperitoneal adenopathies.
FIGURE 2 Lactate production and destination. Glycolysis takes place in the cellular cytosol. The preparatory phase consists of the generation of 1–3 diphosphoglycerate by hekoxinase and phosphofructokinase (PFK), the rate‐limiting enzyme. The pay off phase consists of the generation of pyruvate by pyruvate kinase. Pyruvate can be reduced to lactate by lactate dehydrogenase (LDH) or it can be converted to acetyl‐Co A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. Pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by alanine aminotransferase, resulting in the formation of alanine. Lactate either locally formed after reduction of pyruvate or coming from a distant source, can be consumed in the mitochondria by reformation of pyruvate by mitochondrial lactate dehydrogenase (mLDH) after diffusion across membranes via monocarboxylate transporters (MCTs). This concept is better known as the cell‐to‐cell lactate shuttle.
FIGURE 3 Lactate/pyruvate ratio. In aerobic glycolysis, the physiologic ratio of lactate/pyruvate is approximately 10 and is warranted by lactate dehydrogenase (LDH) catalyzing the reduction of pyruvate in lactate. When there is any perturbation of tissular oxygenation, cellular oxygenation is inhibited causing and acceleration of the reduction in pyruvate into lactate by LDH which results in a pathological lactate/pyruvate ratio above 10. The inhibition of the oxidative phosphorylation avoids any proton recycling leading to high anion gap lactic acidosis. Lactate is mostly converted into glucose through neoglucogenesis in the Cori cycle taking place in the liver and the kidneys. In case of insufficient hepatic perfusion or hepatic failure, lactate will be less cleared causing a variable lactate/pyruvate ratio depending on the source of production of lactate. Protons, normally recycled in the Cori cycle, will accumulate causing acidosis. MTC, monocarboxylate transporter.
He underwent intensive inpatient chemotherapy with one cycle of R‐CHP and six cycles of R‐CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride, O = vincristine sulfate, P = prednisone) and 10 prophylactic intrathecal injections of methotrexate. Chemotherapy was complicated with multiple episodes of febrile agranulocytosis, anemia and thrombocytopenia, which resolved after treatment with antibiotics in combination with filgrastim and multiple transfusions. The patient could be discharged with closed outpatient follow‐up after 5 months of admission. A PET‐CT was carried out 2 months after discharge and showed complete regression of all the lesions. A thoraco‐abdominal CT performed 1 year after the diagnosis seemed to be completely normal.
3 DISCUSSION
3.1 Lactate homeostasis
As with the blood levels of any substance, elevated lactate levels can be the result of increased production or reduced clearance, or both. Under physiological conditions, 1500 mmol of lactate or 20 mmol/kg of body weight is produced daily from various organs, including the muscle, intestine, red blood cells, brain, and skin (Kraut & Madias, 2014). Lactate is metabolized by the liver (60%), kidneys (30%), and other organs. The normal arterial blood lactate level is approximately 1 mmol/L (Kraut & Madias, 2014; Vincent et al., 2016).
3.2 Lactate production
Lactate formation is closely related to glycolysis. Glycolysis takes place in ten steps, five of which are in the preparatory phase and five in the payoff phase. Phosphofructokinase (PFK) is the rate‐limiting enzyme. Two net ATP molecules are generated by phosphorylation by high‐energy compounds. The final product of glycolysis is pyruvate and lactate, to which pyruvate can be reduced. LDH catalyzes the reduction of pyruvate into lactate at a well‐defined rate so that in normal homeostasis, the physiological ratio of lactate/pyruvate is approximately 10. In the presence of oxygen, pyruvate can be converted into acetyl‐coenzyme A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. This respiratory chain of reactions results in a net production of 36 ATP molecules per molecule of glucose. The metabolic yield of glycolysis when participating in the aerobic metabolic pathway (i.e., along with the Krebs cycle and oxidative phosphorylation) is superior to fermentation (without O2) into lactate (38 vs. 2 molecules of ATP). Anaerobic fermentation into lactate may be inefficient compared to oxidative phosphorylation, however, the rate of glucose metabolism into lactate is 10–100 times faster than the complete oxidation of glucose in the mitochondria (Liberti & Locasale, 2016). In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is utilized (Liberti & Locasale, 2016). In addition to the better‐known reduction to lactate and the oxidation to acetyl‐coenzyme A, for the completeness of this review, we need to mention that pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by ALT, resulting in the formation of alanine (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
Experiments by Pasteur (Platt, 1988), Meyerhof (1927), and A.V. Hill (Bassett, 2002) led to the widespread understanding of the glycolytic pathway and the notion that only a limitation of oxygen availability leads to fermentation and lactate accumulation. Out of this early work came the idea that lactate is just an anaerobic waste product that must be cleared from the muscles and blood, preferably by being converted to glucose in the liver via the Cori cycle. However, it has been demonstrated that lactate is a potent fuel and signaling molecule and is constantly being produced and circulated throughout the body, even and most often when there is adequate oxygen. Lactate is more than just a “hypoxic waste product.” Lactate as a result of dysoxia is often the exception rather than the rule, even in critically ill patients (Goodwin et al., 2014).
3.3 Lactate metabolism
Any time glycolysis is active, lactate is formed and equilibrates with local lactate gradients. Lactate equilibrates mainly by diffusing across membranes via monocarboxylate transporters (MCTs). In lactate‐producing tissues, this means exporting lactate into the circulation where both local and distant tissues can take it up and use it.
Lactate is metabolized by the liver (60%), kidneys (30%) and other organs. Lactate can be used for gluconeogenesis by reformation of pyruvate and glucose in the Cori cycle, which takes place in the liver and kidneys. In addition, lactate can readily replace glucose as a fuel for almost all cells of the body (any cell with mitochondria) by reformation and subsequent oxidation of pyruvate in the mitochondria. Lactate clearance occurs in the heart, liver, skeletal muscle and even brain. This observation that lactate is constantly being produced and consumed formed the basis of the cell‐to‐cell lactate shuttle, an energy exchange hypothesis originally introduced by Brooks in 1984 (Brooks, 1986). Lactate seems to be a key intermediate metabolite in whole body metabolism (Ben‐Hamouda et al., 2013; Goodwin et al., 2014; Kraut & Madias, 2014).
3.4 Hyperlactatemia (Table 1)
3.4.1 Elevated production of lactate
As mentioned earlier, normal lactate production is approximately 1 mmol/min or 1500 mmol/24 h, and the normal lactate level is approximately 1 mmol/L (Ben‐Hamouda et al., 2013; Vincent et al., 2016). Elevated lactate production can be the consequence of either an elevated pyruvate concentration (as seen in accelerated glycolysis, in elevated protein catabolism or through inhibition of PDH) or cellular dysoxia. Dysoxic lactic acidosis is better known as type‐A lactic acidosis, and all other nondysoxic causes of lactic acidosis are classified as type B according to the classification of Woods and Cohen (Ben‐Hamouda et al., 2013). Indeed, if lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics (i.e. normal blood pressure, normal volemia, normal blood oxygen, and oxygen‐carrying capacity), it is traditionally termed Type B lactic acidosis. In the present setting, the physiologic ratio value of lactate/pyruvate is around 10 or higher.
TABLE 1 Classification of hyperlactatemia according to Woods and Cohen
Type A: Hyperlactatemia associated with cellular dysoxia due to insufficient oxygen supply
Stagnant dysoxia Low cardiac output
Redistribution of cardiac output at the expense of certain tissues
Vascular occlusion
Dysoxia caused by elevated demand of oxygen Convulsions
Intensive exercise
Dysoxia caused by low oxygen carrying capacity Anemic dysoxia
Carbon monoxide intoxication
Hypoxic dysoxia (low PaO2)
Cytotoxic dysoxia due to inefficient mitochondrial consumption of oxygen Sepsis
Cyanide intoxication
Type B1: Hyperlactatemia due to an underlying disease
Accelerated glycolysis Hyperglycemia
Sepsis
Endogenous catecholamines
Lactagenic cancer
Elevated protein catabolism Burn victims
Severe septic shock
Acquired inhibition of pyruvate dehydrogenase (PDH) Sepsis
Thiamine deficiency
Lactagenic cancer
Reduced lactate clearance Reduced liver blood flow
Hepatic failure
Type B2: Hyperlactatemia due to drugs and toxins
Exogenous catecholamines (adrenaline, dobutamine, terbutaline) Cocaine, metamphetamines
Propofol Salicylates
Metformine Antiretroviral drugs
Linezolid Toxic alcohols (ethanol, methanol, propylene glycol, ethylene glycol)
Paracetamol
Type B3: Hyperlactatemia due to inborn errors of metabolism (enzymatic deficiencies)
Congenital PDH deficiency
Glucose‐6‐phosphatase deficiency (von Gierke disease)
Pyruvate carboxylase deficiency
Methylmalonic aciduria
Mitochondrial encephalomyopathies
John Wiley & Sons, LtdAccelerated glycolysis
Any cause of an accelerated level of glycolysis causes an expected elevation of pyruvate and thus of lactate, as the physiologic ratio of lactate/pyruvate of approximately 10 or higher is always warranted by LDH. Accelerated glycolysis is the case in hyperglycemia, sepsis, or other situations with elevated endogenous or exogenous catecholamines (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014). Finally, accelerated aerobic glycolysis may partially explain the hyperlactatemia caused by tumoral cells of lactagenic cancers, known as the Warburg effect (San‐Millán & Brooks, 2017), the cause of lactic acidosis in the present case.
Elevated protein catabolism
Elevated protein catabolism can also cause a rise in pyruvate levels. As mentioned earlier, pyruvate can be transaminated into alanine, and the reverse can be witnessed through the activity of the ALT enzyme, forming pyruvate in the liver. This mechanism contributes to hepatic neoglucogenesis. Accelerated protein catabolism is seen as muscle wasting, present in many critically ill patients, most severely in burn victims and in patients with severe septic shock. The elevated alanine supply in the liver contributes to the elevated pyruvate concentration and, ultimately, to hyperlactatemia, as the physiologic lactate/pyruvate ratio is always warranted by LDH (Ben‐Hamouda et al., 2013).
Inhibition of PDH
As discussed earlier, pyruvate is oxidized into acetyl‐coenzyme‐A by PDH. A congenital or an acquired reduction in the enzymatic activity of PDH can cause an accumulation of pyruvate and therefore of lactate. An acquired reduction in PDH can be caused by certain endotoxins and inflammatory cytokines in sepsis. This explains why hemodynamically stable patients with sepsis and normal liver function may have lactic acidosis (Kraut & Madias, 2014). It can also be caused by nucleoside reverse transcriptase inhibitors used to treat patients with HIV or by a thiamine deficiency, as in patients receiving parenteral nutrition or with severe Beri‐beri. Thiamine is an important cofactor in the PDH complex. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead, conversion into lactate takes place (Friedenberg et al., 2007). Finally, certain oncogenes express PDH kinase, which inactivates PDH and inhibits the Krebs cycle (San‐Millán & Brooks, 2017; Swenson, 2016) and partially explains the development of hyperlactatemia caused by tumoral cells.
Cellular dysoxia
Perturbations of tissular oxygenation, termed “cellular dysoxia”, are caused by insufficient oxygen supply. This dysoxia can be either generalized due to a low cardiac output, carbon monoxide intoxication, profound arterial hemoglobin desaturation, and reduced oxygen content or either localized in the context of redistribution of the cardiac output at the expense of certain tissues or due to a vascular occlusion (Swenson, 2016). It can also be caused by mitochondrial enzyme defects and by inhibitors of aerobic metabolism, such as cyanide. Every drop in cellular oxygenation causes an acceleration of the reduction in pyruvate to lactate by LDH, which results in a pathological augmentation of the lactate/pyruvate ratio above 10 (Ben‐Hamouda et al., 2013). Even if the pyruvate dosage is expensive, its use and the finding of a pathological L/P level confirm cellular dysoxia and excludes other causes.
3.4.2 Reduced lactate clearance
Lactate is partly transported to the liver and the kidneys and converted to glucose through gluconeogenesis (the Cori cycle). The hepatic clearance of lactate thus depends on hepatic extraction and hepatic functioning. Hepatic extraction is determined by the liver blood flow, which needs no less than one‐fourth of its normal flow. The capture of lactate by hepatocytes depends on its transportation by a family of MCTs with different isoforms (MCT1‐4). Thus, neoglucogenesis will depend on hepatic functioning. Its activity is decreased in hepatic failure and inhibited in shock states and severe acidosis (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
3.5 Distinction between hyperlactatemia and lactic acidosis
Hyperlactatemia and lactic acidosis are frequently mixed, which may cause confusion. However, the two are governed by a different concept. Glycolysis causes lactate formation without lactic acidosis when there is no net H+ production. The H+ protons may arise following ATP hydrolyzation and are produced through glycolysis. However, those protons are recycled by lactate consumption either through the Krebs cycle or through the hepatic Cori cycle, hence maintaining the internal acid‐base balance (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
In this regard, acquired or congenital inhibition of PDH, inhibition of oxidative phosphorylation due to cellular dysoxia, medication or intoxication and hepatic insufficiency are all causes of reduced proton recycling in either the Krebs or the Cori cycle, therefore causing high anion gap lactic acidosis. Other causes of hyperlactatemia, such as elevated glycolysis in hyperglycemia, arising from beta‐adrenergic stimulation or muscular catabolism, will only cause an elevated production of lactate without proton recycling impairment and without ensuing concomitant lactic acidosis (Kraut & Madias, 2014).
3.6 Lactagenic cancers
3.6.1 Warburg effect
In glycolytic tumors, lactate levels of cancer cells are markedly elevated up to 40‐fold and are highly associated with cancer aggressiveness and poor survival (Brizel et al., 2001; San‐Millán & Brooks, 2017). In fast‐growing malignancies, the rate of tumor metabolism may be great enough to exceed normal muscle and liver lactate clearance and cause systemic type B lactic acidosis (Sillos et al., 2001; Swenson, 2016). The majority of lactic acidosis in malignancies is reported in cases of hematologic malignancies. Only a few cases have been reported for solid tumors presenting with lactic acidosis (Nair & Shah, 2017).
In 1923, Warburg observed in his Nobel Prize winning studies that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions and that tumor cells live and grow in a more acidic milieu as a result of increased lactic acid production not generally tolerated by normal cells (San‐Millán & Brooks, 2017; Swenson, 2016). His discovery was named the “Warburg effect” by Racker in 1972 (San‐Millán & Brooks, 2017). The Warburg effect is a hallmark of cancer, and its significance is still apparent in the common cancer diagnostic test using fluorodeoxyglucose positron emission tomography, which has a high diagnostic accuracy (Potter et al., 2016).
From a contemporary perspective of cell metabolic efficiency, it seems difficult to understand why, despite fully aerobic conditions, cancer cells choose an inefficient pathway producing two ATP molecules per molecule of glucose instead of 38 via coupled mitochondrial respiration. However, as mentioned earlier, the amount of ATP synthesized over any given period of time is comparable in both ways of glucose metabolism because fermentation into lactate is 10–100 times faster than the completion of oxidative phosphorylation (Liberti & Locasale, 2016). Moreover, the stress of lactate production is simply passed on to the host. Then, the cancer cells proliferate, and the tumor grows and metastasizes because of host exploitation, ending in final host expiration (San‐Millán & Brooks, 2017).
3.6.2 Origin of tumoral lactagenesis
Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous and unstoppable glucose utilization to produce lactate involving five major steps: (i) an increase in glucose uptake; (ii) upregulation of PFK, the rate‐limiting enzyme of glycolysis; (iii) a decrease in mitochondrial respiration by upregulation of PDH kinase (PDK) that inhibits pyruvate uptake in mitochondria; (iv) increased lactate production by LDH upregulation; and (v) upregulation of MCT1 and MCT4 expression, the transmembrane transporters of lactate, for higher lactate plus H+ efflux and further lactate shuttling, thus mediating tumor growth and proliferation (Brahimi‐Horn et al., 2011; San‐Millán & Brooks, 2017; Swenson, 2016).
In our case, the Warburg effect was caused by a Burkitt lymphoma, a B‐cell derived malignancy. The main characteristic of a Burkitt lymphoma is an increased production of the MYC oncoprotein caused by chromosomal rearrangements. This translocation results in inappropriately high expression levels of MYC, which gives cells proliferative capacity. Moreover, MYC also activates the transcription of genes encoding glucose transporter, hexokinase, MCT, PDK, PK (pyruvate kinase), and LDH, resulting in the accelerated aerobic glycolysis or the Warburg effect. The MYC protein is the master regulator of the Warburg effect in BL cells (Mushtaq et al., 2015).
3.6.3 Aim of tumoral lactagenesis
The role of the Warburg effect in the pathogenesis of cancer has not yet been completely established. Lactate is the end product of the Warburg effect, but lactate production or lactagenesis is probably the purpose of the Warburg effect as well.
In addition to being a potent oxidative fuel, lactate is also a potent signaling molecule necessary for all the major steps in carcinogenesis, as follows: (i) angiogenesis, (ii) cell migration, (iii) metastasis, (iv) immune escape, and (v) self‐sufficiency of cancer cells (San‐Millán & Brooks, 2017).
Lactate released from tumor cells by MCT4 plays a role in stimulating angiogenesis (i) by increasing the expression of vascular endothelial growth factor protein in endothelial cells (Goodwin et al., 2014; San‐Millán & Brooks, 2017). Cell migration (ii) is another essential step in carcinogenesis and metastasis in which lactate seems to be a key element to increase cell migration. Marked extracellular acidosis appears to promote the migration and metastasis (iii) of cancer cells by disrupting normal cell‐matrix interactions that act to maintain stable growth patterns (Swenson, 2016). Lactate levels are highly associated with a high incidence of distant metastasis. Acidosis reduces host defense against malignant cells and contributes to immune escape (iv) in many different ways: first, by inhibiting the release of the cytokines tumor necrosis factor and interleukin‐6; and second, by inhibiting the activation of T‐cells with a decrease in the cytotoxic activity of T‐cells and inhibition of natural killer cell functioning. Lactate also plays a central role in the self‐sufficiency and sustainability (v) of cancer cells. Cancer cells at the hypoxic core might use glucose and produce lactate, whereas cells on the periphery, close to a robust vascular supply, might take up this lactate and oxidize it as a fuel. The self‐sufficiency depending upon high glycolytic flux also allows cancer cells to produce lactate for carcinogenesis by angiogenesis, immune escape, cell migration, and metastasis. A glucose to lactate shunt occurs in which the host bears the burden of providing a limitless glucose supply as well as a sink for disposal of lactate and hydrogen ions. This may even explain why the actual cause of cachexia and death due to cancer appears to be multifactorial, with organ failure rather than the tumor itself (San‐Millán & Brooks, 2017).
3.6.4 Targeting lactate production and shuttling: Future direction in cancer treatment
Given the profound changes in acid‐base balance in tumors and the role of pH in tumor survival and growth, altering the acid‐base milieu has presented itself as an interesting approach for treating cancer (Swenson, 2016), but the development of these new adjuvant therapies goes way beyond the scope of this article. Nevertheless, after explaining all the pathophysiology, it seems important to shed light on some future possible treatments: on the one hand, medication increasing PDH activity, such as dichloroacetate, seems to halt carcinogenesis by lowering cytosolic lactate production; on the other hand, MCT1 and MCT4 inhibitors seem to have enormous potential in cancer treatment by inhibiting lactate shuttling, even if there is still a lack of specificity (San‐Millán & Brooks, 2017). Furthermore, simpler approaches such as aerobic exercise seem to have beneficial effects by augmenting mitochondrial size and function and thus lactate clearance capacity. Further research is necessary to identify possible targets and create tumor‐specific treatments.
3.6.5 Treatment options in patients with type‐B LA due to malignancies
Lactic acidosis in association with malignancies carries an extremely poor prognosis with a mortality rate over 90% (Nair & Shah, 2017; Sillos et al., 2001). Moreover, the high mortality associated with lactic acidosis has prompted some oncologists to consider this an oncological emergency (Nair & Shah, 2017). The best treatment for patients with hematologic malignancies who develop type B lactic acidosis is not yet clear.
Chemotherapy
Initiating aggressive chemotherapy has been effective in correcting acute acidosis (Friedenberg et al., 2007). It is actually the only treatment modality that consistently leads to remission. Resolution of lactic acidosis was reported to occur as early as 15 h and up to 3 days after starting chemotherapy. This treatment would not be effective in patients whose tumors are unresponsive to chemotherapy. Lactic acidosis improves with chemotherapy, and resolution of the lactic acidosis could be a surrogate marker of inducing remission (Chan et al., 2009).
Intravenous bicarbonate
The use of IV bicarbonate as a treatment for profound acidosis has never shown a meaningful clinical benefit, even in the worst cases (Swenson, 2016). As severe acidosis can cause respiratory fatigue and hemodynamic instability, intravenous bicarbonate is often used to attenuate systemic acidosis and increase the responsiveness to catecholamines. However, it would appear that the benefits of sodium bicarbonate are outweighed by its disadvantages, such as hypernatremia and hyperosmolality (Swenson, 2016). Acidemia leads to unloading oxygen from hemoglobin by shifting the hemoglobin‐oxygen dissociation curve to the right, and reducing acidosis will hinder oxygen release. Studies have shown that intracellular acidosis tends to slow lactate production (Madias, 1986; Sillos et al., 2001). Alkalinization has been shown to potentiate lactate production in patients with malignancy‐induced chronic lactic acidosis (Fields et al., 1981; Fraley et al., 1980). The effect of IV bicarbonate on mortality or lactate concentration in the setting of malignancy‐induced type B lactic acidosis has not been studied directly, as the incidence is very low. In a case report by Fraley et al. (1980), administration of bicarbonate improved pH but not the serum bicarbonate level. Intravenous bicarbonate corrected the extracellular pH but did not affect the significant intracellular acid production due to high tumor cell turnover. The use of sodium bicarbonate may not be recommended in these patient groups.
Renal replacement therapy
Renal replacement therapy, continuous or intermittent, in patients with renal dysfunction may be useful in addition to chemotherapy to correct metabolic acidosis. Here, once again, since the prognosis of type B lactic acidosis related to malignancies is grim, the only chance for remission is starting cytoreductive chemotherapy. Intravenous bicarbonate and hemodialysis will no longer act as a bridge to stabilize the patient enough so that the underlying cause can be treated (Chan et al., 2009).
Intravenous insulin
Lactic acidosis has also been treated with intravenous administration of insulin, which increases the conversion of pyruvate to acetyl‐coenzyme A and consequently facilitates oxidation of lactate to pyruvate (Sillos et al., 2001). Administration of glucose can actually induce lactic acidosis by increasing the availability of glucose and thus increasing the production of lactate by the tumor. Returning to the case presented in this manuscript, the patient was severely hypoglycemic, which is the reason why we substituted for intravenous glucose to maintain the patient's euglycemia. However, in a provocative hypothesis in 2009, Nijsten & van Dam (2009) presented a hypothetical treatment whereby glucose might be systemically lowered. If tumors are glucose consumers and lactate producers and all other tissues in the body can actively take up and use lactate as a fuel, why not systemically induce hypoglycemia to starve tumor cells? In this configuration, lactate would provide salvage fuel for the other tissues (Goodwin et al., 2014). Work to investigate this concept should be pursued.
4 CONCLUSION
Lactic acidosis is a commonly encountered problem in intensive care units and is most commonly associated with dysoxia, better known as type A lactic acidosis. Type B is more uncommon and can be life‐threatening and sometimes even a lethal complication in patients with malignancies. Due to its rareness, it is likely to be under recognized and therefore underdiagnosed. If oncological patients develop high anion gap lactic acidosis without hemodynamic compromise associated with acute respiratory distress without a pulmonary source, the possibility for tumor‐induced type B lactic acidosis through the “Warburg effect” should be considered. Awareness about this condition is important in the clinical practice of intensive care physicians since it will allow a timely diagnosis and the implementation of subsequent therapy. Currently, effective chemotherapy seems to be the only hope for survival.
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
Carole Looyens, and Karim Bendjelid designed the present review. Carole Looyens, and Karim Bendjelid analyzed data and references. Carole Looyens, Raphael Giraud, Ivo Neto Silva, and Karim Bendjelid wrote the manuscript. All authors read and approved the final manuscript.
DATA AVAILABILITY STATEMENT
The data that support these findings are available upon reasonable request from the corresponding author. | Recovered | ReactionOutcome | CC BY | 33611854 | 19,181,715 | 2021-02 |
What was the outcome of reaction 'Thrombocytopenia'? | Burkitt lymphoma and lactic acidosis: A case report and review of the literature.
Type A lactic acidosis is a potentially life-threatening complication in critically ill patients and is the hallmark of a shock state as a result of tissue hypoperfusion and dysoxia. Type B lactic acidosis results from mechanisms other than dysoxia and is a rare condition in patients with solid tumors or hematological malignancies. We present a case of a 60-year-old man with lactic acidosis who was found to have a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Lactagenic cancers are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Warburg in 1923 that is correlated with cancer aggressiveness and poor survival. There is increased glucose utilization with the purpose of lactagenesis under fully oxygenated conditions, as lactate seems to be a potent signaling molecule for angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism, which are five essential steps of carcinogenesis. Type B lactic acidosis in association with malignancies carries an extremely poor prognosis. Currently, effective chemotherapy seems to be the only hope for survival.
1 INTRODUCTION
A high arterial lactate level in critically ill patients has been associated with significant morbidity and mortality ever since the first description two centuries ago (Kompanje et al., 2007). Hyperlactatemia in the critically ill is the hallmark of shock states (Kraut & Madias, 2014; Levy, 2006; Nichol et al., 2010; Vincent & De Backer, 2013; Vincent et al., 2016), and the degree of increase in arterial lactate concentrations is directly related to the severity of the shock state (Haas et al., 2016; Nichol et al., 2011; Vincent et al., 2016). In this regard, the prognostic value of arterial lactate levels seems to be independent of the underlying critical illness (Jansen et al., 2010). Serial lactate measurements are widely used in intensive care medicine in the evaluation of the progression of a shock state and the response to intensive and urgent therapy (Levy et al., 2018; Vincent et al., 2016).
Although high lactate levels have been widely used as a marker of altered tissue perfusion in critically ill patients, this condition does not always simply reflect the development of anaerobic metabolism and cellular dysoxia better known as Type A lactic acidosis (Kraut & Madias, 2014; Vincent et al., 2016). While a lack of oxygen forbids the continuation of oxidative phosphorylation in the Krebs cycle, a normal oxygen supply does not impose a complete cessation of anaerobic metabolism. Type B lactic acidosis results from mechanisms other than dysoxia, including inborn errors of metabolism, drugs and toxins, systemic diseases (i.e., diabetes and sepsis), and less commonly malignancy. In this case report, we try to emphasize the pathophysiology leading to hyperlactatemia, and we will focus on the hyperlactatemia caused by lactagenic cancers and the Warburg effect.
2 CASE SUMMARY
A 60‐year‐old‐male patient presented at the emergency department with increasing abdominal girth, abdominal discomfort, severe asthenia, malaise, and profuse diaphoresis without fever. His medical history highlighted chronic renal failure (stage G3bA1) and a cardiac transplant 4 years ago due to terminal ischemic cardiomyopathy. His recent cardiac biopsy was free from any signs of rejection. He was taking immunosuppression with cyclosporine and mycophenolic acid. On admission, the clinical examination revealed a tense and distended abdomen with abdominal ascites. Initial vital signs were stable except for tachycardia at 110 beat per minute. The respiratory rate was 22 breath per minute, and the temperature was within the normal range. Physical exam was otherwise normal.
Laboratory analysis showed leukocytosis with a left shift, signs of hepatocellular injury without cholestasis, and chronic renal failure. His white blood count count was 14.8 G/L, C‐reactive protein was 45 mg/L (normal <10 mg/L), aspartate aminotransferase (AST) was 144 IU/L (normal, 14–50 IU/L), alanine aminotransferase (ALT) was 79 IU/L (normal, 12–50 IU/L), lactate dehydrogenase (LDH) was 1082 IU/L (normal, 87–210 IU/L), total bilirubin was 4 μmol/L (normal, 7–25 μmol/L), alkaline phosphatase was 82 IU/L (normal, 25–102 IU/L), gamma‐glutamyl transferase was 41 IU/L (normal, 9–40 IU/L), creatinine was 198 µmol/L (normal, 62–106 µmol/L), with an estimated glomerular filtration rate of 31 ml/min/1.73 m2. An ultrasound assessment confirmed the presence of moderate ascites in all four abdominal quadrants. Ascites liquid puncture showed leukocytosis, but the liquid culture remained sterile. Abdominal CT was then performed following a rapid clinical deterioration for abdominal sepsis, showing signs of diffuse peritonitis with a pelvic abscess located adjacent to the small intestine. The patient was therefore immediately started on broad‐spectrum antibiotics and antifungal treatment. In addition, a median laparotomy was performed to remove the pelvic abscess. The resected mass (suspect for any neoplasm) was sent for an extemporaneous analysis that elicited a high‐grade lymphoma. Later pathology testing confirmed a Burkitt lymphoma related to a posttransplant lymphoproliferative disorder. Following emergency department admission and immediate surgery, the patient was admitted to the intensive care unit for high anion gap lactic acidosis, with a pH of 7.29 and a lactate level of 7.4 mmol/L on the arterial blood gas analysis. However, the patient's vital signs remained stable, and he could be extubated on the same day. Signs of hypoxia or circulatory failure were absent, capillary refill time was within normal limits and there was no skin mottling. Moreover, lactate/pyruvate ratio value was 19.0. In contrast, he simultaneously developed profuse hypoglycemia necessitating continuous high‐dose intravenous glucose supplementation. Cardiac output measured with bedside echocardiography appeared to be within the normal ranges. A new postoperative abdominal CT angiography was performed to exclude abdominal ischemia. The lactic acidosis (mean pH 7.3) remained for several days with lactate levels fluctuating around approximately 7 mmol/L. A concomitant thiamine deficiency was excluded by intravenous supplementation. Lactic acidosis started to decrease once chemotherapy with cyclophosphamide and vincristine, initiated 5 days after surgical resection, began to have an effect.
The interpretation of an initial positron emission tomography–computed tomography (PET‐CT) (Figures 1, 2, 3) 6 days after surgery was not clear due to the difficult differentiation between an infectious versus an oncological process. In addition to diffuse hypermetabolism in the peritoneal cavity associated with retroperitoneal adenopathies, it revealed supradiaphragmatic invasion of the lymphoma with a mass located in the right cardiophrenic recess, left mammary adenopathies, and pleural and pericardial nodules. There were also two hypermetabolic, osseous spots, suspected of metastasis, one in the second cervical vertebrae and one in the left scapula.
FIGURE 1 Left: Transversal image from patient's abdominal positron emission tomography–computed tomography (PET‐CT) post tumoral resection revealing diffuse peritoneal hypermetabolism with difficult differentiation between an infectious versus an oncological process. Middle: Transversal image from patients thoracic PET‐CT revealing supradiafragmatic invasion of the lymphoma with a mass and a nodule located in the right cardiophrenic recess with diffuse bilateral pleural nodular thickening. Right: Transversal image from patient's abdominal PET‐CT showing retroperitoneal adenopathies.
FIGURE 2 Lactate production and destination. Glycolysis takes place in the cellular cytosol. The preparatory phase consists of the generation of 1–3 diphosphoglycerate by hekoxinase and phosphofructokinase (PFK), the rate‐limiting enzyme. The pay off phase consists of the generation of pyruvate by pyruvate kinase. Pyruvate can be reduced to lactate by lactate dehydrogenase (LDH) or it can be converted to acetyl‐Co A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. Pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by alanine aminotransferase, resulting in the formation of alanine. Lactate either locally formed after reduction of pyruvate or coming from a distant source, can be consumed in the mitochondria by reformation of pyruvate by mitochondrial lactate dehydrogenase (mLDH) after diffusion across membranes via monocarboxylate transporters (MCTs). This concept is better known as the cell‐to‐cell lactate shuttle.
FIGURE 3 Lactate/pyruvate ratio. In aerobic glycolysis, the physiologic ratio of lactate/pyruvate is approximately 10 and is warranted by lactate dehydrogenase (LDH) catalyzing the reduction of pyruvate in lactate. When there is any perturbation of tissular oxygenation, cellular oxygenation is inhibited causing and acceleration of the reduction in pyruvate into lactate by LDH which results in a pathological lactate/pyruvate ratio above 10. The inhibition of the oxidative phosphorylation avoids any proton recycling leading to high anion gap lactic acidosis. Lactate is mostly converted into glucose through neoglucogenesis in the Cori cycle taking place in the liver and the kidneys. In case of insufficient hepatic perfusion or hepatic failure, lactate will be less cleared causing a variable lactate/pyruvate ratio depending on the source of production of lactate. Protons, normally recycled in the Cori cycle, will accumulate causing acidosis. MTC, monocarboxylate transporter.
He underwent intensive inpatient chemotherapy with one cycle of R‐CHP and six cycles of R‐CHOP (R = rituximab, C = cyclophosphamide, H = doxorubicin hydrochloride, O = vincristine sulfate, P = prednisone) and 10 prophylactic intrathecal injections of methotrexate. Chemotherapy was complicated with multiple episodes of febrile agranulocytosis, anemia and thrombocytopenia, which resolved after treatment with antibiotics in combination with filgrastim and multiple transfusions. The patient could be discharged with closed outpatient follow‐up after 5 months of admission. A PET‐CT was carried out 2 months after discharge and showed complete regression of all the lesions. A thoraco‐abdominal CT performed 1 year after the diagnosis seemed to be completely normal.
3 DISCUSSION
3.1 Lactate homeostasis
As with the blood levels of any substance, elevated lactate levels can be the result of increased production or reduced clearance, or both. Under physiological conditions, 1500 mmol of lactate or 20 mmol/kg of body weight is produced daily from various organs, including the muscle, intestine, red blood cells, brain, and skin (Kraut & Madias, 2014). Lactate is metabolized by the liver (60%), kidneys (30%), and other organs. The normal arterial blood lactate level is approximately 1 mmol/L (Kraut & Madias, 2014; Vincent et al., 2016).
3.2 Lactate production
Lactate formation is closely related to glycolysis. Glycolysis takes place in ten steps, five of which are in the preparatory phase and five in the payoff phase. Phosphofructokinase (PFK) is the rate‐limiting enzyme. Two net ATP molecules are generated by phosphorylation by high‐energy compounds. The final product of glycolysis is pyruvate and lactate, to which pyruvate can be reduced. LDH catalyzes the reduction of pyruvate into lactate at a well‐defined rate so that in normal homeostasis, the physiological ratio of lactate/pyruvate is approximately 10. In the presence of oxygen, pyruvate can be converted into acetyl‐coenzyme A by pyruvate dehydrogenase (PDH) and enters the mitochondrial Krebs cycle for further oxidative phosphorylation and energy production. This respiratory chain of reactions results in a net production of 36 ATP molecules per molecule of glucose. The metabolic yield of glycolysis when participating in the aerobic metabolic pathway (i.e., along with the Krebs cycle and oxidative phosphorylation) is superior to fermentation (without O2) into lactate (38 vs. 2 molecules of ATP). Anaerobic fermentation into lactate may be inefficient compared to oxidative phosphorylation, however, the rate of glucose metabolism into lactate is 10–100 times faster than the complete oxidation of glucose in the mitochondria (Liberti & Locasale, 2016). In fact, the amount of ATP synthesized over any given period of time is comparable when either form of glucose metabolism is utilized (Liberti & Locasale, 2016). In addition to the better‐known reduction to lactate and the oxidation to acetyl‐coenzyme A, for the completeness of this review, we need to mention that pyruvate can also undergo carboxylation into oxaloacetate, thereby initiating neoglucogenesis, or undergo a transamination by ALT, resulting in the formation of alanine (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
Experiments by Pasteur (Platt, 1988), Meyerhof (1927), and A.V. Hill (Bassett, 2002) led to the widespread understanding of the glycolytic pathway and the notion that only a limitation of oxygen availability leads to fermentation and lactate accumulation. Out of this early work came the idea that lactate is just an anaerobic waste product that must be cleared from the muscles and blood, preferably by being converted to glucose in the liver via the Cori cycle. However, it has been demonstrated that lactate is a potent fuel and signaling molecule and is constantly being produced and circulated throughout the body, even and most often when there is adequate oxygen. Lactate is more than just a “hypoxic waste product.” Lactate as a result of dysoxia is often the exception rather than the rule, even in critically ill patients (Goodwin et al., 2014).
3.3 Lactate metabolism
Any time glycolysis is active, lactate is formed and equilibrates with local lactate gradients. Lactate equilibrates mainly by diffusing across membranes via monocarboxylate transporters (MCTs). In lactate‐producing tissues, this means exporting lactate into the circulation where both local and distant tissues can take it up and use it.
Lactate is metabolized by the liver (60%), kidneys (30%) and other organs. Lactate can be used for gluconeogenesis by reformation of pyruvate and glucose in the Cori cycle, which takes place in the liver and kidneys. In addition, lactate can readily replace glucose as a fuel for almost all cells of the body (any cell with mitochondria) by reformation and subsequent oxidation of pyruvate in the mitochondria. Lactate clearance occurs in the heart, liver, skeletal muscle and even brain. This observation that lactate is constantly being produced and consumed formed the basis of the cell‐to‐cell lactate shuttle, an energy exchange hypothesis originally introduced by Brooks in 1984 (Brooks, 1986). Lactate seems to be a key intermediate metabolite in whole body metabolism (Ben‐Hamouda et al., 2013; Goodwin et al., 2014; Kraut & Madias, 2014).
3.4 Hyperlactatemia (Table 1)
3.4.1 Elevated production of lactate
As mentioned earlier, normal lactate production is approximately 1 mmol/min or 1500 mmol/24 h, and the normal lactate level is approximately 1 mmol/L (Ben‐Hamouda et al., 2013; Vincent et al., 2016). Elevated lactate production can be the consequence of either an elevated pyruvate concentration (as seen in accelerated glycolysis, in elevated protein catabolism or through inhibition of PDH) or cellular dysoxia. Dysoxic lactic acidosis is better known as type‐A lactic acidosis, and all other nondysoxic causes of lactic acidosis are classified as type B according to the classification of Woods and Cohen (Ben‐Hamouda et al., 2013). Indeed, if lactic acidosis occurs in the context of apparently adequate tissue oxygenation and normal hemodynamics (i.e. normal blood pressure, normal volemia, normal blood oxygen, and oxygen‐carrying capacity), it is traditionally termed Type B lactic acidosis. In the present setting, the physiologic ratio value of lactate/pyruvate is around 10 or higher.
TABLE 1 Classification of hyperlactatemia according to Woods and Cohen
Type A: Hyperlactatemia associated with cellular dysoxia due to insufficient oxygen supply
Stagnant dysoxia Low cardiac output
Redistribution of cardiac output at the expense of certain tissues
Vascular occlusion
Dysoxia caused by elevated demand of oxygen Convulsions
Intensive exercise
Dysoxia caused by low oxygen carrying capacity Anemic dysoxia
Carbon monoxide intoxication
Hypoxic dysoxia (low PaO2)
Cytotoxic dysoxia due to inefficient mitochondrial consumption of oxygen Sepsis
Cyanide intoxication
Type B1: Hyperlactatemia due to an underlying disease
Accelerated glycolysis Hyperglycemia
Sepsis
Endogenous catecholamines
Lactagenic cancer
Elevated protein catabolism Burn victims
Severe septic shock
Acquired inhibition of pyruvate dehydrogenase (PDH) Sepsis
Thiamine deficiency
Lactagenic cancer
Reduced lactate clearance Reduced liver blood flow
Hepatic failure
Type B2: Hyperlactatemia due to drugs and toxins
Exogenous catecholamines (adrenaline, dobutamine, terbutaline) Cocaine, metamphetamines
Propofol Salicylates
Metformine Antiretroviral drugs
Linezolid Toxic alcohols (ethanol, methanol, propylene glycol, ethylene glycol)
Paracetamol
Type B3: Hyperlactatemia due to inborn errors of metabolism (enzymatic deficiencies)
Congenital PDH deficiency
Glucose‐6‐phosphatase deficiency (von Gierke disease)
Pyruvate carboxylase deficiency
Methylmalonic aciduria
Mitochondrial encephalomyopathies
John Wiley & Sons, LtdAccelerated glycolysis
Any cause of an accelerated level of glycolysis causes an expected elevation of pyruvate and thus of lactate, as the physiologic ratio of lactate/pyruvate of approximately 10 or higher is always warranted by LDH. Accelerated glycolysis is the case in hyperglycemia, sepsis, or other situations with elevated endogenous or exogenous catecholamines (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014). Finally, accelerated aerobic glycolysis may partially explain the hyperlactatemia caused by tumoral cells of lactagenic cancers, known as the Warburg effect (San‐Millán & Brooks, 2017), the cause of lactic acidosis in the present case.
Elevated protein catabolism
Elevated protein catabolism can also cause a rise in pyruvate levels. As mentioned earlier, pyruvate can be transaminated into alanine, and the reverse can be witnessed through the activity of the ALT enzyme, forming pyruvate in the liver. This mechanism contributes to hepatic neoglucogenesis. Accelerated protein catabolism is seen as muscle wasting, present in many critically ill patients, most severely in burn victims and in patients with severe septic shock. The elevated alanine supply in the liver contributes to the elevated pyruvate concentration and, ultimately, to hyperlactatemia, as the physiologic lactate/pyruvate ratio is always warranted by LDH (Ben‐Hamouda et al., 2013).
Inhibition of PDH
As discussed earlier, pyruvate is oxidized into acetyl‐coenzyme‐A by PDH. A congenital or an acquired reduction in the enzymatic activity of PDH can cause an accumulation of pyruvate and therefore of lactate. An acquired reduction in PDH can be caused by certain endotoxins and inflammatory cytokines in sepsis. This explains why hemodynamically stable patients with sepsis and normal liver function may have lactic acidosis (Kraut & Madias, 2014). It can also be caused by nucleoside reverse transcriptase inhibitors used to treat patients with HIV or by a thiamine deficiency, as in patients receiving parenteral nutrition or with severe Beri‐beri. Thiamine is an important cofactor in the PDH complex. Without thiamine, this enzyme cannot convert pyruvate into acetyl coenzyme A, and instead, conversion into lactate takes place (Friedenberg et al., 2007). Finally, certain oncogenes express PDH kinase, which inactivates PDH and inhibits the Krebs cycle (San‐Millán & Brooks, 2017; Swenson, 2016) and partially explains the development of hyperlactatemia caused by tumoral cells.
Cellular dysoxia
Perturbations of tissular oxygenation, termed “cellular dysoxia”, are caused by insufficient oxygen supply. This dysoxia can be either generalized due to a low cardiac output, carbon monoxide intoxication, profound arterial hemoglobin desaturation, and reduced oxygen content or either localized in the context of redistribution of the cardiac output at the expense of certain tissues or due to a vascular occlusion (Swenson, 2016). It can also be caused by mitochondrial enzyme defects and by inhibitors of aerobic metabolism, such as cyanide. Every drop in cellular oxygenation causes an acceleration of the reduction in pyruvate to lactate by LDH, which results in a pathological augmentation of the lactate/pyruvate ratio above 10 (Ben‐Hamouda et al., 2013). Even if the pyruvate dosage is expensive, its use and the finding of a pathological L/P level confirm cellular dysoxia and excludes other causes.
3.4.2 Reduced lactate clearance
Lactate is partly transported to the liver and the kidneys and converted to glucose through gluconeogenesis (the Cori cycle). The hepatic clearance of lactate thus depends on hepatic extraction and hepatic functioning. Hepatic extraction is determined by the liver blood flow, which needs no less than one‐fourth of its normal flow. The capture of lactate by hepatocytes depends on its transportation by a family of MCTs with different isoforms (MCT1‐4). Thus, neoglucogenesis will depend on hepatic functioning. Its activity is decreased in hepatic failure and inhibited in shock states and severe acidosis (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
3.5 Distinction between hyperlactatemia and lactic acidosis
Hyperlactatemia and lactic acidosis are frequently mixed, which may cause confusion. However, the two are governed by a different concept. Glycolysis causes lactate formation without lactic acidosis when there is no net H+ production. The H+ protons may arise following ATP hydrolyzation and are produced through glycolysis. However, those protons are recycled by lactate consumption either through the Krebs cycle or through the hepatic Cori cycle, hence maintaining the internal acid‐base balance (Ben‐Hamouda et al., 2013; Kraut & Madias, 2014).
In this regard, acquired or congenital inhibition of PDH, inhibition of oxidative phosphorylation due to cellular dysoxia, medication or intoxication and hepatic insufficiency are all causes of reduced proton recycling in either the Krebs or the Cori cycle, therefore causing high anion gap lactic acidosis. Other causes of hyperlactatemia, such as elevated glycolysis in hyperglycemia, arising from beta‐adrenergic stimulation or muscular catabolism, will only cause an elevated production of lactate without proton recycling impairment and without ensuing concomitant lactic acidosis (Kraut & Madias, 2014).
3.6 Lactagenic cancers
3.6.1 Warburg effect
In glycolytic tumors, lactate levels of cancer cells are markedly elevated up to 40‐fold and are highly associated with cancer aggressiveness and poor survival (Brizel et al., 2001; San‐Millán & Brooks, 2017). In fast‐growing malignancies, the rate of tumor metabolism may be great enough to exceed normal muscle and liver lactate clearance and cause systemic type B lactic acidosis (Sillos et al., 2001; Swenson, 2016). The majority of lactic acidosis in malignancies is reported in cases of hematologic malignancies. Only a few cases have been reported for solid tumors presenting with lactic acidosis (Nair & Shah, 2017).
In 1923, Warburg observed in his Nobel Prize winning studies that cancer cells were characterized by accelerated glycolysis and excessive lactate formation even under fully oxygenated conditions and that tumor cells live and grow in a more acidic milieu as a result of increased lactic acid production not generally tolerated by normal cells (San‐Millán & Brooks, 2017; Swenson, 2016). His discovery was named the “Warburg effect” by Racker in 1972 (San‐Millán & Brooks, 2017). The Warburg effect is a hallmark of cancer, and its significance is still apparent in the common cancer diagnostic test using fluorodeoxyglucose positron emission tomography, which has a high diagnostic accuracy (Potter et al., 2016).
From a contemporary perspective of cell metabolic efficiency, it seems difficult to understand why, despite fully aerobic conditions, cancer cells choose an inefficient pathway producing two ATP molecules per molecule of glucose instead of 38 via coupled mitochondrial respiration. However, as mentioned earlier, the amount of ATP synthesized over any given period of time is comparable in both ways of glucose metabolism because fermentation into lactate is 10–100 times faster than the completion of oxidative phosphorylation (Liberti & Locasale, 2016). Moreover, the stress of lactate production is simply passed on to the host. Then, the cancer cells proliferate, and the tumor grows and metastasizes because of host exploitation, ending in final host expiration (San‐Millán & Brooks, 2017).
3.6.2 Origin of tumoral lactagenesis
Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous and unstoppable glucose utilization to produce lactate involving five major steps: (i) an increase in glucose uptake; (ii) upregulation of PFK, the rate‐limiting enzyme of glycolysis; (iii) a decrease in mitochondrial respiration by upregulation of PDH kinase (PDK) that inhibits pyruvate uptake in mitochondria; (iv) increased lactate production by LDH upregulation; and (v) upregulation of MCT1 and MCT4 expression, the transmembrane transporters of lactate, for higher lactate plus H+ efflux and further lactate shuttling, thus mediating tumor growth and proliferation (Brahimi‐Horn et al., 2011; San‐Millán & Brooks, 2017; Swenson, 2016).
In our case, the Warburg effect was caused by a Burkitt lymphoma, a B‐cell derived malignancy. The main characteristic of a Burkitt lymphoma is an increased production of the MYC oncoprotein caused by chromosomal rearrangements. This translocation results in inappropriately high expression levels of MYC, which gives cells proliferative capacity. Moreover, MYC also activates the transcription of genes encoding glucose transporter, hexokinase, MCT, PDK, PK (pyruvate kinase), and LDH, resulting in the accelerated aerobic glycolysis or the Warburg effect. The MYC protein is the master regulator of the Warburg effect in BL cells (Mushtaq et al., 2015).
3.6.3 Aim of tumoral lactagenesis
The role of the Warburg effect in the pathogenesis of cancer has not yet been completely established. Lactate is the end product of the Warburg effect, but lactate production or lactagenesis is probably the purpose of the Warburg effect as well.
In addition to being a potent oxidative fuel, lactate is also a potent signaling molecule necessary for all the major steps in carcinogenesis, as follows: (i) angiogenesis, (ii) cell migration, (iii) metastasis, (iv) immune escape, and (v) self‐sufficiency of cancer cells (San‐Millán & Brooks, 2017).
Lactate released from tumor cells by MCT4 plays a role in stimulating angiogenesis (i) by increasing the expression of vascular endothelial growth factor protein in endothelial cells (Goodwin et al., 2014; San‐Millán & Brooks, 2017). Cell migration (ii) is another essential step in carcinogenesis and metastasis in which lactate seems to be a key element to increase cell migration. Marked extracellular acidosis appears to promote the migration and metastasis (iii) of cancer cells by disrupting normal cell‐matrix interactions that act to maintain stable growth patterns (Swenson, 2016). Lactate levels are highly associated with a high incidence of distant metastasis. Acidosis reduces host defense against malignant cells and contributes to immune escape (iv) in many different ways: first, by inhibiting the release of the cytokines tumor necrosis factor and interleukin‐6; and second, by inhibiting the activation of T‐cells with a decrease in the cytotoxic activity of T‐cells and inhibition of natural killer cell functioning. Lactate also plays a central role in the self‐sufficiency and sustainability (v) of cancer cells. Cancer cells at the hypoxic core might use glucose and produce lactate, whereas cells on the periphery, close to a robust vascular supply, might take up this lactate and oxidize it as a fuel. The self‐sufficiency depending upon high glycolytic flux also allows cancer cells to produce lactate for carcinogenesis by angiogenesis, immune escape, cell migration, and metastasis. A glucose to lactate shunt occurs in which the host bears the burden of providing a limitless glucose supply as well as a sink for disposal of lactate and hydrogen ions. This may even explain why the actual cause of cachexia and death due to cancer appears to be multifactorial, with organ failure rather than the tumor itself (San‐Millán & Brooks, 2017).
3.6.4 Targeting lactate production and shuttling: Future direction in cancer treatment
Given the profound changes in acid‐base balance in tumors and the role of pH in tumor survival and growth, altering the acid‐base milieu has presented itself as an interesting approach for treating cancer (Swenson, 2016), but the development of these new adjuvant therapies goes way beyond the scope of this article. Nevertheless, after explaining all the pathophysiology, it seems important to shed light on some future possible treatments: on the one hand, medication increasing PDH activity, such as dichloroacetate, seems to halt carcinogenesis by lowering cytosolic lactate production; on the other hand, MCT1 and MCT4 inhibitors seem to have enormous potential in cancer treatment by inhibiting lactate shuttling, even if there is still a lack of specificity (San‐Millán & Brooks, 2017). Furthermore, simpler approaches such as aerobic exercise seem to have beneficial effects by augmenting mitochondrial size and function and thus lactate clearance capacity. Further research is necessary to identify possible targets and create tumor‐specific treatments.
3.6.5 Treatment options in patients with type‐B LA due to malignancies
Lactic acidosis in association with malignancies carries an extremely poor prognosis with a mortality rate over 90% (Nair & Shah, 2017; Sillos et al., 2001). Moreover, the high mortality associated with lactic acidosis has prompted some oncologists to consider this an oncological emergency (Nair & Shah, 2017). The best treatment for patients with hematologic malignancies who develop type B lactic acidosis is not yet clear.
Chemotherapy
Initiating aggressive chemotherapy has been effective in correcting acute acidosis (Friedenberg et al., 2007). It is actually the only treatment modality that consistently leads to remission. Resolution of lactic acidosis was reported to occur as early as 15 h and up to 3 days after starting chemotherapy. This treatment would not be effective in patients whose tumors are unresponsive to chemotherapy. Lactic acidosis improves with chemotherapy, and resolution of the lactic acidosis could be a surrogate marker of inducing remission (Chan et al., 2009).
Intravenous bicarbonate
The use of IV bicarbonate as a treatment for profound acidosis has never shown a meaningful clinical benefit, even in the worst cases (Swenson, 2016). As severe acidosis can cause respiratory fatigue and hemodynamic instability, intravenous bicarbonate is often used to attenuate systemic acidosis and increase the responsiveness to catecholamines. However, it would appear that the benefits of sodium bicarbonate are outweighed by its disadvantages, such as hypernatremia and hyperosmolality (Swenson, 2016). Acidemia leads to unloading oxygen from hemoglobin by shifting the hemoglobin‐oxygen dissociation curve to the right, and reducing acidosis will hinder oxygen release. Studies have shown that intracellular acidosis tends to slow lactate production (Madias, 1986; Sillos et al., 2001). Alkalinization has been shown to potentiate lactate production in patients with malignancy‐induced chronic lactic acidosis (Fields et al., 1981; Fraley et al., 1980). The effect of IV bicarbonate on mortality or lactate concentration in the setting of malignancy‐induced type B lactic acidosis has not been studied directly, as the incidence is very low. In a case report by Fraley et al. (1980), administration of bicarbonate improved pH but not the serum bicarbonate level. Intravenous bicarbonate corrected the extracellular pH but did not affect the significant intracellular acid production due to high tumor cell turnover. The use of sodium bicarbonate may not be recommended in these patient groups.
Renal replacement therapy
Renal replacement therapy, continuous or intermittent, in patients with renal dysfunction may be useful in addition to chemotherapy to correct metabolic acidosis. Here, once again, since the prognosis of type B lactic acidosis related to malignancies is grim, the only chance for remission is starting cytoreductive chemotherapy. Intravenous bicarbonate and hemodialysis will no longer act as a bridge to stabilize the patient enough so that the underlying cause can be treated (Chan et al., 2009).
Intravenous insulin
Lactic acidosis has also been treated with intravenous administration of insulin, which increases the conversion of pyruvate to acetyl‐coenzyme A and consequently facilitates oxidation of lactate to pyruvate (Sillos et al., 2001). Administration of glucose can actually induce lactic acidosis by increasing the availability of glucose and thus increasing the production of lactate by the tumor. Returning to the case presented in this manuscript, the patient was severely hypoglycemic, which is the reason why we substituted for intravenous glucose to maintain the patient's euglycemia. However, in a provocative hypothesis in 2009, Nijsten & van Dam (2009) presented a hypothetical treatment whereby glucose might be systemically lowered. If tumors are glucose consumers and lactate producers and all other tissues in the body can actively take up and use lactate as a fuel, why not systemically induce hypoglycemia to starve tumor cells? In this configuration, lactate would provide salvage fuel for the other tissues (Goodwin et al., 2014). Work to investigate this concept should be pursued.
4 CONCLUSION
Lactic acidosis is a commonly encountered problem in intensive care units and is most commonly associated with dysoxia, better known as type A lactic acidosis. Type B is more uncommon and can be life‐threatening and sometimes even a lethal complication in patients with malignancies. Due to its rareness, it is likely to be under recognized and therefore underdiagnosed. If oncological patients develop high anion gap lactic acidosis without hemodynamic compromise associated with acute respiratory distress without a pulmonary source, the possibility for tumor‐induced type B lactic acidosis through the “Warburg effect” should be considered. Awareness about this condition is important in the clinical practice of intensive care physicians since it will allow a timely diagnosis and the implementation of subsequent therapy. Currently, effective chemotherapy seems to be the only hope for survival.
CONFLICT OF INTERESTS
The authors declare that they have no competing interests.
AUTHORS' CONTRIBUTIONS
Carole Looyens, and Karim Bendjelid designed the present review. Carole Looyens, and Karim Bendjelid analyzed data and references. Carole Looyens, Raphael Giraud, Ivo Neto Silva, and Karim Bendjelid wrote the manuscript. All authors read and approved the final manuscript.
DATA AVAILABILITY STATEMENT
The data that support these findings are available upon reasonable request from the corresponding author. | Recovered | ReactionOutcome | CC BY | 33611854 | 19,114,934 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'COVID-19'. | Preferences of inflammatory arthritis patients for biological disease-modifying antirheumatic drugs in the first 100 days of the COVID-19 pandemic
To evaluate treatment adherence and predictors of drug discontinuation among patients with inflammatory arthritis
receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.
A total of 1871 patients recorded in TReasure registry for whom advanced therapy was prescribed for rheumatoid arthritis (RA) or spondyloarthritis (SpA) within the 3 months (6–9 months for rituximab) before the declaration of COVID-19 pandemic were evaluated, and 1394 (74.5%) responded to the phone survey. Patients’ data regarding demographic, clinical characteristics and disease activity before the pandemic were recorded. The patients were inquired about the diagnosis of COVID-19, the rate of continuation on bDMARDs, the reasons for treatment discontinuation, if any, and the current general disease activity (visual analog scale, [VAS]).
A total of 1394 patients (493 RA [47.3% on anti-TNF] patients and 901 SpA [90.0% on anti-TNF] patients) were included in the study. Overall, 2.8% of the patients had symptoms suggesting COVID-19, and 2 (0.15%) patients had PCR-confirmed COVID-19. Overall, 18.1% of all patients (13.8% of the RA and 20.5% of the SpA; p = 0.003) discontinued their bDMARDs. In the SpA group, the patients who discontinued bDMARDs were younger (40 [21–73] vs. 44 years [20–79]; p = 0.005) and had higher general disease activity; however, no difference was relevant for RA patients.
Although the COVID-19 was quite uncommon in the first 100 days of the pandemic, nearly one-fifth of the patients discontinued bDMARDs within this period. The long-term effects of the pandemic should be monitored.
pmc1. Introduction
The recent coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Fever, dry cough, sore throat, and muscle and joint pain are general disease manifestations, and a severe clinical picture requiring hospital admission is encountered in 15%–20% of the patients [1,2]. According to the data collected from various countries, the COVID-19 fatality rate is about 1%–10% [3]. Patients with inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA) regularly and continuously receive synthetic or biological disease-modifying antirheumatic drugs (DMARDs) as the main component of their treatment. On the other hand, temporary discontinuation of particularly biological DMARDs (bDMARDs) in the presence of infection is an accepted recommendation [4]. Currently, the world is reexperiencing a pandemic after a period of nearly 100 years. After March 11, 2020, when the World Health Organization announced the pandemic, American, European, and local societies of rheumatology have claimed general recommendations about drug usage [4–6]. The Turkish Society for Rheumatology released COVID-19 recommendations on March 27, 2020, and left the decision to use synthetic/biological DMARDs during the pandemic mainly to the primary physician that follows the patient [6]. On the other hand, the behavioral pattern of patients with inflammatory arthritis using biological/synthetic DMARDs during the COVID-19 pandemic is unknown in Turkey or the rest of the world.
Accordingly, the present study aimed to evaluate treatment adherence of patients with inflammatory arthritis receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.
2. Methods
2.1. Patient selection
The TReasure registry is a web-based, prospective, observational cohort including RA and spondyloarthritis (SpA) patients from 17 centers in different regions of Turkey and was established in December 2017. Details of the establishment of TReasure registry were previously reported [7]. As of March 2020, there were a total of 7471 patients with inflammatory arthritis (2560 RA patients and 4911 SpA patients) receiving bDMARDs in this registry. The bDMARDs were as follows (arranged alphabetically): abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, secukinumab, and tocilizumab.
The present study included patients who were prescribed bDMARDs and for whom disease activity was recorded within the 3-month period before the declaration date of pandemic (March 2020) in the TReasure registry. For rituximab therapy, this period was determined to be 6–9 months before the declaration date of the pandemic. In the TReasure registry, the target population consisted of 1871 patients, of whom 1394 (74.5%) completed the standard phone questionnaire, 39 (2.1%) refused to participate in the study, and the remaining could not be reached. The patients who participated and those who did not participate in the study did not differ in demographic and clinical characteristics (data not shown).
2.2. Demographic and clinical characteristics of the patients
The demographic and clinical data collected from the patients were defined previously [7]. In brief, the following data were recorded for both RA and SpA patients: age, sex, disease duration, comorbidities (the Charlson comorbidity index), erythrocyte sedimentation rate (ESR) (mm/h), C-reactive protein (CRP) level (mg/L), number of swollen (66 joints) and tender (68 joints) joints, visual analog scale (VAS)-pain score, patients’ global assessment-VAS, and VAS-fatigue score, and the names of the currently used synthetic DMARDs or bDMARDs. Additionally, in RA patients, positivity for rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) was determined, and the scores of the disease activity score-28 (DAS-28), the Crohn’s Disease Activity Index (CDAI), the Simple Disease Activity Index (SDAI), and the Health Assessment Questionnaire (HAQ) were calculated to assess disease activity. In SpA patients, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), and the Ankylosing Spondylitis Disease Activity Score (ASDAS) based on CRP (ASDAS-CRP) were used for the assessment of disease activity. The diagnoses in SpA patients were classified as ankylosing spondylitis (according to the modified New York criteria), nonradiographic SpA (according to the axial SpA criteria), peripheral SpA (according to the peripheral SpA criteria), psoriatic arthritis (according to the CASPAR criteria), and enteropathic arthritis (based on the presence of inflammatory bowel disease [IBD] and arthritis/sacroiliitis) [8–11]. In SpA patients, the positivity of HLA-B27 and the presence of psoriasis, IBD, uveitis, dactylitis, and enthesitis (according to the Leeds enthesitis index [LEI]) were also recorded.
2.3. Questionnaire inquiring the pandemic period
A standard questionnaire was applied to the patients via phone call. The phone calls were made in June 2020. Accordingly, the following information questioned for the period between March 10, 2020, and the day of phone call: the presence of any signs of coronavirus infection; whether or not being diagnosed with COVID-19; if diagnosed with COVID-19, the place (hospital, home) where the patient was followed up; whether or not being quarantined due to COVID-19 infection; whether or not having biological or synthetic DMARDs on hand; whether or not the medications were administered during this time; if not administered, the reason(s); whether or not being contacted with his/her physician; and the current disease activity. For the assessment of the current general health status and disease activity, the patients were asked about their general health status (global patient assessment) and to rate it from 0 (excellent) to 10 (very bad), and about current disease activity, the patients were asked to rate their disease activity as “completely under control”, “mild”, “moderate”, “active”, and “highly active”.
2.4. Assessments in the study
In the present study, for the patients who discontinued their bDMARDs, comparisons were performed for the following parameters: age (also categorized in decades), sex, mean disease duration (categorized as 1, 5, and 10 years), seropositivity, sequence of use of bDMARDs (bDMARD-naïve, second-line, third-line), and usage of anti-TNF versus nonanti-TNF bDMARDs. The disease activity scores within the 3 months before the declaration of the pandemic was also recorded; these included mean DAS-28 score, CDAI, and SDAI scores (patients were dichotomized as those with and without low disease activity according to the DAS-28, SDAI, and CDAI scores), mean HAQ score (patients were dichotomized according to the scores of 0.5 and 1), mean BASDAI, BASFI, and ASDAS-CRP scores (patients were grouped according to ASDAS-CRP score), CRP level (<5 mg/L and >5 mg/L), patients’ global assessments-VAS score (grouping with 10-unit intervals), general health status (completely under control, mild, moderate, severe, highly severe), and presence of suspected COVID-19. Patients’ global assessment-VAS scores before the pandemic were compared with those during the pandemic. Accordingly, an increase by >2 units in the score was defined as worsened disease activity, and a decrease by <2 units in the score was defined as improved disease activity. Remission was defined as a general health status-VAS score of ≤2, whereas active disease was defined as a VAS score of ≥4.
Our study is compliant with the Helsinki Declaration and approved by both the local ethical committee (Hacettepe University; Approval number: 2020/08-25 (KA-17058)) and the Turkish Ministry of Health (Approval number: 66175679-514.05.01-E.170548).
2.5. Patient and public involvement
There is no patient or public involvement in this study.
2.6. Statistical analysis
Data analyses were performed using the Predictive Analytics SoftWare (PASW) 18.0 (SPSS Inc., Chicago, IL, USA) for Windows. The variables were investigated using visual (histogram, probability plots) and analytic methods (Kolmogorov–Smirnov, skewness, and kurtosis) to determine whether they are normally distributed or not. The descriptive analysis data were expressed as mean, standard deviation (SD), the median (minimum-maximum), or percentages for categorical variables. Chi-square test or Fisher’s exact test was used for categorical variables. Student’s t-test was used to compare normally distributed variables, while the Mann–Whitney U test was used to compare nonnormally distributed variables. The variables identified with univariate analyses (p < 0.20) were further entered the logistic regression analysis to determine independent predictors of drug discontinuation separately for RA and SpA patients. A p-value of <0.05 was considered statistically significant.
3. Results
3.1. Demographic and clinical characteristics of the patients
The demographic and clinical data and drug preferences of 1394 patients who participated in the study are presented in Table 1. In the RA group, RF was positive in 267 (62.7%) patients, anti-CCP was positive in 206 (56.4%) patients, and RF and/or anti-CCP were positive in 368 (74.5%) patients. In the SpA group, there were 664 (73.7%) patients with ankylosing spondylitis, 57 (6.3%) patients with nonradiographic SpA, 101 (11.2%) patients with peripheral SpA, 111 (12.3%) patients with psoriatic arthritis, and 21 (2.3%) patients with enteropathic arthritis. Extraarticular signs of the SpA patients were uveitis in 110 (12.5%) patients, IBD in 40 (4.6%) patients, and psoriasis in 141 (16.1%) patients. The HLA-B27 positivity was determined in 333 (59.1%) of 563 patients. Thirty-seven (4.8%) patients had dactylitis, and 120 (19.3%) patients had enthesitis (at least one entheseal region according to the LEI). Of the RA patients, 233 (47.3%) were receiving antitumor necrosis factor (TNF) agents, and 260 (52.7%) were receiving nonanti-TNF bDMARDs. On the other hand, of the SpA patients, 811 (90%) were receiving anti-TNF agents, and 90 (10%) were receiving antiinterleukin (IL)-17 treatment.
Table 1 Demographic and clinical characteristics of the patients.
Patients with RAn = 493 Patients with SpAn = 901
Female sex, n (%) 400 (81.1) 398 (44.2)
Age, years, median (range) 55 (18–86) 43 (20–79)
Disease duration, months, median (range) 131 (2–509) 111 (2–672)
ESR, mm/h, median (range) 16 (1–120) 12 (1–103)
CRP, mg/L, median (range) 3.96 (0.1–98.9) 3.84 (0.1–91.1)
Global assessment of health–VAS score, median (range) 30 (0–100) 25 (0–100)
Pain–VAS score, median (range) 30 (0–100) 20 (0–100)
Fatigue–VAS score, median (range) 30 (0–100) 20 (0–100)
HAQ score, median (range) 0.38 (0–90) –
Number of swollen joints, mean ± SD 0.58 ± 2.21 0.1 ± 0.71
Number of tender joints, mean ± SD 1.31 ± 3.41 0.29 ± 1.6
DAS-28-ESR score, median (range) 2.55 (0.56–8.16) –
CDAI score, mean ± SD 7.97 ± 8.92 –
SDAI score, mean ± SD 17.83 ± 20.08 –
BASDAI score, n (%) – 1.55 (0–9.5)
BASFI score, n (%) – 1.2 (0–9.7)
Hypertension, n (%) 143 (29.7) 137 (15.4)
Obesity, n (%) 166 (35.3) 220 (24.4)
Diabetes mellitus, n (%) 48 (9.9) 57 (6.4)
Hyperlipidemia, n (%) 71 (15.1) 98 (11.2)
Coronary artery disease, n (%) 20 (4.3) 17 (1.9)
COPD, n (%) 11 (2.4) 3 (0.3)
Asthma, n (%) 26 (5.6) 28 (3.3)
Malignancy, n (%) 5 (1) 8 (0.9)
Presence of at least1 comorbidity, n (%) 186 (38.2) 462 (51.6)
Presence of ≥2 comorbidities, n (%) 121 (24.8) 229 (25.6)
Presence of ≥3 comorbidities, n (%) 167 (34.3) 160 (17.9)
ASDAS–CRP, median (range) – 1.84 (0–5.2)
Abatacept, n (%) 32 (6.5) –
Adalimumab, n (%) 89 (18.1) 270 (30)
Certolizumab, n (%) 38 (7.7) 146 (16.2)
Etanercept, n (%) 75 (15.2) 182 (20.2)
Golimumab, n (%) 18 (3.7) 90 (10)
Infliximab, n (%) 13 (2.6) 123 (13.7)
Rituximab, n (%) 40 (8.1) –
Secukinumab, n (%) – 90 (10)
Tofacitinib, n (%) 77 (15.6) –
Tocilizumab, n (%) 111 (22.5) –
Hydroxychloroquine, n (%) 164 (33.3) 13 (1.4)
Leflunomide, n (%) 117 (23.7) 17 (1.9)
Methotrexate , n (%) 135 (27.4) 57 (6.3)
Sulfasalazine, n (%) 23 (4.7) 71 (7.9)
RA, rheumatoid arthritis; SpA, spondyloarthritis; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein, VAS, Visual Analog Scale; HAQ, Health Assessment Questionnaire; DAS-28, the Disease Activity Score-28; CDAI, the Crohn’s Disease Activity Index; SDAI, the Simple Disease Activity Index; BASDAI, the Bath Ankylosing Spondylitis Disease Activity Index; BASFI, the Bath Ankylosing Spondylitis Functional Index; COPD, chronic obstructive pulmonary disease; ASDAS, Ankylosing Spondylitis Disease Activity Score; SD, standard deviation.
3.2. Detecting COVID-19 in the inflammatory arthritis patients receiving bDMARDs
A total of 1353 patients were questioned about COVID-19 status. Of all the patients, 39 (2.8%) had at least one suspicious sign of COVID-19, and 26 (1.9%) visited a healthcare center for this reason (Table 2). Fever (body temperature ≥ 38°C) was the suspicious sign in 14 (1.0%) patients. The PCR test was positive for COVID-19 only in 2 (0.15%) of all patients. Both of these patients were treated at home.
Table 2 Results of the questions about COVID-19 status in the study patients during the pandemic.
All patients n = 1353 RA n = 487 SpA n = 866
Presence of any suspected sign of COVID-19 39 (2.8) 6 (1.2) 33 (3.7)
Admission to a healthcare center for suspected COVID-19 26 (1.9) 5 (1.0) 22 (2.5)
Having PCR testing for COVID-19 21 (1.6) 5 (1.0) 16 (1.8)
Quarantine recommendation for suspected COVID-19 10 (0.73) 0 (0) 10 (1.15)
PCR positivity for COVID-19 2 (0.15) 0 (0) 2 (0.23)
Family history of COVID-19 positivity 9 (0.66) 3 (0.6) 6 (0.7)
3.3. Use of biological DMARDs during the pandemic
A total of 1362 patients responded to the question about the continuation of bDMARDs during the pandemic. Overall, 247 (18.1%) patients discontinued their bDMARDs. Sixty-six (13.8%) of the RA patients and 181 (20.5%) of the SpA patients discontinued their bDMARDs (p = 0.003). The distribution of the patients who discontinued/did not receive their bDMARDs is demonstrated in Table 3. Among RA patients, etanercept (%5.4) was the least frequently discontinued bDMARD, whereas tocilizumab (%20.5) was the most frequently discontinued bDMARD. The clinical characteristics and disease activity parameters did not differ between the RA patients who discontinued and those who did not discontinue their bDMARDs. In the SpA patient group, those who discontinued their bDMARDs were younger than those who did not (median age, 40 years [range, 21–73 years] vs. median age, 44 years [range, 20–79 years]; p = 0.005). Moreover, the SpA patients who continued their bDMARDs had lower disease activity. The multivariate analysis revealed that age of <40 years, a poorer general health status, a poorer VAS score, and the suspicion for the presence of COVID-19 were the factors that determine the discontinuation of bDMARD therapy in SpA patients (Table 4).
Table 3 Distribution of the patients who discontinued their biological disease-modifying antirheumatic drugs.
Patients with RA n/N (%) Patients with SpA n/N (%)
All bDMARDs 66 (14.0) 181 (20.5)
Abatacept 4/31 (12.9) NA
Adalimumab 15/86 (17.4) 46/264 (17.4)
Etanercept 4/74 (5.4) 38/180 (21.1)
Golimumab 3/18 (16.7) 15/86 (15.6)
Infliximab 2/12 (16.7) 29/118 (24.5)
Certolizumab 3/37 (8.1) 31/146 (21.2)
Rituximab 7/39 (17.9) NA
Tofacitinib 6/75 (8.0) NA
Tocilizumab 22/107 (20.5) NA
Secukinumab NA 22/89 (24.7)
Hydroxychloroquine 19/157 (12.1) 5/181 (2.8)
Leflunomide 14/113 (12.4) 4/181 (2.2)
Methotrexate 14/134 (10.4) 13/181 (7.2)
Sulfasalazine 2/22 (9.1) 13/181 (7.2)
RA, rheumatoid arthritis; SpA, spondyloarthritis; bDMARDs, biological disease-modifying antirheumatic drugs; NA, not applicable.
Table 4 Characteristics of the patients with spondyloarthritis who discontinued their biological disease-modifying antirheumatic drugs
Patients with SpA who discontinued bDMARDs Patients with SpA who continued bDMARDs Univariatep Odds Ratio95% CI Multivariatep Odds ratio95% CI
Age (<40 vs. ≥40) 84 (46.4) 243 (34.6) 0.004 1.64 (1.18–2.28) 0.002 1.76 (1.24–2.51)
General health status
Completely under control 51 (28.2) 390 (55.8) Reference
Mild 52 (28.7) 103 (14.7) <0.001 3.86 (2.48–6.01) <0.001 3.20 (1.99–5.15)
Moderate 51 (28.2) 153 (21.9) <0.001 2.55 (1.66–3.92) 0.003 2.03 (1.26–3.27)
Severe 21 (11.6) 41 (5.9) <0.001 3.92 (2.15–7.15) 0.003 2.65 (1.38–5.10)
Extremely severe 6 (3.3) 12 (1.7) 0.010 3.82 (1.38–10.63) 0.103 2.46 (0.83–7.28)
VAS-PGA, <20 vs. ≥20 38 (21.1) 281 (40.2) <0.001 2.51 (1.70–3.71) 0.016 1.74 (1.11–2.75)
Suspected COVID-19 12 (6.6) 20 (2.9) 0.019 2.41 (1.16–5.04) 0.136 1.83 (0.83–4.03)
Data are presented as numbers (percentage, %).SpA, spondyloarthritis; bDMARDs, biological disease-modifying antirheumatic drugs; CI, confidence interval; VAS-PGA, visual analog scale-patient global assessment; COVID-19, coronavirus disease 2019.
The data on the reasons for drug discontinuation were available in 186 (75.3%) of 247 patients who discontinued their bDMARDs. Of these patients, 60 (32.2%) discontinued the therapy based on the recommendation of his/her physician, 84 (45.1%) discontinued on their own demand/fear, 13 (6.9%) discontinued due to suspected COVID-19, 8 (4.3%) discontinued due to the lack of disease activity, and 21 (11.3%) discontinued due to other reasons. No difference was determined between RA and SpA patients in terms of reasons for discontinuation of bDMARDs. During the pandemic, 550 patients (213 RA patients and 337 SpA patients) were able to communicate with their physicians. The patients communicated with their physicians through phone calls (314 [57.1%] patients), face-to-face interview (203 [36.9%] patients), text message (39 [7.1%] patients), e-mail (19 [3.5%] patients), healthcare staff (assistant, nurse) (13 [2.4%] patients), and relatives (5 [0.9%] patients). In 425 (77.3%) of 550 patients, their physicians recommended them to continue bDMARD therapy. In 37 (6.7%) of 550 patients, their physicians recommended them to receive bDMARDs on demand and/or to extent drug application intervals.
3.4. Disease activity during the pandemic
Evaluation of the disease activity during the pandemic in all patients revealed that the disease was completely under control in 46.8% of the patients (in 40.8% of the RA patients and in 50.0% of the SpA patients), whereas 19.1% of the patients (21.7% of the RA patients and 17.7% of the SpA patients) had mild disease activity, 24.7% of the patients (27.9% of the RA patients and 23.1% of the SpA patients) had moderate disease activity, 7.0% of the patients (6.8% of the RA patients and 7.1% of the SpA patients) had active disease, and 2.4% of the patients (2.9% of the RA patients and 2.1% of the SpA patients) had very high disease activity (p = 0.016). The mean general health status-VAS score in all patients during the pandemic was 3.1 ± 2.5; it was 3.4 ± 2.6 in the RA patients and 2.9 ± 2.5 in the SpA patients (p < 0.001). The mean general health status-VAS score in all patients in the prepandemic period was 3.2 ± 2.5; it was 3.6 ± 2.6 in the RA patients and 3 ± 2.4 in the SpA patients (p < 0.001).
As compared with the period before the pandemic, the ratios of patients with worsened disease activity, those with improved disease activity, those in whom the disease has become active (while in remission), those with ongoing remission, those with ongoing active disease, and those showing remission (while having active disease) in the first 100 days of the pandemic are demonstrated in Table 5. In the RA patients, these variables did not show difference between the patients who discontinued and those who did not discontinue their bDMARDs. In the SpA patients, the ratio of those who remained in remission before and during the pandemic was 32.1%. The rate of drug discontinuation was lower in the SpA patients who remained in remission (22.0% in those who discontinued bDMARDs and 34.8% in those who did not discontinue bDMARDs; p = 0.002); other parameters showed no difference between the patients who discontinued and those who did not discontinue bDMARDs.
Table 5 As assessed according to the prepandemic period, changes in disease activity determined by the general health status-Visual Analog Scale scores during the pandemic.
Status Definition Patients with RAn = 428 Patients with SpAn = 809
Worsened disease activity during the pandemic >2 units increase in the VAS score after the pandemic as compared with before the pandemic 100 (23.4) 137 (16.9)
Patients with improved disease activity during the pandemic <2 units decrease in the VAS score after the pandemic as compared with before the pandemic 89 (20.8) 118 (14.6)
While in remission before the pandemic, becoming active during the pandemic A VAS score of ≤2 before pandemic and ≥4 after the pandemic, 69 (16.1) 100 (12.4)
Remission both before and during the pandemic A VAS score of ≤2 before the pandemic and ≤2 after the pandemic 91 (21.3) 260 (32.1)
Active disease both before and during the pandemic A VAS score of ≥4 before the pandemic and ≥4 after the pandemic 121 (28.3) 175 (21.6)
Active disease before the pandemic, remission during the pandemic A VAS score of ≥4 before the pandemic and ≤2 after the pandemic 52 (12.1) 86 (10.6)
Data are presented as numbers (percentage, %).RA, rheumatoid arthritis; SpA, spondyloarthritis; VAS, visual analog scale; bDMARDs, biological disease-modifying antirheumatic drugs; NA, not applicable.
4. Discussion
The COVID 19 pandemic, which was announced in March 2020 by the WHO, has directly influenced the daily life of both healthy individuals and individuals with chronic illnesses1. Immunosuppressed patients rank first among the patient groups influenced by the pandemic most. Biological DMARDs, which have been used in the last two decades, have been the group of medications primarily focused on due to their potential to increase the risk of infection. The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), which are among the international expert societies on rheumatology, have recommended identification of the risk groups and continuation of bDMARDs as long as possible within the frame of patient–physician communication [4,5]. However, the pandemic has caused severe anxiety and fear in some patients. Uncertainty and fear were more prominent particularly in the early period of the pandemic.
The present study investigated the therapeutic approaches in the first 100 days after the declaration of the pandemic in inflammatory arthritis patients known to receive bDMARD therapy. It was observed that the rate of confirmed COVID-19 cases (0.15%) was extremely low in the first 100 days and that nearly 3% of the patients needed to be evaluated for suspected COVID-19. The first 100 days of the pandemic in Turkey was when a strict lockdown was implemented particularly for the people over the age of 65 and under the age of 18. In that period, people with chronic illnesses in particular were on administrative leave, and many patients self-quarantined themselves. It is likely that such a low rate of COVID-19 determined among the patients with inflammatory rheumatic diseases is associated with the abovementioned strict lockdown. After that period, people began to return to their normal life; therefore, how many of the patients evaluated in the present study will develop COVID-19 infection during their follow-up is an investigation that needs to be performed in the future.
Recent studies supported that patients who take biological and conventional DMARDs have less morbidity in the case of COVID-19 [2]. Moreover, in another study from Turkey consisting of 167 patients with inflammatory rheumatic disease, biologic and conventional DMARDs did not seem to cause worse outcomes [12]. However, overall, 18% of all the inflammatory arthritis patients discontinued bDMARDs in the first 100 days of the pandemic. It was observed that drug discontinuation was more common, particularly in the SpA patients, than in the RA patients. Etanercept was the least frequently discontinued bDMARD in the RA patients. It was understood that etanercept has been used for longer than 20 years and thus considered a relatively reliable therapeutic option for both patients and physicians. The main reason for drug discontinuation was the patients’ fear of bDMARD therapy; on the other hand, drug discontinuation was recommended by the physicians in one-third of the patients. In Italy, a survey was conducted between February 2020 and April 2020 in 955 rheumatic patients [13]. In that patient group receiving advanced treatment, modification of biological therapy was performed in nearly 6% of the patients, which is quite low as compared with the finding of the present survey study. Accordingly, different cultural factors can be considered determinative. In the present study, among the patients who were able to communicate with their physicians, about 7% were recommended to receive treatment on demand or could extent drug application intervals. Receiving bDMARD therapy on demand or extending drug application intervals is a method implemented by clinicians for a long time in daily practice with efficacy and safety proven in the controlled studies. During the pandemic, the physicians preferred this method in some of their patients. On the other hand, there is a patient group trying to reach their physicians but could not reach them. It was understood that a change occurred in the physician–patient communication during the pandemic. Specific to rheumatology, patients’ methods of reaching their physicians should be dwelled on, and further studies are needed on this subject.
Any factor that might explain bDMARD discontinuation in the RA patients could not be determined. On the other hand, it was observed that the SpA patients with the disease under control were more likely to continue their drugs. This finding is likely to indicate that the SpA patients with the disease under control were more adherent to their medications, and they avoided recurrent exacerbations. Fluctuations in disease activity were observed in the first 100 days of the pandemic as assessed according to the prepandemic period. The rate of remaining in remission during the pandemic for the patients in remission before the pandemic was 21% in the RA group and 32% in the SpA group. It was understood that the patients with high disease activity in the prepandemic period experienced more difficulty in the early period of the pandemic.
The present survey study was conducted through phone interviews. We could reach three-fourth of the patients; the rates of drug discontinuation and COVID-19 might be higher among those that could not be reached; thus, the results need to be evaluated within the scope of this limitation. The fact that the information regarding steroid use was not inquired could be considered another limitation.
In conclusion, nearly one-fifth of the RA and SpA patients recorded in the TReasure registry and known to receive bDMARD therapy in the prepandemic period discontinued their drugs in the first 100 days of the pandemic. The frequency of COVID-19 was found to be low in the first 100 days of the pandemic, which corresponds to a period when a strict lockdown was implemented in Turkey. Further investigations need to be performed to find out what will happen when people return to their normal active life. Although patients’ fear of treatment appeared to be the main factor, the treatment was discontinued or also interrupted due to physicians’ recommendations. These treatment modifications in the early period of the COVID-19 pandemic may appear as a worsened disease activity in time. Treatment approaches need to be monitored closely in the following period.
Authors’ contributions
All authors contributed equally to conceiving and designing the analysis and collecting the data. UK and EB performed the analysis and wrote the paper; all authors revised and edited the final version of manuscript.
Informed consent
Our study is compliant with the Helsinki Declaration and was approved by both the local ethical committee (Hacettepe University; Approval number: 2020/08-25 (KA-17058)) and the Turkish Ministry of Health (Approval number: 66175679-514.05.01-E.170548).
Acknowledgments
UK received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. YP received honorary from Abbvie, Roche, Novartis, MSD, Pfizer. SA received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. TK received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. GK received honorary from Abbvie, Amgen, Novartis, Pfizer, UCB. OK received honorary from Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. ED received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. IE received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. LK received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. DE received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, UCB. CB received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. HE received honorary from Novartis, Roche. RM received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. NK received honorary from Novartis, UCB. MC received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. SSK received honorary from Abbvie, MSD, Novartis, Pfizer, Roche, UCB. OK received honorary from Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. SK received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. Other authors declare no conflict of interest.
This study was funded by Hacettepe Rheumatology Society.
World Health Organization (2020). The director-general’s opening remarks at the media briefing on COVID-19 [online]. Website https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. [accessed 27 September 2020]). | ADALIMUMAB | DrugsGivenReaction | CC BY | 33611869 | 20,063,722 | 2021-08-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Preferences of inflammatory arthritis patients for biological disease-modifying antirheumatic drugs in the first 100 days of the COVID-19 pandemic
To evaluate treatment adherence and predictors of drug discontinuation among patients with inflammatory arthritis
receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.
A total of 1871 patients recorded in TReasure registry for whom advanced therapy was prescribed for rheumatoid arthritis (RA) or spondyloarthritis (SpA) within the 3 months (6–9 months for rituximab) before the declaration of COVID-19 pandemic were evaluated, and 1394 (74.5%) responded to the phone survey. Patients’ data regarding demographic, clinical characteristics and disease activity before the pandemic were recorded. The patients were inquired about the diagnosis of COVID-19, the rate of continuation on bDMARDs, the reasons for treatment discontinuation, if any, and the current general disease activity (visual analog scale, [VAS]).
A total of 1394 patients (493 RA [47.3% on anti-TNF] patients and 901 SpA [90.0% on anti-TNF] patients) were included in the study. Overall, 2.8% of the patients had symptoms suggesting COVID-19, and 2 (0.15%) patients had PCR-confirmed COVID-19. Overall, 18.1% of all patients (13.8% of the RA and 20.5% of the SpA; p = 0.003) discontinued their bDMARDs. In the SpA group, the patients who discontinued bDMARDs were younger (40 [21–73] vs. 44 years [20–79]; p = 0.005) and had higher general disease activity; however, no difference was relevant for RA patients.
Although the COVID-19 was quite uncommon in the first 100 days of the pandemic, nearly one-fifth of the patients discontinued bDMARDs within this period. The long-term effects of the pandemic should be monitored.
pmc1. Introduction
The recent coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Fever, dry cough, sore throat, and muscle and joint pain are general disease manifestations, and a severe clinical picture requiring hospital admission is encountered in 15%–20% of the patients [1,2]. According to the data collected from various countries, the COVID-19 fatality rate is about 1%–10% [3]. Patients with inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA) regularly and continuously receive synthetic or biological disease-modifying antirheumatic drugs (DMARDs) as the main component of their treatment. On the other hand, temporary discontinuation of particularly biological DMARDs (bDMARDs) in the presence of infection is an accepted recommendation [4]. Currently, the world is reexperiencing a pandemic after a period of nearly 100 years. After March 11, 2020, when the World Health Organization announced the pandemic, American, European, and local societies of rheumatology have claimed general recommendations about drug usage [4–6]. The Turkish Society for Rheumatology released COVID-19 recommendations on March 27, 2020, and left the decision to use synthetic/biological DMARDs during the pandemic mainly to the primary physician that follows the patient [6]. On the other hand, the behavioral pattern of patients with inflammatory arthritis using biological/synthetic DMARDs during the COVID-19 pandemic is unknown in Turkey or the rest of the world.
Accordingly, the present study aimed to evaluate treatment adherence of patients with inflammatory arthritis receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.
2. Methods
2.1. Patient selection
The TReasure registry is a web-based, prospective, observational cohort including RA and spondyloarthritis (SpA) patients from 17 centers in different regions of Turkey and was established in December 2017. Details of the establishment of TReasure registry were previously reported [7]. As of March 2020, there were a total of 7471 patients with inflammatory arthritis (2560 RA patients and 4911 SpA patients) receiving bDMARDs in this registry. The bDMARDs were as follows (arranged alphabetically): abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, secukinumab, and tocilizumab.
The present study included patients who were prescribed bDMARDs and for whom disease activity was recorded within the 3-month period before the declaration date of pandemic (March 2020) in the TReasure registry. For rituximab therapy, this period was determined to be 6–9 months before the declaration date of the pandemic. In the TReasure registry, the target population consisted of 1871 patients, of whom 1394 (74.5%) completed the standard phone questionnaire, 39 (2.1%) refused to participate in the study, and the remaining could not be reached. The patients who participated and those who did not participate in the study did not differ in demographic and clinical characteristics (data not shown).
2.2. Demographic and clinical characteristics of the patients
The demographic and clinical data collected from the patients were defined previously [7]. In brief, the following data were recorded for both RA and SpA patients: age, sex, disease duration, comorbidities (the Charlson comorbidity index), erythrocyte sedimentation rate (ESR) (mm/h), C-reactive protein (CRP) level (mg/L), number of swollen (66 joints) and tender (68 joints) joints, visual analog scale (VAS)-pain score, patients’ global assessment-VAS, and VAS-fatigue score, and the names of the currently used synthetic DMARDs or bDMARDs. Additionally, in RA patients, positivity for rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) was determined, and the scores of the disease activity score-28 (DAS-28), the Crohn’s Disease Activity Index (CDAI), the Simple Disease Activity Index (SDAI), and the Health Assessment Questionnaire (HAQ) were calculated to assess disease activity. In SpA patients, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), and the Ankylosing Spondylitis Disease Activity Score (ASDAS) based on CRP (ASDAS-CRP) were used for the assessment of disease activity. The diagnoses in SpA patients were classified as ankylosing spondylitis (according to the modified New York criteria), nonradiographic SpA (according to the axial SpA criteria), peripheral SpA (according to the peripheral SpA criteria), psoriatic arthritis (according to the CASPAR criteria), and enteropathic arthritis (based on the presence of inflammatory bowel disease [IBD] and arthritis/sacroiliitis) [8–11]. In SpA patients, the positivity of HLA-B27 and the presence of psoriasis, IBD, uveitis, dactylitis, and enthesitis (according to the Leeds enthesitis index [LEI]) were also recorded.
2.3. Questionnaire inquiring the pandemic period
A standard questionnaire was applied to the patients via phone call. The phone calls were made in June 2020. Accordingly, the following information questioned for the period between March 10, 2020, and the day of phone call: the presence of any signs of coronavirus infection; whether or not being diagnosed with COVID-19; if diagnosed with COVID-19, the place (hospital, home) where the patient was followed up; whether or not being quarantined due to COVID-19 infection; whether or not having biological or synthetic DMARDs on hand; whether or not the medications were administered during this time; if not administered, the reason(s); whether or not being contacted with his/her physician; and the current disease activity. For the assessment of the current general health status and disease activity, the patients were asked about their general health status (global patient assessment) and to rate it from 0 (excellent) to 10 (very bad), and about current disease activity, the patients were asked to rate their disease activity as “completely under control”, “mild”, “moderate”, “active”, and “highly active”.
2.4. Assessments in the study
In the present study, for the patients who discontinued their bDMARDs, comparisons were performed for the following parameters: age (also categorized in decades), sex, mean disease duration (categorized as 1, 5, and 10 years), seropositivity, sequence of use of bDMARDs (bDMARD-naïve, second-line, third-line), and usage of anti-TNF versus nonanti-TNF bDMARDs. The disease activity scores within the 3 months before the declaration of the pandemic was also recorded; these included mean DAS-28 score, CDAI, and SDAI scores (patients were dichotomized as those with and without low disease activity according to the DAS-28, SDAI, and CDAI scores), mean HAQ score (patients were dichotomized according to the scores of 0.5 and 1), mean BASDAI, BASFI, and ASDAS-CRP scores (patients were grouped according to ASDAS-CRP score), CRP level (<5 mg/L and >5 mg/L), patients’ global assessments-VAS score (grouping with 10-unit intervals), general health status (completely under control, mild, moderate, severe, highly severe), and presence of suspected COVID-19. Patients’ global assessment-VAS scores before the pandemic were compared with those during the pandemic. Accordingly, an increase by >2 units in the score was defined as worsened disease activity, and a decrease by <2 units in the score was defined as improved disease activity. Remission was defined as a general health status-VAS score of ≤2, whereas active disease was defined as a VAS score of ≥4.
Our study is compliant with the Helsinki Declaration and approved by both the local ethical committee (Hacettepe University; Approval number: 2020/08-25 (KA-17058)) and the Turkish Ministry of Health (Approval number: 66175679-514.05.01-E.170548).
2.5. Patient and public involvement
There is no patient or public involvement in this study.
2.6. Statistical analysis
Data analyses were performed using the Predictive Analytics SoftWare (PASW) 18.0 (SPSS Inc., Chicago, IL, USA) for Windows. The variables were investigated using visual (histogram, probability plots) and analytic methods (Kolmogorov–Smirnov, skewness, and kurtosis) to determine whether they are normally distributed or not. The descriptive analysis data were expressed as mean, standard deviation (SD), the median (minimum-maximum), or percentages for categorical variables. Chi-square test or Fisher’s exact test was used for categorical variables. Student’s t-test was used to compare normally distributed variables, while the Mann–Whitney U test was used to compare nonnormally distributed variables. The variables identified with univariate analyses (p < 0.20) were further entered the logistic regression analysis to determine independent predictors of drug discontinuation separately for RA and SpA patients. A p-value of <0.05 was considered statistically significant.
3. Results
3.1. Demographic and clinical characteristics of the patients
The demographic and clinical data and drug preferences of 1394 patients who participated in the study are presented in Table 1. In the RA group, RF was positive in 267 (62.7%) patients, anti-CCP was positive in 206 (56.4%) patients, and RF and/or anti-CCP were positive in 368 (74.5%) patients. In the SpA group, there were 664 (73.7%) patients with ankylosing spondylitis, 57 (6.3%) patients with nonradiographic SpA, 101 (11.2%) patients with peripheral SpA, 111 (12.3%) patients with psoriatic arthritis, and 21 (2.3%) patients with enteropathic arthritis. Extraarticular signs of the SpA patients were uveitis in 110 (12.5%) patients, IBD in 40 (4.6%) patients, and psoriasis in 141 (16.1%) patients. The HLA-B27 positivity was determined in 333 (59.1%) of 563 patients. Thirty-seven (4.8%) patients had dactylitis, and 120 (19.3%) patients had enthesitis (at least one entheseal region according to the LEI). Of the RA patients, 233 (47.3%) were receiving antitumor necrosis factor (TNF) agents, and 260 (52.7%) were receiving nonanti-TNF bDMARDs. On the other hand, of the SpA patients, 811 (90%) were receiving anti-TNF agents, and 90 (10%) were receiving antiinterleukin (IL)-17 treatment.
Table 1 Demographic and clinical characteristics of the patients.
Patients with RAn = 493 Patients with SpAn = 901
Female sex, n (%) 400 (81.1) 398 (44.2)
Age, years, median (range) 55 (18–86) 43 (20–79)
Disease duration, months, median (range) 131 (2–509) 111 (2–672)
ESR, mm/h, median (range) 16 (1–120) 12 (1–103)
CRP, mg/L, median (range) 3.96 (0.1–98.9) 3.84 (0.1–91.1)
Global assessment of health–VAS score, median (range) 30 (0–100) 25 (0–100)
Pain–VAS score, median (range) 30 (0–100) 20 (0–100)
Fatigue–VAS score, median (range) 30 (0–100) 20 (0–100)
HAQ score, median (range) 0.38 (0–90) –
Number of swollen joints, mean ± SD 0.58 ± 2.21 0.1 ± 0.71
Number of tender joints, mean ± SD 1.31 ± 3.41 0.29 ± 1.6
DAS-28-ESR score, median (range) 2.55 (0.56–8.16) –
CDAI score, mean ± SD 7.97 ± 8.92 –
SDAI score, mean ± SD 17.83 ± 20.08 –
BASDAI score, n (%) – 1.55 (0–9.5)
BASFI score, n (%) – 1.2 (0–9.7)
Hypertension, n (%) 143 (29.7) 137 (15.4)
Obesity, n (%) 166 (35.3) 220 (24.4)
Diabetes mellitus, n (%) 48 (9.9) 57 (6.4)
Hyperlipidemia, n (%) 71 (15.1) 98 (11.2)
Coronary artery disease, n (%) 20 (4.3) 17 (1.9)
COPD, n (%) 11 (2.4) 3 (0.3)
Asthma, n (%) 26 (5.6) 28 (3.3)
Malignancy, n (%) 5 (1) 8 (0.9)
Presence of at least1 comorbidity, n (%) 186 (38.2) 462 (51.6)
Presence of ≥2 comorbidities, n (%) 121 (24.8) 229 (25.6)
Presence of ≥3 comorbidities, n (%) 167 (34.3) 160 (17.9)
ASDAS–CRP, median (range) – 1.84 (0–5.2)
Abatacept, n (%) 32 (6.5) –
Adalimumab, n (%) 89 (18.1) 270 (30)
Certolizumab, n (%) 38 (7.7) 146 (16.2)
Etanercept, n (%) 75 (15.2) 182 (20.2)
Golimumab, n (%) 18 (3.7) 90 (10)
Infliximab, n (%) 13 (2.6) 123 (13.7)
Rituximab, n (%) 40 (8.1) –
Secukinumab, n (%) – 90 (10)
Tofacitinib, n (%) 77 (15.6) –
Tocilizumab, n (%) 111 (22.5) –
Hydroxychloroquine, n (%) 164 (33.3) 13 (1.4)
Leflunomide, n (%) 117 (23.7) 17 (1.9)
Methotrexate , n (%) 135 (27.4) 57 (6.3)
Sulfasalazine, n (%) 23 (4.7) 71 (7.9)
RA, rheumatoid arthritis; SpA, spondyloarthritis; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein, VAS, Visual Analog Scale; HAQ, Health Assessment Questionnaire; DAS-28, the Disease Activity Score-28; CDAI, the Crohn’s Disease Activity Index; SDAI, the Simple Disease Activity Index; BASDAI, the Bath Ankylosing Spondylitis Disease Activity Index; BASFI, the Bath Ankylosing Spondylitis Functional Index; COPD, chronic obstructive pulmonary disease; ASDAS, Ankylosing Spondylitis Disease Activity Score; SD, standard deviation.
3.2. Detecting COVID-19 in the inflammatory arthritis patients receiving bDMARDs
A total of 1353 patients were questioned about COVID-19 status. Of all the patients, 39 (2.8%) had at least one suspicious sign of COVID-19, and 26 (1.9%) visited a healthcare center for this reason (Table 2). Fever (body temperature ≥ 38°C) was the suspicious sign in 14 (1.0%) patients. The PCR test was positive for COVID-19 only in 2 (0.15%) of all patients. Both of these patients were treated at home.
Table 2 Results of the questions about COVID-19 status in the study patients during the pandemic.
All patients n = 1353 RA n = 487 SpA n = 866
Presence of any suspected sign of COVID-19 39 (2.8) 6 (1.2) 33 (3.7)
Admission to a healthcare center for suspected COVID-19 26 (1.9) 5 (1.0) 22 (2.5)
Having PCR testing for COVID-19 21 (1.6) 5 (1.0) 16 (1.8)
Quarantine recommendation for suspected COVID-19 10 (0.73) 0 (0) 10 (1.15)
PCR positivity for COVID-19 2 (0.15) 0 (0) 2 (0.23)
Family history of COVID-19 positivity 9 (0.66) 3 (0.6) 6 (0.7)
3.3. Use of biological DMARDs during the pandemic
A total of 1362 patients responded to the question about the continuation of bDMARDs during the pandemic. Overall, 247 (18.1%) patients discontinued their bDMARDs. Sixty-six (13.8%) of the RA patients and 181 (20.5%) of the SpA patients discontinued their bDMARDs (p = 0.003). The distribution of the patients who discontinued/did not receive their bDMARDs is demonstrated in Table 3. Among RA patients, etanercept (%5.4) was the least frequently discontinued bDMARD, whereas tocilizumab (%20.5) was the most frequently discontinued bDMARD. The clinical characteristics and disease activity parameters did not differ between the RA patients who discontinued and those who did not discontinue their bDMARDs. In the SpA patient group, those who discontinued their bDMARDs were younger than those who did not (median age, 40 years [range, 21–73 years] vs. median age, 44 years [range, 20–79 years]; p = 0.005). Moreover, the SpA patients who continued their bDMARDs had lower disease activity. The multivariate analysis revealed that age of <40 years, a poorer general health status, a poorer VAS score, and the suspicion for the presence of COVID-19 were the factors that determine the discontinuation of bDMARD therapy in SpA patients (Table 4).
Table 3 Distribution of the patients who discontinued their biological disease-modifying antirheumatic drugs.
Patients with RA n/N (%) Patients with SpA n/N (%)
All bDMARDs 66 (14.0) 181 (20.5)
Abatacept 4/31 (12.9) NA
Adalimumab 15/86 (17.4) 46/264 (17.4)
Etanercept 4/74 (5.4) 38/180 (21.1)
Golimumab 3/18 (16.7) 15/86 (15.6)
Infliximab 2/12 (16.7) 29/118 (24.5)
Certolizumab 3/37 (8.1) 31/146 (21.2)
Rituximab 7/39 (17.9) NA
Tofacitinib 6/75 (8.0) NA
Tocilizumab 22/107 (20.5) NA
Secukinumab NA 22/89 (24.7)
Hydroxychloroquine 19/157 (12.1) 5/181 (2.8)
Leflunomide 14/113 (12.4) 4/181 (2.2)
Methotrexate 14/134 (10.4) 13/181 (7.2)
Sulfasalazine 2/22 (9.1) 13/181 (7.2)
RA, rheumatoid arthritis; SpA, spondyloarthritis; bDMARDs, biological disease-modifying antirheumatic drugs; NA, not applicable.
Table 4 Characteristics of the patients with spondyloarthritis who discontinued their biological disease-modifying antirheumatic drugs
Patients with SpA who discontinued bDMARDs Patients with SpA who continued bDMARDs Univariatep Odds Ratio95% CI Multivariatep Odds ratio95% CI
Age (<40 vs. ≥40) 84 (46.4) 243 (34.6) 0.004 1.64 (1.18–2.28) 0.002 1.76 (1.24–2.51)
General health status
Completely under control 51 (28.2) 390 (55.8) Reference
Mild 52 (28.7) 103 (14.7) <0.001 3.86 (2.48–6.01) <0.001 3.20 (1.99–5.15)
Moderate 51 (28.2) 153 (21.9) <0.001 2.55 (1.66–3.92) 0.003 2.03 (1.26–3.27)
Severe 21 (11.6) 41 (5.9) <0.001 3.92 (2.15–7.15) 0.003 2.65 (1.38–5.10)
Extremely severe 6 (3.3) 12 (1.7) 0.010 3.82 (1.38–10.63) 0.103 2.46 (0.83–7.28)
VAS-PGA, <20 vs. ≥20 38 (21.1) 281 (40.2) <0.001 2.51 (1.70–3.71) 0.016 1.74 (1.11–2.75)
Suspected COVID-19 12 (6.6) 20 (2.9) 0.019 2.41 (1.16–5.04) 0.136 1.83 (0.83–4.03)
Data are presented as numbers (percentage, %).SpA, spondyloarthritis; bDMARDs, biological disease-modifying antirheumatic drugs; CI, confidence interval; VAS-PGA, visual analog scale-patient global assessment; COVID-19, coronavirus disease 2019.
The data on the reasons for drug discontinuation were available in 186 (75.3%) of 247 patients who discontinued their bDMARDs. Of these patients, 60 (32.2%) discontinued the therapy based on the recommendation of his/her physician, 84 (45.1%) discontinued on their own demand/fear, 13 (6.9%) discontinued due to suspected COVID-19, 8 (4.3%) discontinued due to the lack of disease activity, and 21 (11.3%) discontinued due to other reasons. No difference was determined between RA and SpA patients in terms of reasons for discontinuation of bDMARDs. During the pandemic, 550 patients (213 RA patients and 337 SpA patients) were able to communicate with their physicians. The patients communicated with their physicians through phone calls (314 [57.1%] patients), face-to-face interview (203 [36.9%] patients), text message (39 [7.1%] patients), e-mail (19 [3.5%] patients), healthcare staff (assistant, nurse) (13 [2.4%] patients), and relatives (5 [0.9%] patients). In 425 (77.3%) of 550 patients, their physicians recommended them to continue bDMARD therapy. In 37 (6.7%) of 550 patients, their physicians recommended them to receive bDMARDs on demand and/or to extent drug application intervals.
3.4. Disease activity during the pandemic
Evaluation of the disease activity during the pandemic in all patients revealed that the disease was completely under control in 46.8% of the patients (in 40.8% of the RA patients and in 50.0% of the SpA patients), whereas 19.1% of the patients (21.7% of the RA patients and 17.7% of the SpA patients) had mild disease activity, 24.7% of the patients (27.9% of the RA patients and 23.1% of the SpA patients) had moderate disease activity, 7.0% of the patients (6.8% of the RA patients and 7.1% of the SpA patients) had active disease, and 2.4% of the patients (2.9% of the RA patients and 2.1% of the SpA patients) had very high disease activity (p = 0.016). The mean general health status-VAS score in all patients during the pandemic was 3.1 ± 2.5; it was 3.4 ± 2.6 in the RA patients and 2.9 ± 2.5 in the SpA patients (p < 0.001). The mean general health status-VAS score in all patients in the prepandemic period was 3.2 ± 2.5; it was 3.6 ± 2.6 in the RA patients and 3 ± 2.4 in the SpA patients (p < 0.001).
As compared with the period before the pandemic, the ratios of patients with worsened disease activity, those with improved disease activity, those in whom the disease has become active (while in remission), those with ongoing remission, those with ongoing active disease, and those showing remission (while having active disease) in the first 100 days of the pandemic are demonstrated in Table 5. In the RA patients, these variables did not show difference between the patients who discontinued and those who did not discontinue their bDMARDs. In the SpA patients, the ratio of those who remained in remission before and during the pandemic was 32.1%. The rate of drug discontinuation was lower in the SpA patients who remained in remission (22.0% in those who discontinued bDMARDs and 34.8% in those who did not discontinue bDMARDs; p = 0.002); other parameters showed no difference between the patients who discontinued and those who did not discontinue bDMARDs.
Table 5 As assessed according to the prepandemic period, changes in disease activity determined by the general health status-Visual Analog Scale scores during the pandemic.
Status Definition Patients with RAn = 428 Patients with SpAn = 809
Worsened disease activity during the pandemic >2 units increase in the VAS score after the pandemic as compared with before the pandemic 100 (23.4) 137 (16.9)
Patients with improved disease activity during the pandemic <2 units decrease in the VAS score after the pandemic as compared with before the pandemic 89 (20.8) 118 (14.6)
While in remission before the pandemic, becoming active during the pandemic A VAS score of ≤2 before pandemic and ≥4 after the pandemic, 69 (16.1) 100 (12.4)
Remission both before and during the pandemic A VAS score of ≤2 before the pandemic and ≤2 after the pandemic 91 (21.3) 260 (32.1)
Active disease both before and during the pandemic A VAS score of ≥4 before the pandemic and ≥4 after the pandemic 121 (28.3) 175 (21.6)
Active disease before the pandemic, remission during the pandemic A VAS score of ≥4 before the pandemic and ≤2 after the pandemic 52 (12.1) 86 (10.6)
Data are presented as numbers (percentage, %).RA, rheumatoid arthritis; SpA, spondyloarthritis; VAS, visual analog scale; bDMARDs, biological disease-modifying antirheumatic drugs; NA, not applicable.
4. Discussion
The COVID 19 pandemic, which was announced in March 2020 by the WHO, has directly influenced the daily life of both healthy individuals and individuals with chronic illnesses1. Immunosuppressed patients rank first among the patient groups influenced by the pandemic most. Biological DMARDs, which have been used in the last two decades, have been the group of medications primarily focused on due to their potential to increase the risk of infection. The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), which are among the international expert societies on rheumatology, have recommended identification of the risk groups and continuation of bDMARDs as long as possible within the frame of patient–physician communication [4,5]. However, the pandemic has caused severe anxiety and fear in some patients. Uncertainty and fear were more prominent particularly in the early period of the pandemic.
The present study investigated the therapeutic approaches in the first 100 days after the declaration of the pandemic in inflammatory arthritis patients known to receive bDMARD therapy. It was observed that the rate of confirmed COVID-19 cases (0.15%) was extremely low in the first 100 days and that nearly 3% of the patients needed to be evaluated for suspected COVID-19. The first 100 days of the pandemic in Turkey was when a strict lockdown was implemented particularly for the people over the age of 65 and under the age of 18. In that period, people with chronic illnesses in particular were on administrative leave, and many patients self-quarantined themselves. It is likely that such a low rate of COVID-19 determined among the patients with inflammatory rheumatic diseases is associated with the abovementioned strict lockdown. After that period, people began to return to their normal life; therefore, how many of the patients evaluated in the present study will develop COVID-19 infection during their follow-up is an investigation that needs to be performed in the future.
Recent studies supported that patients who take biological and conventional DMARDs have less morbidity in the case of COVID-19 [2]. Moreover, in another study from Turkey consisting of 167 patients with inflammatory rheumatic disease, biologic and conventional DMARDs did not seem to cause worse outcomes [12]. However, overall, 18% of all the inflammatory arthritis patients discontinued bDMARDs in the first 100 days of the pandemic. It was observed that drug discontinuation was more common, particularly in the SpA patients, than in the RA patients. Etanercept was the least frequently discontinued bDMARD in the RA patients. It was understood that etanercept has been used for longer than 20 years and thus considered a relatively reliable therapeutic option for both patients and physicians. The main reason for drug discontinuation was the patients’ fear of bDMARD therapy; on the other hand, drug discontinuation was recommended by the physicians in one-third of the patients. In Italy, a survey was conducted between February 2020 and April 2020 in 955 rheumatic patients [13]. In that patient group receiving advanced treatment, modification of biological therapy was performed in nearly 6% of the patients, which is quite low as compared with the finding of the present survey study. Accordingly, different cultural factors can be considered determinative. In the present study, among the patients who were able to communicate with their physicians, about 7% were recommended to receive treatment on demand or could extent drug application intervals. Receiving bDMARD therapy on demand or extending drug application intervals is a method implemented by clinicians for a long time in daily practice with efficacy and safety proven in the controlled studies. During the pandemic, the physicians preferred this method in some of their patients. On the other hand, there is a patient group trying to reach their physicians but could not reach them. It was understood that a change occurred in the physician–patient communication during the pandemic. Specific to rheumatology, patients’ methods of reaching their physicians should be dwelled on, and further studies are needed on this subject.
Any factor that might explain bDMARD discontinuation in the RA patients could not be determined. On the other hand, it was observed that the SpA patients with the disease under control were more likely to continue their drugs. This finding is likely to indicate that the SpA patients with the disease under control were more adherent to their medications, and they avoided recurrent exacerbations. Fluctuations in disease activity were observed in the first 100 days of the pandemic as assessed according to the prepandemic period. The rate of remaining in remission during the pandemic for the patients in remission before the pandemic was 21% in the RA group and 32% in the SpA group. It was understood that the patients with high disease activity in the prepandemic period experienced more difficulty in the early period of the pandemic.
The present survey study was conducted through phone interviews. We could reach three-fourth of the patients; the rates of drug discontinuation and COVID-19 might be higher among those that could not be reached; thus, the results need to be evaluated within the scope of this limitation. The fact that the information regarding steroid use was not inquired could be considered another limitation.
In conclusion, nearly one-fifth of the RA and SpA patients recorded in the TReasure registry and known to receive bDMARD therapy in the prepandemic period discontinued their drugs in the first 100 days of the pandemic. The frequency of COVID-19 was found to be low in the first 100 days of the pandemic, which corresponds to a period when a strict lockdown was implemented in Turkey. Further investigations need to be performed to find out what will happen when people return to their normal active life. Although patients’ fear of treatment appeared to be the main factor, the treatment was discontinued or also interrupted due to physicians’ recommendations. These treatment modifications in the early period of the COVID-19 pandemic may appear as a worsened disease activity in time. Treatment approaches need to be monitored closely in the following period.
Authors’ contributions
All authors contributed equally to conceiving and designing the analysis and collecting the data. UK and EB performed the analysis and wrote the paper; all authors revised and edited the final version of manuscript.
Informed consent
Our study is compliant with the Helsinki Declaration and was approved by both the local ethical committee (Hacettepe University; Approval number: 2020/08-25 (KA-17058)) and the Turkish Ministry of Health (Approval number: 66175679-514.05.01-E.170548).
Acknowledgments
UK received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. YP received honorary from Abbvie, Roche, Novartis, MSD, Pfizer. SA received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. TK received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. GK received honorary from Abbvie, Amgen, Novartis, Pfizer, UCB. OK received honorary from Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. ED received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. IE received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. LK received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. DE received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, UCB. CB received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. HE received honorary from Novartis, Roche. RM received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. NK received honorary from Novartis, UCB. MC received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. SSK received honorary from Abbvie, MSD, Novartis, Pfizer, Roche, UCB. OK received honorary from Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. SK received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. Other authors declare no conflict of interest.
This study was funded by Hacettepe Rheumatology Society.
World Health Organization (2020). The director-general’s opening remarks at the media briefing on COVID-19 [online]. Website https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. [accessed 27 September 2020]). | ADALIMUMAB | DrugsGivenReaction | CC BY | 33611869 | 20,063,722 | 2021-08-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Psoriatic arthropathy'. | Preferences of inflammatory arthritis patients for biological disease-modifying antirheumatic drugs in the first 100 days of the COVID-19 pandemic
To evaluate treatment adherence and predictors of drug discontinuation among patients with inflammatory arthritis
receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.
A total of 1871 patients recorded in TReasure registry for whom advanced therapy was prescribed for rheumatoid arthritis (RA) or spondyloarthritis (SpA) within the 3 months (6–9 months for rituximab) before the declaration of COVID-19 pandemic were evaluated, and 1394 (74.5%) responded to the phone survey. Patients’ data regarding demographic, clinical characteristics and disease activity before the pandemic were recorded. The patients were inquired about the diagnosis of COVID-19, the rate of continuation on bDMARDs, the reasons for treatment discontinuation, if any, and the current general disease activity (visual analog scale, [VAS]).
A total of 1394 patients (493 RA [47.3% on anti-TNF] patients and 901 SpA [90.0% on anti-TNF] patients) were included in the study. Overall, 2.8% of the patients had symptoms suggesting COVID-19, and 2 (0.15%) patients had PCR-confirmed COVID-19. Overall, 18.1% of all patients (13.8% of the RA and 20.5% of the SpA; p = 0.003) discontinued their bDMARDs. In the SpA group, the patients who discontinued bDMARDs were younger (40 [21–73] vs. 44 years [20–79]; p = 0.005) and had higher general disease activity; however, no difference was relevant for RA patients.
Although the COVID-19 was quite uncommon in the first 100 days of the pandemic, nearly one-fifth of the patients discontinued bDMARDs within this period. The long-term effects of the pandemic should be monitored.
pmc1. Introduction
The recent coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Fever, dry cough, sore throat, and muscle and joint pain are general disease manifestations, and a severe clinical picture requiring hospital admission is encountered in 15%–20% of the patients [1,2]. According to the data collected from various countries, the COVID-19 fatality rate is about 1%–10% [3]. Patients with inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA) regularly and continuously receive synthetic or biological disease-modifying antirheumatic drugs (DMARDs) as the main component of their treatment. On the other hand, temporary discontinuation of particularly biological DMARDs (bDMARDs) in the presence of infection is an accepted recommendation [4]. Currently, the world is reexperiencing a pandemic after a period of nearly 100 years. After March 11, 2020, when the World Health Organization announced the pandemic, American, European, and local societies of rheumatology have claimed general recommendations about drug usage [4–6]. The Turkish Society for Rheumatology released COVID-19 recommendations on March 27, 2020, and left the decision to use synthetic/biological DMARDs during the pandemic mainly to the primary physician that follows the patient [6]. On the other hand, the behavioral pattern of patients with inflammatory arthritis using biological/synthetic DMARDs during the COVID-19 pandemic is unknown in Turkey or the rest of the world.
Accordingly, the present study aimed to evaluate treatment adherence of patients with inflammatory arthritis receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.
2. Methods
2.1. Patient selection
The TReasure registry is a web-based, prospective, observational cohort including RA and spondyloarthritis (SpA) patients from 17 centers in different regions of Turkey and was established in December 2017. Details of the establishment of TReasure registry were previously reported [7]. As of March 2020, there were a total of 7471 patients with inflammatory arthritis (2560 RA patients and 4911 SpA patients) receiving bDMARDs in this registry. The bDMARDs were as follows (arranged alphabetically): abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, secukinumab, and tocilizumab.
The present study included patients who were prescribed bDMARDs and for whom disease activity was recorded within the 3-month period before the declaration date of pandemic (March 2020) in the TReasure registry. For rituximab therapy, this period was determined to be 6–9 months before the declaration date of the pandemic. In the TReasure registry, the target population consisted of 1871 patients, of whom 1394 (74.5%) completed the standard phone questionnaire, 39 (2.1%) refused to participate in the study, and the remaining could not be reached. The patients who participated and those who did not participate in the study did not differ in demographic and clinical characteristics (data not shown).
2.2. Demographic and clinical characteristics of the patients
The demographic and clinical data collected from the patients were defined previously [7]. In brief, the following data were recorded for both RA and SpA patients: age, sex, disease duration, comorbidities (the Charlson comorbidity index), erythrocyte sedimentation rate (ESR) (mm/h), C-reactive protein (CRP) level (mg/L), number of swollen (66 joints) and tender (68 joints) joints, visual analog scale (VAS)-pain score, patients’ global assessment-VAS, and VAS-fatigue score, and the names of the currently used synthetic DMARDs or bDMARDs. Additionally, in RA patients, positivity for rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) was determined, and the scores of the disease activity score-28 (DAS-28), the Crohn’s Disease Activity Index (CDAI), the Simple Disease Activity Index (SDAI), and the Health Assessment Questionnaire (HAQ) were calculated to assess disease activity. In SpA patients, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), and the Ankylosing Spondylitis Disease Activity Score (ASDAS) based on CRP (ASDAS-CRP) were used for the assessment of disease activity. The diagnoses in SpA patients were classified as ankylosing spondylitis (according to the modified New York criteria), nonradiographic SpA (according to the axial SpA criteria), peripheral SpA (according to the peripheral SpA criteria), psoriatic arthritis (according to the CASPAR criteria), and enteropathic arthritis (based on the presence of inflammatory bowel disease [IBD] and arthritis/sacroiliitis) [8–11]. In SpA patients, the positivity of HLA-B27 and the presence of psoriasis, IBD, uveitis, dactylitis, and enthesitis (according to the Leeds enthesitis index [LEI]) were also recorded.
2.3. Questionnaire inquiring the pandemic period
A standard questionnaire was applied to the patients via phone call. The phone calls were made in June 2020. Accordingly, the following information questioned for the period between March 10, 2020, and the day of phone call: the presence of any signs of coronavirus infection; whether or not being diagnosed with COVID-19; if diagnosed with COVID-19, the place (hospital, home) where the patient was followed up; whether or not being quarantined due to COVID-19 infection; whether or not having biological or synthetic DMARDs on hand; whether or not the medications were administered during this time; if not administered, the reason(s); whether or not being contacted with his/her physician; and the current disease activity. For the assessment of the current general health status and disease activity, the patients were asked about their general health status (global patient assessment) and to rate it from 0 (excellent) to 10 (very bad), and about current disease activity, the patients were asked to rate their disease activity as “completely under control”, “mild”, “moderate”, “active”, and “highly active”.
2.4. Assessments in the study
In the present study, for the patients who discontinued their bDMARDs, comparisons were performed for the following parameters: age (also categorized in decades), sex, mean disease duration (categorized as 1, 5, and 10 years), seropositivity, sequence of use of bDMARDs (bDMARD-naïve, second-line, third-line), and usage of anti-TNF versus nonanti-TNF bDMARDs. The disease activity scores within the 3 months before the declaration of the pandemic was also recorded; these included mean DAS-28 score, CDAI, and SDAI scores (patients were dichotomized as those with and without low disease activity according to the DAS-28, SDAI, and CDAI scores), mean HAQ score (patients were dichotomized according to the scores of 0.5 and 1), mean BASDAI, BASFI, and ASDAS-CRP scores (patients were grouped according to ASDAS-CRP score), CRP level (<5 mg/L and >5 mg/L), patients’ global assessments-VAS score (grouping with 10-unit intervals), general health status (completely under control, mild, moderate, severe, highly severe), and presence of suspected COVID-19. Patients’ global assessment-VAS scores before the pandemic were compared with those during the pandemic. Accordingly, an increase by >2 units in the score was defined as worsened disease activity, and a decrease by <2 units in the score was defined as improved disease activity. Remission was defined as a general health status-VAS score of ≤2, whereas active disease was defined as a VAS score of ≥4.
Our study is compliant with the Helsinki Declaration and approved by both the local ethical committee (Hacettepe University; Approval number: 2020/08-25 (KA-17058)) and the Turkish Ministry of Health (Approval number: 66175679-514.05.01-E.170548).
2.5. Patient and public involvement
There is no patient or public involvement in this study.
2.6. Statistical analysis
Data analyses were performed using the Predictive Analytics SoftWare (PASW) 18.0 (SPSS Inc., Chicago, IL, USA) for Windows. The variables were investigated using visual (histogram, probability plots) and analytic methods (Kolmogorov–Smirnov, skewness, and kurtosis) to determine whether they are normally distributed or not. The descriptive analysis data were expressed as mean, standard deviation (SD), the median (minimum-maximum), or percentages for categorical variables. Chi-square test or Fisher’s exact test was used for categorical variables. Student’s t-test was used to compare normally distributed variables, while the Mann–Whitney U test was used to compare nonnormally distributed variables. The variables identified with univariate analyses (p < 0.20) were further entered the logistic regression analysis to determine independent predictors of drug discontinuation separately for RA and SpA patients. A p-value of <0.05 was considered statistically significant.
3. Results
3.1. Demographic and clinical characteristics of the patients
The demographic and clinical data and drug preferences of 1394 patients who participated in the study are presented in Table 1. In the RA group, RF was positive in 267 (62.7%) patients, anti-CCP was positive in 206 (56.4%) patients, and RF and/or anti-CCP were positive in 368 (74.5%) patients. In the SpA group, there were 664 (73.7%) patients with ankylosing spondylitis, 57 (6.3%) patients with nonradiographic SpA, 101 (11.2%) patients with peripheral SpA, 111 (12.3%) patients with psoriatic arthritis, and 21 (2.3%) patients with enteropathic arthritis. Extraarticular signs of the SpA patients were uveitis in 110 (12.5%) patients, IBD in 40 (4.6%) patients, and psoriasis in 141 (16.1%) patients. The HLA-B27 positivity was determined in 333 (59.1%) of 563 patients. Thirty-seven (4.8%) patients had dactylitis, and 120 (19.3%) patients had enthesitis (at least one entheseal region according to the LEI). Of the RA patients, 233 (47.3%) were receiving antitumor necrosis factor (TNF) agents, and 260 (52.7%) were receiving nonanti-TNF bDMARDs. On the other hand, of the SpA patients, 811 (90%) were receiving anti-TNF agents, and 90 (10%) were receiving antiinterleukin (IL)-17 treatment.
Table 1 Demographic and clinical characteristics of the patients.
Patients with RAn = 493 Patients with SpAn = 901
Female sex, n (%) 400 (81.1) 398 (44.2)
Age, years, median (range) 55 (18–86) 43 (20–79)
Disease duration, months, median (range) 131 (2–509) 111 (2–672)
ESR, mm/h, median (range) 16 (1–120) 12 (1–103)
CRP, mg/L, median (range) 3.96 (0.1–98.9) 3.84 (0.1–91.1)
Global assessment of health–VAS score, median (range) 30 (0–100) 25 (0–100)
Pain–VAS score, median (range) 30 (0–100) 20 (0–100)
Fatigue–VAS score, median (range) 30 (0–100) 20 (0–100)
HAQ score, median (range) 0.38 (0–90) –
Number of swollen joints, mean ± SD 0.58 ± 2.21 0.1 ± 0.71
Number of tender joints, mean ± SD 1.31 ± 3.41 0.29 ± 1.6
DAS-28-ESR score, median (range) 2.55 (0.56–8.16) –
CDAI score, mean ± SD 7.97 ± 8.92 –
SDAI score, mean ± SD 17.83 ± 20.08 –
BASDAI score, n (%) – 1.55 (0–9.5)
BASFI score, n (%) – 1.2 (0–9.7)
Hypertension, n (%) 143 (29.7) 137 (15.4)
Obesity, n (%) 166 (35.3) 220 (24.4)
Diabetes mellitus, n (%) 48 (9.9) 57 (6.4)
Hyperlipidemia, n (%) 71 (15.1) 98 (11.2)
Coronary artery disease, n (%) 20 (4.3) 17 (1.9)
COPD, n (%) 11 (2.4) 3 (0.3)
Asthma, n (%) 26 (5.6) 28 (3.3)
Malignancy, n (%) 5 (1) 8 (0.9)
Presence of at least1 comorbidity, n (%) 186 (38.2) 462 (51.6)
Presence of ≥2 comorbidities, n (%) 121 (24.8) 229 (25.6)
Presence of ≥3 comorbidities, n (%) 167 (34.3) 160 (17.9)
ASDAS–CRP, median (range) – 1.84 (0–5.2)
Abatacept, n (%) 32 (6.5) –
Adalimumab, n (%) 89 (18.1) 270 (30)
Certolizumab, n (%) 38 (7.7) 146 (16.2)
Etanercept, n (%) 75 (15.2) 182 (20.2)
Golimumab, n (%) 18 (3.7) 90 (10)
Infliximab, n (%) 13 (2.6) 123 (13.7)
Rituximab, n (%) 40 (8.1) –
Secukinumab, n (%) – 90 (10)
Tofacitinib, n (%) 77 (15.6) –
Tocilizumab, n (%) 111 (22.5) –
Hydroxychloroquine, n (%) 164 (33.3) 13 (1.4)
Leflunomide, n (%) 117 (23.7) 17 (1.9)
Methotrexate , n (%) 135 (27.4) 57 (6.3)
Sulfasalazine, n (%) 23 (4.7) 71 (7.9)
RA, rheumatoid arthritis; SpA, spondyloarthritis; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein, VAS, Visual Analog Scale; HAQ, Health Assessment Questionnaire; DAS-28, the Disease Activity Score-28; CDAI, the Crohn’s Disease Activity Index; SDAI, the Simple Disease Activity Index; BASDAI, the Bath Ankylosing Spondylitis Disease Activity Index; BASFI, the Bath Ankylosing Spondylitis Functional Index; COPD, chronic obstructive pulmonary disease; ASDAS, Ankylosing Spondylitis Disease Activity Score; SD, standard deviation.
3.2. Detecting COVID-19 in the inflammatory arthritis patients receiving bDMARDs
A total of 1353 patients were questioned about COVID-19 status. Of all the patients, 39 (2.8%) had at least one suspicious sign of COVID-19, and 26 (1.9%) visited a healthcare center for this reason (Table 2). Fever (body temperature ≥ 38°C) was the suspicious sign in 14 (1.0%) patients. The PCR test was positive for COVID-19 only in 2 (0.15%) of all patients. Both of these patients were treated at home.
Table 2 Results of the questions about COVID-19 status in the study patients during the pandemic.
All patients n = 1353 RA n = 487 SpA n = 866
Presence of any suspected sign of COVID-19 39 (2.8) 6 (1.2) 33 (3.7)
Admission to a healthcare center for suspected COVID-19 26 (1.9) 5 (1.0) 22 (2.5)
Having PCR testing for COVID-19 21 (1.6) 5 (1.0) 16 (1.8)
Quarantine recommendation for suspected COVID-19 10 (0.73) 0 (0) 10 (1.15)
PCR positivity for COVID-19 2 (0.15) 0 (0) 2 (0.23)
Family history of COVID-19 positivity 9 (0.66) 3 (0.6) 6 (0.7)
3.3. Use of biological DMARDs during the pandemic
A total of 1362 patients responded to the question about the continuation of bDMARDs during the pandemic. Overall, 247 (18.1%) patients discontinued their bDMARDs. Sixty-six (13.8%) of the RA patients and 181 (20.5%) of the SpA patients discontinued their bDMARDs (p = 0.003). The distribution of the patients who discontinued/did not receive their bDMARDs is demonstrated in Table 3. Among RA patients, etanercept (%5.4) was the least frequently discontinued bDMARD, whereas tocilizumab (%20.5) was the most frequently discontinued bDMARD. The clinical characteristics and disease activity parameters did not differ between the RA patients who discontinued and those who did not discontinue their bDMARDs. In the SpA patient group, those who discontinued their bDMARDs were younger than those who did not (median age, 40 years [range, 21–73 years] vs. median age, 44 years [range, 20–79 years]; p = 0.005). Moreover, the SpA patients who continued their bDMARDs had lower disease activity. The multivariate analysis revealed that age of <40 years, a poorer general health status, a poorer VAS score, and the suspicion for the presence of COVID-19 were the factors that determine the discontinuation of bDMARD therapy in SpA patients (Table 4).
Table 3 Distribution of the patients who discontinued their biological disease-modifying antirheumatic drugs.
Patients with RA n/N (%) Patients with SpA n/N (%)
All bDMARDs 66 (14.0) 181 (20.5)
Abatacept 4/31 (12.9) NA
Adalimumab 15/86 (17.4) 46/264 (17.4)
Etanercept 4/74 (5.4) 38/180 (21.1)
Golimumab 3/18 (16.7) 15/86 (15.6)
Infliximab 2/12 (16.7) 29/118 (24.5)
Certolizumab 3/37 (8.1) 31/146 (21.2)
Rituximab 7/39 (17.9) NA
Tofacitinib 6/75 (8.0) NA
Tocilizumab 22/107 (20.5) NA
Secukinumab NA 22/89 (24.7)
Hydroxychloroquine 19/157 (12.1) 5/181 (2.8)
Leflunomide 14/113 (12.4) 4/181 (2.2)
Methotrexate 14/134 (10.4) 13/181 (7.2)
Sulfasalazine 2/22 (9.1) 13/181 (7.2)
RA, rheumatoid arthritis; SpA, spondyloarthritis; bDMARDs, biological disease-modifying antirheumatic drugs; NA, not applicable.
Table 4 Characteristics of the patients with spondyloarthritis who discontinued their biological disease-modifying antirheumatic drugs
Patients with SpA who discontinued bDMARDs Patients with SpA who continued bDMARDs Univariatep Odds Ratio95% CI Multivariatep Odds ratio95% CI
Age (<40 vs. ≥40) 84 (46.4) 243 (34.6) 0.004 1.64 (1.18–2.28) 0.002 1.76 (1.24–2.51)
General health status
Completely under control 51 (28.2) 390 (55.8) Reference
Mild 52 (28.7) 103 (14.7) <0.001 3.86 (2.48–6.01) <0.001 3.20 (1.99–5.15)
Moderate 51 (28.2) 153 (21.9) <0.001 2.55 (1.66–3.92) 0.003 2.03 (1.26–3.27)
Severe 21 (11.6) 41 (5.9) <0.001 3.92 (2.15–7.15) 0.003 2.65 (1.38–5.10)
Extremely severe 6 (3.3) 12 (1.7) 0.010 3.82 (1.38–10.63) 0.103 2.46 (0.83–7.28)
VAS-PGA, <20 vs. ≥20 38 (21.1) 281 (40.2) <0.001 2.51 (1.70–3.71) 0.016 1.74 (1.11–2.75)
Suspected COVID-19 12 (6.6) 20 (2.9) 0.019 2.41 (1.16–5.04) 0.136 1.83 (0.83–4.03)
Data are presented as numbers (percentage, %).SpA, spondyloarthritis; bDMARDs, biological disease-modifying antirheumatic drugs; CI, confidence interval; VAS-PGA, visual analog scale-patient global assessment; COVID-19, coronavirus disease 2019.
The data on the reasons for drug discontinuation were available in 186 (75.3%) of 247 patients who discontinued their bDMARDs. Of these patients, 60 (32.2%) discontinued the therapy based on the recommendation of his/her physician, 84 (45.1%) discontinued on their own demand/fear, 13 (6.9%) discontinued due to suspected COVID-19, 8 (4.3%) discontinued due to the lack of disease activity, and 21 (11.3%) discontinued due to other reasons. No difference was determined between RA and SpA patients in terms of reasons for discontinuation of bDMARDs. During the pandemic, 550 patients (213 RA patients and 337 SpA patients) were able to communicate with their physicians. The patients communicated with their physicians through phone calls (314 [57.1%] patients), face-to-face interview (203 [36.9%] patients), text message (39 [7.1%] patients), e-mail (19 [3.5%] patients), healthcare staff (assistant, nurse) (13 [2.4%] patients), and relatives (5 [0.9%] patients). In 425 (77.3%) of 550 patients, their physicians recommended them to continue bDMARD therapy. In 37 (6.7%) of 550 patients, their physicians recommended them to receive bDMARDs on demand and/or to extent drug application intervals.
3.4. Disease activity during the pandemic
Evaluation of the disease activity during the pandemic in all patients revealed that the disease was completely under control in 46.8% of the patients (in 40.8% of the RA patients and in 50.0% of the SpA patients), whereas 19.1% of the patients (21.7% of the RA patients and 17.7% of the SpA patients) had mild disease activity, 24.7% of the patients (27.9% of the RA patients and 23.1% of the SpA patients) had moderate disease activity, 7.0% of the patients (6.8% of the RA patients and 7.1% of the SpA patients) had active disease, and 2.4% of the patients (2.9% of the RA patients and 2.1% of the SpA patients) had very high disease activity (p = 0.016). The mean general health status-VAS score in all patients during the pandemic was 3.1 ± 2.5; it was 3.4 ± 2.6 in the RA patients and 2.9 ± 2.5 in the SpA patients (p < 0.001). The mean general health status-VAS score in all patients in the prepandemic period was 3.2 ± 2.5; it was 3.6 ± 2.6 in the RA patients and 3 ± 2.4 in the SpA patients (p < 0.001).
As compared with the period before the pandemic, the ratios of patients with worsened disease activity, those with improved disease activity, those in whom the disease has become active (while in remission), those with ongoing remission, those with ongoing active disease, and those showing remission (while having active disease) in the first 100 days of the pandemic are demonstrated in Table 5. In the RA patients, these variables did not show difference between the patients who discontinued and those who did not discontinue their bDMARDs. In the SpA patients, the ratio of those who remained in remission before and during the pandemic was 32.1%. The rate of drug discontinuation was lower in the SpA patients who remained in remission (22.0% in those who discontinued bDMARDs and 34.8% in those who did not discontinue bDMARDs; p = 0.002); other parameters showed no difference between the patients who discontinued and those who did not discontinue bDMARDs.
Table 5 As assessed according to the prepandemic period, changes in disease activity determined by the general health status-Visual Analog Scale scores during the pandemic.
Status Definition Patients with RAn = 428 Patients with SpAn = 809
Worsened disease activity during the pandemic >2 units increase in the VAS score after the pandemic as compared with before the pandemic 100 (23.4) 137 (16.9)
Patients with improved disease activity during the pandemic <2 units decrease in the VAS score after the pandemic as compared with before the pandemic 89 (20.8) 118 (14.6)
While in remission before the pandemic, becoming active during the pandemic A VAS score of ≤2 before pandemic and ≥4 after the pandemic, 69 (16.1) 100 (12.4)
Remission both before and during the pandemic A VAS score of ≤2 before the pandemic and ≤2 after the pandemic 91 (21.3) 260 (32.1)
Active disease both before and during the pandemic A VAS score of ≥4 before the pandemic and ≥4 after the pandemic 121 (28.3) 175 (21.6)
Active disease before the pandemic, remission during the pandemic A VAS score of ≥4 before the pandemic and ≤2 after the pandemic 52 (12.1) 86 (10.6)
Data are presented as numbers (percentage, %).RA, rheumatoid arthritis; SpA, spondyloarthritis; VAS, visual analog scale; bDMARDs, biological disease-modifying antirheumatic drugs; NA, not applicable.
4. Discussion
The COVID 19 pandemic, which was announced in March 2020 by the WHO, has directly influenced the daily life of both healthy individuals and individuals with chronic illnesses1. Immunosuppressed patients rank first among the patient groups influenced by the pandemic most. Biological DMARDs, which have been used in the last two decades, have been the group of medications primarily focused on due to their potential to increase the risk of infection. The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), which are among the international expert societies on rheumatology, have recommended identification of the risk groups and continuation of bDMARDs as long as possible within the frame of patient–physician communication [4,5]. However, the pandemic has caused severe anxiety and fear in some patients. Uncertainty and fear were more prominent particularly in the early period of the pandemic.
The present study investigated the therapeutic approaches in the first 100 days after the declaration of the pandemic in inflammatory arthritis patients known to receive bDMARD therapy. It was observed that the rate of confirmed COVID-19 cases (0.15%) was extremely low in the first 100 days and that nearly 3% of the patients needed to be evaluated for suspected COVID-19. The first 100 days of the pandemic in Turkey was when a strict lockdown was implemented particularly for the people over the age of 65 and under the age of 18. In that period, people with chronic illnesses in particular were on administrative leave, and many patients self-quarantined themselves. It is likely that such a low rate of COVID-19 determined among the patients with inflammatory rheumatic diseases is associated with the abovementioned strict lockdown. After that period, people began to return to their normal life; therefore, how many of the patients evaluated in the present study will develop COVID-19 infection during their follow-up is an investigation that needs to be performed in the future.
Recent studies supported that patients who take biological and conventional DMARDs have less morbidity in the case of COVID-19 [2]. Moreover, in another study from Turkey consisting of 167 patients with inflammatory rheumatic disease, biologic and conventional DMARDs did not seem to cause worse outcomes [12]. However, overall, 18% of all the inflammatory arthritis patients discontinued bDMARDs in the first 100 days of the pandemic. It was observed that drug discontinuation was more common, particularly in the SpA patients, than in the RA patients. Etanercept was the least frequently discontinued bDMARD in the RA patients. It was understood that etanercept has been used for longer than 20 years and thus considered a relatively reliable therapeutic option for both patients and physicians. The main reason for drug discontinuation was the patients’ fear of bDMARD therapy; on the other hand, drug discontinuation was recommended by the physicians in one-third of the patients. In Italy, a survey was conducted between February 2020 and April 2020 in 955 rheumatic patients [13]. In that patient group receiving advanced treatment, modification of biological therapy was performed in nearly 6% of the patients, which is quite low as compared with the finding of the present survey study. Accordingly, different cultural factors can be considered determinative. In the present study, among the patients who were able to communicate with their physicians, about 7% were recommended to receive treatment on demand or could extent drug application intervals. Receiving bDMARD therapy on demand or extending drug application intervals is a method implemented by clinicians for a long time in daily practice with efficacy and safety proven in the controlled studies. During the pandemic, the physicians preferred this method in some of their patients. On the other hand, there is a patient group trying to reach their physicians but could not reach them. It was understood that a change occurred in the physician–patient communication during the pandemic. Specific to rheumatology, patients’ methods of reaching their physicians should be dwelled on, and further studies are needed on this subject.
Any factor that might explain bDMARD discontinuation in the RA patients could not be determined. On the other hand, it was observed that the SpA patients with the disease under control were more likely to continue their drugs. This finding is likely to indicate that the SpA patients with the disease under control were more adherent to their medications, and they avoided recurrent exacerbations. Fluctuations in disease activity were observed in the first 100 days of the pandemic as assessed according to the prepandemic period. The rate of remaining in remission during the pandemic for the patients in remission before the pandemic was 21% in the RA group and 32% in the SpA group. It was understood that the patients with high disease activity in the prepandemic period experienced more difficulty in the early period of the pandemic.
The present survey study was conducted through phone interviews. We could reach three-fourth of the patients; the rates of drug discontinuation and COVID-19 might be higher among those that could not be reached; thus, the results need to be evaluated within the scope of this limitation. The fact that the information regarding steroid use was not inquired could be considered another limitation.
In conclusion, nearly one-fifth of the RA and SpA patients recorded in the TReasure registry and known to receive bDMARD therapy in the prepandemic period discontinued their drugs in the first 100 days of the pandemic. The frequency of COVID-19 was found to be low in the first 100 days of the pandemic, which corresponds to a period when a strict lockdown was implemented in Turkey. Further investigations need to be performed to find out what will happen when people return to their normal active life. Although patients’ fear of treatment appeared to be the main factor, the treatment was discontinued or also interrupted due to physicians’ recommendations. These treatment modifications in the early period of the COVID-19 pandemic may appear as a worsened disease activity in time. Treatment approaches need to be monitored closely in the following period.
Authors’ contributions
All authors contributed equally to conceiving and designing the analysis and collecting the data. UK and EB performed the analysis and wrote the paper; all authors revised and edited the final version of manuscript.
Informed consent
Our study is compliant with the Helsinki Declaration and was approved by both the local ethical committee (Hacettepe University; Approval number: 2020/08-25 (KA-17058)) and the Turkish Ministry of Health (Approval number: 66175679-514.05.01-E.170548).
Acknowledgments
UK received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. YP received honorary from Abbvie, Roche, Novartis, MSD, Pfizer. SA received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. TK received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. GK received honorary from Abbvie, Amgen, Novartis, Pfizer, UCB. OK received honorary from Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. ED received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. IE received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. LK received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. DE received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, UCB. CB received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. HE received honorary from Novartis, Roche. RM received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. NK received honorary from Novartis, UCB. MC received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. SSK received honorary from Abbvie, MSD, Novartis, Pfizer, Roche, UCB. OK received honorary from Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. SK received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. Other authors declare no conflict of interest.
This study was funded by Hacettepe Rheumatology Society.
World Health Organization (2020). The director-general’s opening remarks at the media briefing on COVID-19 [online]. Website https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. [accessed 27 September 2020]). | ADALIMUMAB | DrugsGivenReaction | CC BY | 33611869 | 20,063,722 | 2021-08-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rheumatoid arthritis'. | Preferences of inflammatory arthritis patients for biological disease-modifying antirheumatic drugs in the first 100 days of the COVID-19 pandemic
To evaluate treatment adherence and predictors of drug discontinuation among patients with inflammatory arthritis
receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.
A total of 1871 patients recorded in TReasure registry for whom advanced therapy was prescribed for rheumatoid arthritis (RA) or spondyloarthritis (SpA) within the 3 months (6–9 months for rituximab) before the declaration of COVID-19 pandemic were evaluated, and 1394 (74.5%) responded to the phone survey. Patients’ data regarding demographic, clinical characteristics and disease activity before the pandemic were recorded. The patients were inquired about the diagnosis of COVID-19, the rate of continuation on bDMARDs, the reasons for treatment discontinuation, if any, and the current general disease activity (visual analog scale, [VAS]).
A total of 1394 patients (493 RA [47.3% on anti-TNF] patients and 901 SpA [90.0% on anti-TNF] patients) were included in the study. Overall, 2.8% of the patients had symptoms suggesting COVID-19, and 2 (0.15%) patients had PCR-confirmed COVID-19. Overall, 18.1% of all patients (13.8% of the RA and 20.5% of the SpA; p = 0.003) discontinued their bDMARDs. In the SpA group, the patients who discontinued bDMARDs were younger (40 [21–73] vs. 44 years [20–79]; p = 0.005) and had higher general disease activity; however, no difference was relevant for RA patients.
Although the COVID-19 was quite uncommon in the first 100 days of the pandemic, nearly one-fifth of the patients discontinued bDMARDs within this period. The long-term effects of the pandemic should be monitored.
pmc1. Introduction
The recent coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Fever, dry cough, sore throat, and muscle and joint pain are general disease manifestations, and a severe clinical picture requiring hospital admission is encountered in 15%–20% of the patients [1,2]. According to the data collected from various countries, the COVID-19 fatality rate is about 1%–10% [3]. Patients with inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA) regularly and continuously receive synthetic or biological disease-modifying antirheumatic drugs (DMARDs) as the main component of their treatment. On the other hand, temporary discontinuation of particularly biological DMARDs (bDMARDs) in the presence of infection is an accepted recommendation [4]. Currently, the world is reexperiencing a pandemic after a period of nearly 100 years. After March 11, 2020, when the World Health Organization announced the pandemic, American, European, and local societies of rheumatology have claimed general recommendations about drug usage [4–6]. The Turkish Society for Rheumatology released COVID-19 recommendations on March 27, 2020, and left the decision to use synthetic/biological DMARDs during the pandemic mainly to the primary physician that follows the patient [6]. On the other hand, the behavioral pattern of patients with inflammatory arthritis using biological/synthetic DMARDs during the COVID-19 pandemic is unknown in Turkey or the rest of the world.
Accordingly, the present study aimed to evaluate treatment adherence of patients with inflammatory arthritis receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.
2. Methods
2.1. Patient selection
The TReasure registry is a web-based, prospective, observational cohort including RA and spondyloarthritis (SpA) patients from 17 centers in different regions of Turkey and was established in December 2017. Details of the establishment of TReasure registry were previously reported [7]. As of March 2020, there were a total of 7471 patients with inflammatory arthritis (2560 RA patients and 4911 SpA patients) receiving bDMARDs in this registry. The bDMARDs were as follows (arranged alphabetically): abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, secukinumab, and tocilizumab.
The present study included patients who were prescribed bDMARDs and for whom disease activity was recorded within the 3-month period before the declaration date of pandemic (March 2020) in the TReasure registry. For rituximab therapy, this period was determined to be 6–9 months before the declaration date of the pandemic. In the TReasure registry, the target population consisted of 1871 patients, of whom 1394 (74.5%) completed the standard phone questionnaire, 39 (2.1%) refused to participate in the study, and the remaining could not be reached. The patients who participated and those who did not participate in the study did not differ in demographic and clinical characteristics (data not shown).
2.2. Demographic and clinical characteristics of the patients
The demographic and clinical data collected from the patients were defined previously [7]. In brief, the following data were recorded for both RA and SpA patients: age, sex, disease duration, comorbidities (the Charlson comorbidity index), erythrocyte sedimentation rate (ESR) (mm/h), C-reactive protein (CRP) level (mg/L), number of swollen (66 joints) and tender (68 joints) joints, visual analog scale (VAS)-pain score, patients’ global assessment-VAS, and VAS-fatigue score, and the names of the currently used synthetic DMARDs or bDMARDs. Additionally, in RA patients, positivity for rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) was determined, and the scores of the disease activity score-28 (DAS-28), the Crohn’s Disease Activity Index (CDAI), the Simple Disease Activity Index (SDAI), and the Health Assessment Questionnaire (HAQ) were calculated to assess disease activity. In SpA patients, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), and the Ankylosing Spondylitis Disease Activity Score (ASDAS) based on CRP (ASDAS-CRP) were used for the assessment of disease activity. The diagnoses in SpA patients were classified as ankylosing spondylitis (according to the modified New York criteria), nonradiographic SpA (according to the axial SpA criteria), peripheral SpA (according to the peripheral SpA criteria), psoriatic arthritis (according to the CASPAR criteria), and enteropathic arthritis (based on the presence of inflammatory bowel disease [IBD] and arthritis/sacroiliitis) [8–11]. In SpA patients, the positivity of HLA-B27 and the presence of psoriasis, IBD, uveitis, dactylitis, and enthesitis (according to the Leeds enthesitis index [LEI]) were also recorded.
2.3. Questionnaire inquiring the pandemic period
A standard questionnaire was applied to the patients via phone call. The phone calls were made in June 2020. Accordingly, the following information questioned for the period between March 10, 2020, and the day of phone call: the presence of any signs of coronavirus infection; whether or not being diagnosed with COVID-19; if diagnosed with COVID-19, the place (hospital, home) where the patient was followed up; whether or not being quarantined due to COVID-19 infection; whether or not having biological or synthetic DMARDs on hand; whether or not the medications were administered during this time; if not administered, the reason(s); whether or not being contacted with his/her physician; and the current disease activity. For the assessment of the current general health status and disease activity, the patients were asked about their general health status (global patient assessment) and to rate it from 0 (excellent) to 10 (very bad), and about current disease activity, the patients were asked to rate their disease activity as “completely under control”, “mild”, “moderate”, “active”, and “highly active”.
2.4. Assessments in the study
In the present study, for the patients who discontinued their bDMARDs, comparisons were performed for the following parameters: age (also categorized in decades), sex, mean disease duration (categorized as 1, 5, and 10 years), seropositivity, sequence of use of bDMARDs (bDMARD-naïve, second-line, third-line), and usage of anti-TNF versus nonanti-TNF bDMARDs. The disease activity scores within the 3 months before the declaration of the pandemic was also recorded; these included mean DAS-28 score, CDAI, and SDAI scores (patients were dichotomized as those with and without low disease activity according to the DAS-28, SDAI, and CDAI scores), mean HAQ score (patients were dichotomized according to the scores of 0.5 and 1), mean BASDAI, BASFI, and ASDAS-CRP scores (patients were grouped according to ASDAS-CRP score), CRP level (<5 mg/L and >5 mg/L), patients’ global assessments-VAS score (grouping with 10-unit intervals), general health status (completely under control, mild, moderate, severe, highly severe), and presence of suspected COVID-19. Patients’ global assessment-VAS scores before the pandemic were compared with those during the pandemic. Accordingly, an increase by >2 units in the score was defined as worsened disease activity, and a decrease by <2 units in the score was defined as improved disease activity. Remission was defined as a general health status-VAS score of ≤2, whereas active disease was defined as a VAS score of ≥4.
Our study is compliant with the Helsinki Declaration and approved by both the local ethical committee (Hacettepe University; Approval number: 2020/08-25 (KA-17058)) and the Turkish Ministry of Health (Approval number: 66175679-514.05.01-E.170548).
2.5. Patient and public involvement
There is no patient or public involvement in this study.
2.6. Statistical analysis
Data analyses were performed using the Predictive Analytics SoftWare (PASW) 18.0 (SPSS Inc., Chicago, IL, USA) for Windows. The variables were investigated using visual (histogram, probability plots) and analytic methods (Kolmogorov–Smirnov, skewness, and kurtosis) to determine whether they are normally distributed or not. The descriptive analysis data were expressed as mean, standard deviation (SD), the median (minimum-maximum), or percentages for categorical variables. Chi-square test or Fisher’s exact test was used for categorical variables. Student’s t-test was used to compare normally distributed variables, while the Mann–Whitney U test was used to compare nonnormally distributed variables. The variables identified with univariate analyses (p < 0.20) were further entered the logistic regression analysis to determine independent predictors of drug discontinuation separately for RA and SpA patients. A p-value of <0.05 was considered statistically significant.
3. Results
3.1. Demographic and clinical characteristics of the patients
The demographic and clinical data and drug preferences of 1394 patients who participated in the study are presented in Table 1. In the RA group, RF was positive in 267 (62.7%) patients, anti-CCP was positive in 206 (56.4%) patients, and RF and/or anti-CCP were positive in 368 (74.5%) patients. In the SpA group, there were 664 (73.7%) patients with ankylosing spondylitis, 57 (6.3%) patients with nonradiographic SpA, 101 (11.2%) patients with peripheral SpA, 111 (12.3%) patients with psoriatic arthritis, and 21 (2.3%) patients with enteropathic arthritis. Extraarticular signs of the SpA patients were uveitis in 110 (12.5%) patients, IBD in 40 (4.6%) patients, and psoriasis in 141 (16.1%) patients. The HLA-B27 positivity was determined in 333 (59.1%) of 563 patients. Thirty-seven (4.8%) patients had dactylitis, and 120 (19.3%) patients had enthesitis (at least one entheseal region according to the LEI). Of the RA patients, 233 (47.3%) were receiving antitumor necrosis factor (TNF) agents, and 260 (52.7%) were receiving nonanti-TNF bDMARDs. On the other hand, of the SpA patients, 811 (90%) were receiving anti-TNF agents, and 90 (10%) were receiving antiinterleukin (IL)-17 treatment.
Table 1 Demographic and clinical characteristics of the patients.
Patients with RAn = 493 Patients with SpAn = 901
Female sex, n (%) 400 (81.1) 398 (44.2)
Age, years, median (range) 55 (18–86) 43 (20–79)
Disease duration, months, median (range) 131 (2–509) 111 (2–672)
ESR, mm/h, median (range) 16 (1–120) 12 (1–103)
CRP, mg/L, median (range) 3.96 (0.1–98.9) 3.84 (0.1–91.1)
Global assessment of health–VAS score, median (range) 30 (0–100) 25 (0–100)
Pain–VAS score, median (range) 30 (0–100) 20 (0–100)
Fatigue–VAS score, median (range) 30 (0–100) 20 (0–100)
HAQ score, median (range) 0.38 (0–90) –
Number of swollen joints, mean ± SD 0.58 ± 2.21 0.1 ± 0.71
Number of tender joints, mean ± SD 1.31 ± 3.41 0.29 ± 1.6
DAS-28-ESR score, median (range) 2.55 (0.56–8.16) –
CDAI score, mean ± SD 7.97 ± 8.92 –
SDAI score, mean ± SD 17.83 ± 20.08 –
BASDAI score, n (%) – 1.55 (0–9.5)
BASFI score, n (%) – 1.2 (0–9.7)
Hypertension, n (%) 143 (29.7) 137 (15.4)
Obesity, n (%) 166 (35.3) 220 (24.4)
Diabetes mellitus, n (%) 48 (9.9) 57 (6.4)
Hyperlipidemia, n (%) 71 (15.1) 98 (11.2)
Coronary artery disease, n (%) 20 (4.3) 17 (1.9)
COPD, n (%) 11 (2.4) 3 (0.3)
Asthma, n (%) 26 (5.6) 28 (3.3)
Malignancy, n (%) 5 (1) 8 (0.9)
Presence of at least1 comorbidity, n (%) 186 (38.2) 462 (51.6)
Presence of ≥2 comorbidities, n (%) 121 (24.8) 229 (25.6)
Presence of ≥3 comorbidities, n (%) 167 (34.3) 160 (17.9)
ASDAS–CRP, median (range) – 1.84 (0–5.2)
Abatacept, n (%) 32 (6.5) –
Adalimumab, n (%) 89 (18.1) 270 (30)
Certolizumab, n (%) 38 (7.7) 146 (16.2)
Etanercept, n (%) 75 (15.2) 182 (20.2)
Golimumab, n (%) 18 (3.7) 90 (10)
Infliximab, n (%) 13 (2.6) 123 (13.7)
Rituximab, n (%) 40 (8.1) –
Secukinumab, n (%) – 90 (10)
Tofacitinib, n (%) 77 (15.6) –
Tocilizumab, n (%) 111 (22.5) –
Hydroxychloroquine, n (%) 164 (33.3) 13 (1.4)
Leflunomide, n (%) 117 (23.7) 17 (1.9)
Methotrexate , n (%) 135 (27.4) 57 (6.3)
Sulfasalazine, n (%) 23 (4.7) 71 (7.9)
RA, rheumatoid arthritis; SpA, spondyloarthritis; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein, VAS, Visual Analog Scale; HAQ, Health Assessment Questionnaire; DAS-28, the Disease Activity Score-28; CDAI, the Crohn’s Disease Activity Index; SDAI, the Simple Disease Activity Index; BASDAI, the Bath Ankylosing Spondylitis Disease Activity Index; BASFI, the Bath Ankylosing Spondylitis Functional Index; COPD, chronic obstructive pulmonary disease; ASDAS, Ankylosing Spondylitis Disease Activity Score; SD, standard deviation.
3.2. Detecting COVID-19 in the inflammatory arthritis patients receiving bDMARDs
A total of 1353 patients were questioned about COVID-19 status. Of all the patients, 39 (2.8%) had at least one suspicious sign of COVID-19, and 26 (1.9%) visited a healthcare center for this reason (Table 2). Fever (body temperature ≥ 38°C) was the suspicious sign in 14 (1.0%) patients. The PCR test was positive for COVID-19 only in 2 (0.15%) of all patients. Both of these patients were treated at home.
Table 2 Results of the questions about COVID-19 status in the study patients during the pandemic.
All patients n = 1353 RA n = 487 SpA n = 866
Presence of any suspected sign of COVID-19 39 (2.8) 6 (1.2) 33 (3.7)
Admission to a healthcare center for suspected COVID-19 26 (1.9) 5 (1.0) 22 (2.5)
Having PCR testing for COVID-19 21 (1.6) 5 (1.0) 16 (1.8)
Quarantine recommendation for suspected COVID-19 10 (0.73) 0 (0) 10 (1.15)
PCR positivity for COVID-19 2 (0.15) 0 (0) 2 (0.23)
Family history of COVID-19 positivity 9 (0.66) 3 (0.6) 6 (0.7)
3.3. Use of biological DMARDs during the pandemic
A total of 1362 patients responded to the question about the continuation of bDMARDs during the pandemic. Overall, 247 (18.1%) patients discontinued their bDMARDs. Sixty-six (13.8%) of the RA patients and 181 (20.5%) of the SpA patients discontinued their bDMARDs (p = 0.003). The distribution of the patients who discontinued/did not receive their bDMARDs is demonstrated in Table 3. Among RA patients, etanercept (%5.4) was the least frequently discontinued bDMARD, whereas tocilizumab (%20.5) was the most frequently discontinued bDMARD. The clinical characteristics and disease activity parameters did not differ between the RA patients who discontinued and those who did not discontinue their bDMARDs. In the SpA patient group, those who discontinued their bDMARDs were younger than those who did not (median age, 40 years [range, 21–73 years] vs. median age, 44 years [range, 20–79 years]; p = 0.005). Moreover, the SpA patients who continued their bDMARDs had lower disease activity. The multivariate analysis revealed that age of <40 years, a poorer general health status, a poorer VAS score, and the suspicion for the presence of COVID-19 were the factors that determine the discontinuation of bDMARD therapy in SpA patients (Table 4).
Table 3 Distribution of the patients who discontinued their biological disease-modifying antirheumatic drugs.
Patients with RA n/N (%) Patients with SpA n/N (%)
All bDMARDs 66 (14.0) 181 (20.5)
Abatacept 4/31 (12.9) NA
Adalimumab 15/86 (17.4) 46/264 (17.4)
Etanercept 4/74 (5.4) 38/180 (21.1)
Golimumab 3/18 (16.7) 15/86 (15.6)
Infliximab 2/12 (16.7) 29/118 (24.5)
Certolizumab 3/37 (8.1) 31/146 (21.2)
Rituximab 7/39 (17.9) NA
Tofacitinib 6/75 (8.0) NA
Tocilizumab 22/107 (20.5) NA
Secukinumab NA 22/89 (24.7)
Hydroxychloroquine 19/157 (12.1) 5/181 (2.8)
Leflunomide 14/113 (12.4) 4/181 (2.2)
Methotrexate 14/134 (10.4) 13/181 (7.2)
Sulfasalazine 2/22 (9.1) 13/181 (7.2)
RA, rheumatoid arthritis; SpA, spondyloarthritis; bDMARDs, biological disease-modifying antirheumatic drugs; NA, not applicable.
Table 4 Characteristics of the patients with spondyloarthritis who discontinued their biological disease-modifying antirheumatic drugs
Patients with SpA who discontinued bDMARDs Patients with SpA who continued bDMARDs Univariatep Odds Ratio95% CI Multivariatep Odds ratio95% CI
Age (<40 vs. ≥40) 84 (46.4) 243 (34.6) 0.004 1.64 (1.18–2.28) 0.002 1.76 (1.24–2.51)
General health status
Completely under control 51 (28.2) 390 (55.8) Reference
Mild 52 (28.7) 103 (14.7) <0.001 3.86 (2.48–6.01) <0.001 3.20 (1.99–5.15)
Moderate 51 (28.2) 153 (21.9) <0.001 2.55 (1.66–3.92) 0.003 2.03 (1.26–3.27)
Severe 21 (11.6) 41 (5.9) <0.001 3.92 (2.15–7.15) 0.003 2.65 (1.38–5.10)
Extremely severe 6 (3.3) 12 (1.7) 0.010 3.82 (1.38–10.63) 0.103 2.46 (0.83–7.28)
VAS-PGA, <20 vs. ≥20 38 (21.1) 281 (40.2) <0.001 2.51 (1.70–3.71) 0.016 1.74 (1.11–2.75)
Suspected COVID-19 12 (6.6) 20 (2.9) 0.019 2.41 (1.16–5.04) 0.136 1.83 (0.83–4.03)
Data are presented as numbers (percentage, %).SpA, spondyloarthritis; bDMARDs, biological disease-modifying antirheumatic drugs; CI, confidence interval; VAS-PGA, visual analog scale-patient global assessment; COVID-19, coronavirus disease 2019.
The data on the reasons for drug discontinuation were available in 186 (75.3%) of 247 patients who discontinued their bDMARDs. Of these patients, 60 (32.2%) discontinued the therapy based on the recommendation of his/her physician, 84 (45.1%) discontinued on their own demand/fear, 13 (6.9%) discontinued due to suspected COVID-19, 8 (4.3%) discontinued due to the lack of disease activity, and 21 (11.3%) discontinued due to other reasons. No difference was determined between RA and SpA patients in terms of reasons for discontinuation of bDMARDs. During the pandemic, 550 patients (213 RA patients and 337 SpA patients) were able to communicate with their physicians. The patients communicated with their physicians through phone calls (314 [57.1%] patients), face-to-face interview (203 [36.9%] patients), text message (39 [7.1%] patients), e-mail (19 [3.5%] patients), healthcare staff (assistant, nurse) (13 [2.4%] patients), and relatives (5 [0.9%] patients). In 425 (77.3%) of 550 patients, their physicians recommended them to continue bDMARD therapy. In 37 (6.7%) of 550 patients, their physicians recommended them to receive bDMARDs on demand and/or to extent drug application intervals.
3.4. Disease activity during the pandemic
Evaluation of the disease activity during the pandemic in all patients revealed that the disease was completely under control in 46.8% of the patients (in 40.8% of the RA patients and in 50.0% of the SpA patients), whereas 19.1% of the patients (21.7% of the RA patients and 17.7% of the SpA patients) had mild disease activity, 24.7% of the patients (27.9% of the RA patients and 23.1% of the SpA patients) had moderate disease activity, 7.0% of the patients (6.8% of the RA patients and 7.1% of the SpA patients) had active disease, and 2.4% of the patients (2.9% of the RA patients and 2.1% of the SpA patients) had very high disease activity (p = 0.016). The mean general health status-VAS score in all patients during the pandemic was 3.1 ± 2.5; it was 3.4 ± 2.6 in the RA patients and 2.9 ± 2.5 in the SpA patients (p < 0.001). The mean general health status-VAS score in all patients in the prepandemic period was 3.2 ± 2.5; it was 3.6 ± 2.6 in the RA patients and 3 ± 2.4 in the SpA patients (p < 0.001).
As compared with the period before the pandemic, the ratios of patients with worsened disease activity, those with improved disease activity, those in whom the disease has become active (while in remission), those with ongoing remission, those with ongoing active disease, and those showing remission (while having active disease) in the first 100 days of the pandemic are demonstrated in Table 5. In the RA patients, these variables did not show difference between the patients who discontinued and those who did not discontinue their bDMARDs. In the SpA patients, the ratio of those who remained in remission before and during the pandemic was 32.1%. The rate of drug discontinuation was lower in the SpA patients who remained in remission (22.0% in those who discontinued bDMARDs and 34.8% in those who did not discontinue bDMARDs; p = 0.002); other parameters showed no difference between the patients who discontinued and those who did not discontinue bDMARDs.
Table 5 As assessed according to the prepandemic period, changes in disease activity determined by the general health status-Visual Analog Scale scores during the pandemic.
Status Definition Patients with RAn = 428 Patients with SpAn = 809
Worsened disease activity during the pandemic >2 units increase in the VAS score after the pandemic as compared with before the pandemic 100 (23.4) 137 (16.9)
Patients with improved disease activity during the pandemic <2 units decrease in the VAS score after the pandemic as compared with before the pandemic 89 (20.8) 118 (14.6)
While in remission before the pandemic, becoming active during the pandemic A VAS score of ≤2 before pandemic and ≥4 after the pandemic, 69 (16.1) 100 (12.4)
Remission both before and during the pandemic A VAS score of ≤2 before the pandemic and ≤2 after the pandemic 91 (21.3) 260 (32.1)
Active disease both before and during the pandemic A VAS score of ≥4 before the pandemic and ≥4 after the pandemic 121 (28.3) 175 (21.6)
Active disease before the pandemic, remission during the pandemic A VAS score of ≥4 before the pandemic and ≤2 after the pandemic 52 (12.1) 86 (10.6)
Data are presented as numbers (percentage, %).RA, rheumatoid arthritis; SpA, spondyloarthritis; VAS, visual analog scale; bDMARDs, biological disease-modifying antirheumatic drugs; NA, not applicable.
4. Discussion
The COVID 19 pandemic, which was announced in March 2020 by the WHO, has directly influenced the daily life of both healthy individuals and individuals with chronic illnesses1. Immunosuppressed patients rank first among the patient groups influenced by the pandemic most. Biological DMARDs, which have been used in the last two decades, have been the group of medications primarily focused on due to their potential to increase the risk of infection. The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), which are among the international expert societies on rheumatology, have recommended identification of the risk groups and continuation of bDMARDs as long as possible within the frame of patient–physician communication [4,5]. However, the pandemic has caused severe anxiety and fear in some patients. Uncertainty and fear were more prominent particularly in the early period of the pandemic.
The present study investigated the therapeutic approaches in the first 100 days after the declaration of the pandemic in inflammatory arthritis patients known to receive bDMARD therapy. It was observed that the rate of confirmed COVID-19 cases (0.15%) was extremely low in the first 100 days and that nearly 3% of the patients needed to be evaluated for suspected COVID-19. The first 100 days of the pandemic in Turkey was when a strict lockdown was implemented particularly for the people over the age of 65 and under the age of 18. In that period, people with chronic illnesses in particular were on administrative leave, and many patients self-quarantined themselves. It is likely that such a low rate of COVID-19 determined among the patients with inflammatory rheumatic diseases is associated with the abovementioned strict lockdown. After that period, people began to return to their normal life; therefore, how many of the patients evaluated in the present study will develop COVID-19 infection during their follow-up is an investigation that needs to be performed in the future.
Recent studies supported that patients who take biological and conventional DMARDs have less morbidity in the case of COVID-19 [2]. Moreover, in another study from Turkey consisting of 167 patients with inflammatory rheumatic disease, biologic and conventional DMARDs did not seem to cause worse outcomes [12]. However, overall, 18% of all the inflammatory arthritis patients discontinued bDMARDs in the first 100 days of the pandemic. It was observed that drug discontinuation was more common, particularly in the SpA patients, than in the RA patients. Etanercept was the least frequently discontinued bDMARD in the RA patients. It was understood that etanercept has been used for longer than 20 years and thus considered a relatively reliable therapeutic option for both patients and physicians. The main reason for drug discontinuation was the patients’ fear of bDMARD therapy; on the other hand, drug discontinuation was recommended by the physicians in one-third of the patients. In Italy, a survey was conducted between February 2020 and April 2020 in 955 rheumatic patients [13]. In that patient group receiving advanced treatment, modification of biological therapy was performed in nearly 6% of the patients, which is quite low as compared with the finding of the present survey study. Accordingly, different cultural factors can be considered determinative. In the present study, among the patients who were able to communicate with their physicians, about 7% were recommended to receive treatment on demand or could extent drug application intervals. Receiving bDMARD therapy on demand or extending drug application intervals is a method implemented by clinicians for a long time in daily practice with efficacy and safety proven in the controlled studies. During the pandemic, the physicians preferred this method in some of their patients. On the other hand, there is a patient group trying to reach their physicians but could not reach them. It was understood that a change occurred in the physician–patient communication during the pandemic. Specific to rheumatology, patients’ methods of reaching their physicians should be dwelled on, and further studies are needed on this subject.
Any factor that might explain bDMARD discontinuation in the RA patients could not be determined. On the other hand, it was observed that the SpA patients with the disease under control were more likely to continue their drugs. This finding is likely to indicate that the SpA patients with the disease under control were more adherent to their medications, and they avoided recurrent exacerbations. Fluctuations in disease activity were observed in the first 100 days of the pandemic as assessed according to the prepandemic period. The rate of remaining in remission during the pandemic for the patients in remission before the pandemic was 21% in the RA group and 32% in the SpA group. It was understood that the patients with high disease activity in the prepandemic period experienced more difficulty in the early period of the pandemic.
The present survey study was conducted through phone interviews. We could reach three-fourth of the patients; the rates of drug discontinuation and COVID-19 might be higher among those that could not be reached; thus, the results need to be evaluated within the scope of this limitation. The fact that the information regarding steroid use was not inquired could be considered another limitation.
In conclusion, nearly one-fifth of the RA and SpA patients recorded in the TReasure registry and known to receive bDMARD therapy in the prepandemic period discontinued their drugs in the first 100 days of the pandemic. The frequency of COVID-19 was found to be low in the first 100 days of the pandemic, which corresponds to a period when a strict lockdown was implemented in Turkey. Further investigations need to be performed to find out what will happen when people return to their normal active life. Although patients’ fear of treatment appeared to be the main factor, the treatment was discontinued or also interrupted due to physicians’ recommendations. These treatment modifications in the early period of the COVID-19 pandemic may appear as a worsened disease activity in time. Treatment approaches need to be monitored closely in the following period.
Authors’ contributions
All authors contributed equally to conceiving and designing the analysis and collecting the data. UK and EB performed the analysis and wrote the paper; all authors revised and edited the final version of manuscript.
Informed consent
Our study is compliant with the Helsinki Declaration and was approved by both the local ethical committee (Hacettepe University; Approval number: 2020/08-25 (KA-17058)) and the Turkish Ministry of Health (Approval number: 66175679-514.05.01-E.170548).
Acknowledgments
UK received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. YP received honorary from Abbvie, Roche, Novartis, MSD, Pfizer. SA received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. TK received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. GK received honorary from Abbvie, Amgen, Novartis, Pfizer, UCB. OK received honorary from Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. ED received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. IE received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. LK received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. DE received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, UCB. CB received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. HE received honorary from Novartis, Roche. RM received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. NK received honorary from Novartis, UCB. MC received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. SSK received honorary from Abbvie, MSD, Novartis, Pfizer, Roche, UCB. OK received honorary from Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. SK received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. Other authors declare no conflict of interest.
This study was funded by Hacettepe Rheumatology Society.
World Health Organization (2020). The director-general’s opening remarks at the media briefing on COVID-19 [online]. Website https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. [accessed 27 September 2020]). | ADALIMUMAB | DrugsGivenReaction | CC BY | 33611869 | 20,063,722 | 2021-08-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Unevaluable event'. | Preferences of inflammatory arthritis patients for biological disease-modifying antirheumatic drugs in the first 100 days of the COVID-19 pandemic
To evaluate treatment adherence and predictors of drug discontinuation among patients with inflammatory arthritis
receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.
A total of 1871 patients recorded in TReasure registry for whom advanced therapy was prescribed for rheumatoid arthritis (RA) or spondyloarthritis (SpA) within the 3 months (6–9 months for rituximab) before the declaration of COVID-19 pandemic were evaluated, and 1394 (74.5%) responded to the phone survey. Patients’ data regarding demographic, clinical characteristics and disease activity before the pandemic were recorded. The patients were inquired about the diagnosis of COVID-19, the rate of continuation on bDMARDs, the reasons for treatment discontinuation, if any, and the current general disease activity (visual analog scale, [VAS]).
A total of 1394 patients (493 RA [47.3% on anti-TNF] patients and 901 SpA [90.0% on anti-TNF] patients) were included in the study. Overall, 2.8% of the patients had symptoms suggesting COVID-19, and 2 (0.15%) patients had PCR-confirmed COVID-19. Overall, 18.1% of all patients (13.8% of the RA and 20.5% of the SpA; p = 0.003) discontinued their bDMARDs. In the SpA group, the patients who discontinued bDMARDs were younger (40 [21–73] vs. 44 years [20–79]; p = 0.005) and had higher general disease activity; however, no difference was relevant for RA patients.
Although the COVID-19 was quite uncommon in the first 100 days of the pandemic, nearly one-fifth of the patients discontinued bDMARDs within this period. The long-term effects of the pandemic should be monitored.
pmc1. Introduction
The recent coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Fever, dry cough, sore throat, and muscle and joint pain are general disease manifestations, and a severe clinical picture requiring hospital admission is encountered in 15%–20% of the patients [1,2]. According to the data collected from various countries, the COVID-19 fatality rate is about 1%–10% [3]. Patients with inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA) regularly and continuously receive synthetic or biological disease-modifying antirheumatic drugs (DMARDs) as the main component of their treatment. On the other hand, temporary discontinuation of particularly biological DMARDs (bDMARDs) in the presence of infection is an accepted recommendation [4]. Currently, the world is reexperiencing a pandemic after a period of nearly 100 years. After March 11, 2020, when the World Health Organization announced the pandemic, American, European, and local societies of rheumatology have claimed general recommendations about drug usage [4–6]. The Turkish Society for Rheumatology released COVID-19 recommendations on March 27, 2020, and left the decision to use synthetic/biological DMARDs during the pandemic mainly to the primary physician that follows the patient [6]. On the other hand, the behavioral pattern of patients with inflammatory arthritis using biological/synthetic DMARDs during the COVID-19 pandemic is unknown in Turkey or the rest of the world.
Accordingly, the present study aimed to evaluate treatment adherence of patients with inflammatory arthritis receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic.
2. Methods
2.1. Patient selection
The TReasure registry is a web-based, prospective, observational cohort including RA and spondyloarthritis (SpA) patients from 17 centers in different regions of Turkey and was established in December 2017. Details of the establishment of TReasure registry were previously reported [7]. As of March 2020, there were a total of 7471 patients with inflammatory arthritis (2560 RA patients and 4911 SpA patients) receiving bDMARDs in this registry. The bDMARDs were as follows (arranged alphabetically): abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, secukinumab, and tocilizumab.
The present study included patients who were prescribed bDMARDs and for whom disease activity was recorded within the 3-month period before the declaration date of pandemic (March 2020) in the TReasure registry. For rituximab therapy, this period was determined to be 6–9 months before the declaration date of the pandemic. In the TReasure registry, the target population consisted of 1871 patients, of whom 1394 (74.5%) completed the standard phone questionnaire, 39 (2.1%) refused to participate in the study, and the remaining could not be reached. The patients who participated and those who did not participate in the study did not differ in demographic and clinical characteristics (data not shown).
2.2. Demographic and clinical characteristics of the patients
The demographic and clinical data collected from the patients were defined previously [7]. In brief, the following data were recorded for both RA and SpA patients: age, sex, disease duration, comorbidities (the Charlson comorbidity index), erythrocyte sedimentation rate (ESR) (mm/h), C-reactive protein (CRP) level (mg/L), number of swollen (66 joints) and tender (68 joints) joints, visual analog scale (VAS)-pain score, patients’ global assessment-VAS, and VAS-fatigue score, and the names of the currently used synthetic DMARDs or bDMARDs. Additionally, in RA patients, positivity for rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) was determined, and the scores of the disease activity score-28 (DAS-28), the Crohn’s Disease Activity Index (CDAI), the Simple Disease Activity Index (SDAI), and the Health Assessment Questionnaire (HAQ) were calculated to assess disease activity. In SpA patients, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), and the Ankylosing Spondylitis Disease Activity Score (ASDAS) based on CRP (ASDAS-CRP) were used for the assessment of disease activity. The diagnoses in SpA patients were classified as ankylosing spondylitis (according to the modified New York criteria), nonradiographic SpA (according to the axial SpA criteria), peripheral SpA (according to the peripheral SpA criteria), psoriatic arthritis (according to the CASPAR criteria), and enteropathic arthritis (based on the presence of inflammatory bowel disease [IBD] and arthritis/sacroiliitis) [8–11]. In SpA patients, the positivity of HLA-B27 and the presence of psoriasis, IBD, uveitis, dactylitis, and enthesitis (according to the Leeds enthesitis index [LEI]) were also recorded.
2.3. Questionnaire inquiring the pandemic period
A standard questionnaire was applied to the patients via phone call. The phone calls were made in June 2020. Accordingly, the following information questioned for the period between March 10, 2020, and the day of phone call: the presence of any signs of coronavirus infection; whether or not being diagnosed with COVID-19; if diagnosed with COVID-19, the place (hospital, home) where the patient was followed up; whether or not being quarantined due to COVID-19 infection; whether or not having biological or synthetic DMARDs on hand; whether or not the medications were administered during this time; if not administered, the reason(s); whether or not being contacted with his/her physician; and the current disease activity. For the assessment of the current general health status and disease activity, the patients were asked about their general health status (global patient assessment) and to rate it from 0 (excellent) to 10 (very bad), and about current disease activity, the patients were asked to rate their disease activity as “completely under control”, “mild”, “moderate”, “active”, and “highly active”.
2.4. Assessments in the study
In the present study, for the patients who discontinued their bDMARDs, comparisons were performed for the following parameters: age (also categorized in decades), sex, mean disease duration (categorized as 1, 5, and 10 years), seropositivity, sequence of use of bDMARDs (bDMARD-naïve, second-line, third-line), and usage of anti-TNF versus nonanti-TNF bDMARDs. The disease activity scores within the 3 months before the declaration of the pandemic was also recorded; these included mean DAS-28 score, CDAI, and SDAI scores (patients were dichotomized as those with and without low disease activity according to the DAS-28, SDAI, and CDAI scores), mean HAQ score (patients were dichotomized according to the scores of 0.5 and 1), mean BASDAI, BASFI, and ASDAS-CRP scores (patients were grouped according to ASDAS-CRP score), CRP level (<5 mg/L and >5 mg/L), patients’ global assessments-VAS score (grouping with 10-unit intervals), general health status (completely under control, mild, moderate, severe, highly severe), and presence of suspected COVID-19. Patients’ global assessment-VAS scores before the pandemic were compared with those during the pandemic. Accordingly, an increase by >2 units in the score was defined as worsened disease activity, and a decrease by <2 units in the score was defined as improved disease activity. Remission was defined as a general health status-VAS score of ≤2, whereas active disease was defined as a VAS score of ≥4.
Our study is compliant with the Helsinki Declaration and approved by both the local ethical committee (Hacettepe University; Approval number: 2020/08-25 (KA-17058)) and the Turkish Ministry of Health (Approval number: 66175679-514.05.01-E.170548).
2.5. Patient and public involvement
There is no patient or public involvement in this study.
2.6. Statistical analysis
Data analyses were performed using the Predictive Analytics SoftWare (PASW) 18.0 (SPSS Inc., Chicago, IL, USA) for Windows. The variables were investigated using visual (histogram, probability plots) and analytic methods (Kolmogorov–Smirnov, skewness, and kurtosis) to determine whether they are normally distributed or not. The descriptive analysis data were expressed as mean, standard deviation (SD), the median (minimum-maximum), or percentages for categorical variables. Chi-square test or Fisher’s exact test was used for categorical variables. Student’s t-test was used to compare normally distributed variables, while the Mann–Whitney U test was used to compare nonnormally distributed variables. The variables identified with univariate analyses (p < 0.20) were further entered the logistic regression analysis to determine independent predictors of drug discontinuation separately for RA and SpA patients. A p-value of <0.05 was considered statistically significant.
3. Results
3.1. Demographic and clinical characteristics of the patients
The demographic and clinical data and drug preferences of 1394 patients who participated in the study are presented in Table 1. In the RA group, RF was positive in 267 (62.7%) patients, anti-CCP was positive in 206 (56.4%) patients, and RF and/or anti-CCP were positive in 368 (74.5%) patients. In the SpA group, there were 664 (73.7%) patients with ankylosing spondylitis, 57 (6.3%) patients with nonradiographic SpA, 101 (11.2%) patients with peripheral SpA, 111 (12.3%) patients with psoriatic arthritis, and 21 (2.3%) patients with enteropathic arthritis. Extraarticular signs of the SpA patients were uveitis in 110 (12.5%) patients, IBD in 40 (4.6%) patients, and psoriasis in 141 (16.1%) patients. The HLA-B27 positivity was determined in 333 (59.1%) of 563 patients. Thirty-seven (4.8%) patients had dactylitis, and 120 (19.3%) patients had enthesitis (at least one entheseal region according to the LEI). Of the RA patients, 233 (47.3%) were receiving antitumor necrosis factor (TNF) agents, and 260 (52.7%) were receiving nonanti-TNF bDMARDs. On the other hand, of the SpA patients, 811 (90%) were receiving anti-TNF agents, and 90 (10%) were receiving antiinterleukin (IL)-17 treatment.
Table 1 Demographic and clinical characteristics of the patients.
Patients with RAn = 493 Patients with SpAn = 901
Female sex, n (%) 400 (81.1) 398 (44.2)
Age, years, median (range) 55 (18–86) 43 (20–79)
Disease duration, months, median (range) 131 (2–509) 111 (2–672)
ESR, mm/h, median (range) 16 (1–120) 12 (1–103)
CRP, mg/L, median (range) 3.96 (0.1–98.9) 3.84 (0.1–91.1)
Global assessment of health–VAS score, median (range) 30 (0–100) 25 (0–100)
Pain–VAS score, median (range) 30 (0–100) 20 (0–100)
Fatigue–VAS score, median (range) 30 (0–100) 20 (0–100)
HAQ score, median (range) 0.38 (0–90) –
Number of swollen joints, mean ± SD 0.58 ± 2.21 0.1 ± 0.71
Number of tender joints, mean ± SD 1.31 ± 3.41 0.29 ± 1.6
DAS-28-ESR score, median (range) 2.55 (0.56–8.16) –
CDAI score, mean ± SD 7.97 ± 8.92 –
SDAI score, mean ± SD 17.83 ± 20.08 –
BASDAI score, n (%) – 1.55 (0–9.5)
BASFI score, n (%) – 1.2 (0–9.7)
Hypertension, n (%) 143 (29.7) 137 (15.4)
Obesity, n (%) 166 (35.3) 220 (24.4)
Diabetes mellitus, n (%) 48 (9.9) 57 (6.4)
Hyperlipidemia, n (%) 71 (15.1) 98 (11.2)
Coronary artery disease, n (%) 20 (4.3) 17 (1.9)
COPD, n (%) 11 (2.4) 3 (0.3)
Asthma, n (%) 26 (5.6) 28 (3.3)
Malignancy, n (%) 5 (1) 8 (0.9)
Presence of at least1 comorbidity, n (%) 186 (38.2) 462 (51.6)
Presence of ≥2 comorbidities, n (%) 121 (24.8) 229 (25.6)
Presence of ≥3 comorbidities, n (%) 167 (34.3) 160 (17.9)
ASDAS–CRP, median (range) – 1.84 (0–5.2)
Abatacept, n (%) 32 (6.5) –
Adalimumab, n (%) 89 (18.1) 270 (30)
Certolizumab, n (%) 38 (7.7) 146 (16.2)
Etanercept, n (%) 75 (15.2) 182 (20.2)
Golimumab, n (%) 18 (3.7) 90 (10)
Infliximab, n (%) 13 (2.6) 123 (13.7)
Rituximab, n (%) 40 (8.1) –
Secukinumab, n (%) – 90 (10)
Tofacitinib, n (%) 77 (15.6) –
Tocilizumab, n (%) 111 (22.5) –
Hydroxychloroquine, n (%) 164 (33.3) 13 (1.4)
Leflunomide, n (%) 117 (23.7) 17 (1.9)
Methotrexate , n (%) 135 (27.4) 57 (6.3)
Sulfasalazine, n (%) 23 (4.7) 71 (7.9)
RA, rheumatoid arthritis; SpA, spondyloarthritis; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein, VAS, Visual Analog Scale; HAQ, Health Assessment Questionnaire; DAS-28, the Disease Activity Score-28; CDAI, the Crohn’s Disease Activity Index; SDAI, the Simple Disease Activity Index; BASDAI, the Bath Ankylosing Spondylitis Disease Activity Index; BASFI, the Bath Ankylosing Spondylitis Functional Index; COPD, chronic obstructive pulmonary disease; ASDAS, Ankylosing Spondylitis Disease Activity Score; SD, standard deviation.
3.2. Detecting COVID-19 in the inflammatory arthritis patients receiving bDMARDs
A total of 1353 patients were questioned about COVID-19 status. Of all the patients, 39 (2.8%) had at least one suspicious sign of COVID-19, and 26 (1.9%) visited a healthcare center for this reason (Table 2). Fever (body temperature ≥ 38°C) was the suspicious sign in 14 (1.0%) patients. The PCR test was positive for COVID-19 only in 2 (0.15%) of all patients. Both of these patients were treated at home.
Table 2 Results of the questions about COVID-19 status in the study patients during the pandemic.
All patients n = 1353 RA n = 487 SpA n = 866
Presence of any suspected sign of COVID-19 39 (2.8) 6 (1.2) 33 (3.7)
Admission to a healthcare center for suspected COVID-19 26 (1.9) 5 (1.0) 22 (2.5)
Having PCR testing for COVID-19 21 (1.6) 5 (1.0) 16 (1.8)
Quarantine recommendation for suspected COVID-19 10 (0.73) 0 (0) 10 (1.15)
PCR positivity for COVID-19 2 (0.15) 0 (0) 2 (0.23)
Family history of COVID-19 positivity 9 (0.66) 3 (0.6) 6 (0.7)
3.3. Use of biological DMARDs during the pandemic
A total of 1362 patients responded to the question about the continuation of bDMARDs during the pandemic. Overall, 247 (18.1%) patients discontinued their bDMARDs. Sixty-six (13.8%) of the RA patients and 181 (20.5%) of the SpA patients discontinued their bDMARDs (p = 0.003). The distribution of the patients who discontinued/did not receive their bDMARDs is demonstrated in Table 3. Among RA patients, etanercept (%5.4) was the least frequently discontinued bDMARD, whereas tocilizumab (%20.5) was the most frequently discontinued bDMARD. The clinical characteristics and disease activity parameters did not differ between the RA patients who discontinued and those who did not discontinue their bDMARDs. In the SpA patient group, those who discontinued their bDMARDs were younger than those who did not (median age, 40 years [range, 21–73 years] vs. median age, 44 years [range, 20–79 years]; p = 0.005). Moreover, the SpA patients who continued their bDMARDs had lower disease activity. The multivariate analysis revealed that age of <40 years, a poorer general health status, a poorer VAS score, and the suspicion for the presence of COVID-19 were the factors that determine the discontinuation of bDMARD therapy in SpA patients (Table 4).
Table 3 Distribution of the patients who discontinued their biological disease-modifying antirheumatic drugs.
Patients with RA n/N (%) Patients with SpA n/N (%)
All bDMARDs 66 (14.0) 181 (20.5)
Abatacept 4/31 (12.9) NA
Adalimumab 15/86 (17.4) 46/264 (17.4)
Etanercept 4/74 (5.4) 38/180 (21.1)
Golimumab 3/18 (16.7) 15/86 (15.6)
Infliximab 2/12 (16.7) 29/118 (24.5)
Certolizumab 3/37 (8.1) 31/146 (21.2)
Rituximab 7/39 (17.9) NA
Tofacitinib 6/75 (8.0) NA
Tocilizumab 22/107 (20.5) NA
Secukinumab NA 22/89 (24.7)
Hydroxychloroquine 19/157 (12.1) 5/181 (2.8)
Leflunomide 14/113 (12.4) 4/181 (2.2)
Methotrexate 14/134 (10.4) 13/181 (7.2)
Sulfasalazine 2/22 (9.1) 13/181 (7.2)
RA, rheumatoid arthritis; SpA, spondyloarthritis; bDMARDs, biological disease-modifying antirheumatic drugs; NA, not applicable.
Table 4 Characteristics of the patients with spondyloarthritis who discontinued their biological disease-modifying antirheumatic drugs
Patients with SpA who discontinued bDMARDs Patients with SpA who continued bDMARDs Univariatep Odds Ratio95% CI Multivariatep Odds ratio95% CI
Age (<40 vs. ≥40) 84 (46.4) 243 (34.6) 0.004 1.64 (1.18–2.28) 0.002 1.76 (1.24–2.51)
General health status
Completely under control 51 (28.2) 390 (55.8) Reference
Mild 52 (28.7) 103 (14.7) <0.001 3.86 (2.48–6.01) <0.001 3.20 (1.99–5.15)
Moderate 51 (28.2) 153 (21.9) <0.001 2.55 (1.66–3.92) 0.003 2.03 (1.26–3.27)
Severe 21 (11.6) 41 (5.9) <0.001 3.92 (2.15–7.15) 0.003 2.65 (1.38–5.10)
Extremely severe 6 (3.3) 12 (1.7) 0.010 3.82 (1.38–10.63) 0.103 2.46 (0.83–7.28)
VAS-PGA, <20 vs. ≥20 38 (21.1) 281 (40.2) <0.001 2.51 (1.70–3.71) 0.016 1.74 (1.11–2.75)
Suspected COVID-19 12 (6.6) 20 (2.9) 0.019 2.41 (1.16–5.04) 0.136 1.83 (0.83–4.03)
Data are presented as numbers (percentage, %).SpA, spondyloarthritis; bDMARDs, biological disease-modifying antirheumatic drugs; CI, confidence interval; VAS-PGA, visual analog scale-patient global assessment; COVID-19, coronavirus disease 2019.
The data on the reasons for drug discontinuation were available in 186 (75.3%) of 247 patients who discontinued their bDMARDs. Of these patients, 60 (32.2%) discontinued the therapy based on the recommendation of his/her physician, 84 (45.1%) discontinued on their own demand/fear, 13 (6.9%) discontinued due to suspected COVID-19, 8 (4.3%) discontinued due to the lack of disease activity, and 21 (11.3%) discontinued due to other reasons. No difference was determined between RA and SpA patients in terms of reasons for discontinuation of bDMARDs. During the pandemic, 550 patients (213 RA patients and 337 SpA patients) were able to communicate with their physicians. The patients communicated with their physicians through phone calls (314 [57.1%] patients), face-to-face interview (203 [36.9%] patients), text message (39 [7.1%] patients), e-mail (19 [3.5%] patients), healthcare staff (assistant, nurse) (13 [2.4%] patients), and relatives (5 [0.9%] patients). In 425 (77.3%) of 550 patients, their physicians recommended them to continue bDMARD therapy. In 37 (6.7%) of 550 patients, their physicians recommended them to receive bDMARDs on demand and/or to extent drug application intervals.
3.4. Disease activity during the pandemic
Evaluation of the disease activity during the pandemic in all patients revealed that the disease was completely under control in 46.8% of the patients (in 40.8% of the RA patients and in 50.0% of the SpA patients), whereas 19.1% of the patients (21.7% of the RA patients and 17.7% of the SpA patients) had mild disease activity, 24.7% of the patients (27.9% of the RA patients and 23.1% of the SpA patients) had moderate disease activity, 7.0% of the patients (6.8% of the RA patients and 7.1% of the SpA patients) had active disease, and 2.4% of the patients (2.9% of the RA patients and 2.1% of the SpA patients) had very high disease activity (p = 0.016). The mean general health status-VAS score in all patients during the pandemic was 3.1 ± 2.5; it was 3.4 ± 2.6 in the RA patients and 2.9 ± 2.5 in the SpA patients (p < 0.001). The mean general health status-VAS score in all patients in the prepandemic period was 3.2 ± 2.5; it was 3.6 ± 2.6 in the RA patients and 3 ± 2.4 in the SpA patients (p < 0.001).
As compared with the period before the pandemic, the ratios of patients with worsened disease activity, those with improved disease activity, those in whom the disease has become active (while in remission), those with ongoing remission, those with ongoing active disease, and those showing remission (while having active disease) in the first 100 days of the pandemic are demonstrated in Table 5. In the RA patients, these variables did not show difference between the patients who discontinued and those who did not discontinue their bDMARDs. In the SpA patients, the ratio of those who remained in remission before and during the pandemic was 32.1%. The rate of drug discontinuation was lower in the SpA patients who remained in remission (22.0% in those who discontinued bDMARDs and 34.8% in those who did not discontinue bDMARDs; p = 0.002); other parameters showed no difference between the patients who discontinued and those who did not discontinue bDMARDs.
Table 5 As assessed according to the prepandemic period, changes in disease activity determined by the general health status-Visual Analog Scale scores during the pandemic.
Status Definition Patients with RAn = 428 Patients with SpAn = 809
Worsened disease activity during the pandemic >2 units increase in the VAS score after the pandemic as compared with before the pandemic 100 (23.4) 137 (16.9)
Patients with improved disease activity during the pandemic <2 units decrease in the VAS score after the pandemic as compared with before the pandemic 89 (20.8) 118 (14.6)
While in remission before the pandemic, becoming active during the pandemic A VAS score of ≤2 before pandemic and ≥4 after the pandemic, 69 (16.1) 100 (12.4)
Remission both before and during the pandemic A VAS score of ≤2 before the pandemic and ≤2 after the pandemic 91 (21.3) 260 (32.1)
Active disease both before and during the pandemic A VAS score of ≥4 before the pandemic and ≥4 after the pandemic 121 (28.3) 175 (21.6)
Active disease before the pandemic, remission during the pandemic A VAS score of ≥4 before the pandemic and ≤2 after the pandemic 52 (12.1) 86 (10.6)
Data are presented as numbers (percentage, %).RA, rheumatoid arthritis; SpA, spondyloarthritis; VAS, visual analog scale; bDMARDs, biological disease-modifying antirheumatic drugs; NA, not applicable.
4. Discussion
The COVID 19 pandemic, which was announced in March 2020 by the WHO, has directly influenced the daily life of both healthy individuals and individuals with chronic illnesses1. Immunosuppressed patients rank first among the patient groups influenced by the pandemic most. Biological DMARDs, which have been used in the last two decades, have been the group of medications primarily focused on due to their potential to increase the risk of infection. The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), which are among the international expert societies on rheumatology, have recommended identification of the risk groups and continuation of bDMARDs as long as possible within the frame of patient–physician communication [4,5]. However, the pandemic has caused severe anxiety and fear in some patients. Uncertainty and fear were more prominent particularly in the early period of the pandemic.
The present study investigated the therapeutic approaches in the first 100 days after the declaration of the pandemic in inflammatory arthritis patients known to receive bDMARD therapy. It was observed that the rate of confirmed COVID-19 cases (0.15%) was extremely low in the first 100 days and that nearly 3% of the patients needed to be evaluated for suspected COVID-19. The first 100 days of the pandemic in Turkey was when a strict lockdown was implemented particularly for the people over the age of 65 and under the age of 18. In that period, people with chronic illnesses in particular were on administrative leave, and many patients self-quarantined themselves. It is likely that such a low rate of COVID-19 determined among the patients with inflammatory rheumatic diseases is associated with the abovementioned strict lockdown. After that period, people began to return to their normal life; therefore, how many of the patients evaluated in the present study will develop COVID-19 infection during their follow-up is an investigation that needs to be performed in the future.
Recent studies supported that patients who take biological and conventional DMARDs have less morbidity in the case of COVID-19 [2]. Moreover, in another study from Turkey consisting of 167 patients with inflammatory rheumatic disease, biologic and conventional DMARDs did not seem to cause worse outcomes [12]. However, overall, 18% of all the inflammatory arthritis patients discontinued bDMARDs in the first 100 days of the pandemic. It was observed that drug discontinuation was more common, particularly in the SpA patients, than in the RA patients. Etanercept was the least frequently discontinued bDMARD in the RA patients. It was understood that etanercept has been used for longer than 20 years and thus considered a relatively reliable therapeutic option for both patients and physicians. The main reason for drug discontinuation was the patients’ fear of bDMARD therapy; on the other hand, drug discontinuation was recommended by the physicians in one-third of the patients. In Italy, a survey was conducted between February 2020 and April 2020 in 955 rheumatic patients [13]. In that patient group receiving advanced treatment, modification of biological therapy was performed in nearly 6% of the patients, which is quite low as compared with the finding of the present survey study. Accordingly, different cultural factors can be considered determinative. In the present study, among the patients who were able to communicate with their physicians, about 7% were recommended to receive treatment on demand or could extent drug application intervals. Receiving bDMARD therapy on demand or extending drug application intervals is a method implemented by clinicians for a long time in daily practice with efficacy and safety proven in the controlled studies. During the pandemic, the physicians preferred this method in some of their patients. On the other hand, there is a patient group trying to reach their physicians but could not reach them. It was understood that a change occurred in the physician–patient communication during the pandemic. Specific to rheumatology, patients’ methods of reaching their physicians should be dwelled on, and further studies are needed on this subject.
Any factor that might explain bDMARD discontinuation in the RA patients could not be determined. On the other hand, it was observed that the SpA patients with the disease under control were more likely to continue their drugs. This finding is likely to indicate that the SpA patients with the disease under control were more adherent to their medications, and they avoided recurrent exacerbations. Fluctuations in disease activity were observed in the first 100 days of the pandemic as assessed according to the prepandemic period. The rate of remaining in remission during the pandemic for the patients in remission before the pandemic was 21% in the RA group and 32% in the SpA group. It was understood that the patients with high disease activity in the prepandemic period experienced more difficulty in the early period of the pandemic.
The present survey study was conducted through phone interviews. We could reach three-fourth of the patients; the rates of drug discontinuation and COVID-19 might be higher among those that could not be reached; thus, the results need to be evaluated within the scope of this limitation. The fact that the information regarding steroid use was not inquired could be considered another limitation.
In conclusion, nearly one-fifth of the RA and SpA patients recorded in the TReasure registry and known to receive bDMARD therapy in the prepandemic period discontinued their drugs in the first 100 days of the pandemic. The frequency of COVID-19 was found to be low in the first 100 days of the pandemic, which corresponds to a period when a strict lockdown was implemented in Turkey. Further investigations need to be performed to find out what will happen when people return to their normal active life. Although patients’ fear of treatment appeared to be the main factor, the treatment was discontinued or also interrupted due to physicians’ recommendations. These treatment modifications in the early period of the COVID-19 pandemic may appear as a worsened disease activity in time. Treatment approaches need to be monitored closely in the following period.
Authors’ contributions
All authors contributed equally to conceiving and designing the analysis and collecting the data. UK and EB performed the analysis and wrote the paper; all authors revised and edited the final version of manuscript.
Informed consent
Our study is compliant with the Helsinki Declaration and was approved by both the local ethical committee (Hacettepe University; Approval number: 2020/08-25 (KA-17058)) and the Turkish Ministry of Health (Approval number: 66175679-514.05.01-E.170548).
Acknowledgments
UK received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. YP received honorary from Abbvie, Roche, Novartis, MSD, Pfizer. SA received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. TK received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. GK received honorary from Abbvie, Amgen, Novartis, Pfizer, UCB. OK received honorary from Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. ED received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. IE received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. LK received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. DE received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, UCB. CB received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. HE received honorary from Novartis, Roche. RM received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. NK received honorary from Novartis, UCB. MC received honorary from Abbvie, Amgen, MSD, Novartis, Pfizer, Roche, UCB. SSK received honorary from Abbvie, MSD, Novartis, Pfizer, Roche, UCB. OK received honorary from Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. SK received honorary from Abbvie, Amgen, Johnson and Johnson, MSD, Novartis, Pfizer, Roche, UCB. Other authors declare no conflict of interest.
This study was funded by Hacettepe Rheumatology Society.
World Health Organization (2020). The director-general’s opening remarks at the media briefing on COVID-19 [online]. Website https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. [accessed 27 September 2020]). | ADALIMUMAB | DrugsGivenReaction | CC BY | 33611869 | 20,063,722 | 2021-08-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'. | Rapidly Progressing Anaplastic Carcinoma of the Pancreas with Mucoepidermoid Carcinoma: An Autopsy Case Report.
A 75-year-old man visited our hospital for the examination of a tumor in the pancreas. Computed tomography showed an 85×85-mm low-density tumor in the pancreas. The tumor was pathologically diagnosed as poorly differentiated carcinoma by endoscopic ultrasound-guided fine-needle aspiration. Although we started chemotherapy, the patient died 84 days after the diagnosis. An autopsy demonstrated a ruptured anaplastic carcinoma with mucoepidermoid carcinoma of the pancreas. Anaplastic carcinoma with mucoepidermoid carcinoma is a very rare histologic subtype of pancreatic carcinoma, so pathological findings are important for predicting the patient's prognosis. Physicians should be aware of this rare but fatal disease.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) remains a malignancy with a poor prognosis. Anaplastic carcinoma of the pancreas is a very rare histologic subtype of pancreatic carcinoma and is associated with greater aggression and poorer prognosis than common PDAC. Anaplastic carcinoma shows various morphologies, which include spindle-cell type, pleomorphic cell type and giant cell type (1). Anaplastic carcinoma accounts for 2-7% of all newly diagnosed pancreatic carcinomas each year (2).
Mucoepidermoid carcinoma of the pancreas is categorized as an adenosquamous carcinoma and is characterized by three kinds of cells: squamoid cells, mucinous cells and cells intermediate between ductal basal cells and polygonal epidermoid cells. It is most commonly seen in salivary glands and has a good prognosis. Mucoepidermoid carcinoma is also an uncommon histologic subtype of pancreatic carcinoma and is an extremely rare entity (3-7). Therefore, the malignant potential of mucoepidermoid carcinoma in the pancreas is unknown.
We herein report an autopsy case of anaplastic carcinoma with mucoepidermoid carcinoma of the pancreas with a rapid fatal course.
Case Report
A 75-year-old man visited his physician due to abdominal pain in July 2018. Because an abdominal ultrasound examination revealed a tumor at the pancreas, he was introduced to our hospital for a detailed examination in August 2018. He did not have a family history of carcinoma. He had consumed about 5 g/day of alcohol for 55 years and 20 cigarettes a day for 40 years.
On a physical examination, a hard-tender mass of approximately 5 cm in diameter was palpable in the upper abdominal region. The laboratory findings revealed elevation of white blood cell count, C-reactive protein and duke pancreatic monoclonal antigen type 2 along with mild anemia (Table). The serum levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were within the normal ranges (Table).
Table. Laboratory Data at the First Visit to Our Hospital.
Hematology Serology
WBC 12,700 /µL CRP 8.59 mg/dL
Neutro 85.7 %
Lympho 6.3 %
RBC 352×104 /µL
Hb 10.8 g/dL
Plt 18.7×104 /µL
Biochemistry Coagulation
Alb 3.7 g/dL PT% 69.8 %
T-bil 1.5 mg/dL APTT 59.5 s
AST 16 U/L Fibrinogen 623 mg/dL
ALT 15 U/L FDP 12.1 µg/mL
LDH 228 U/L
ALP 229 U/L Tumor marker
γGTP 33 U/L CEA 1.4 ng/mL
BUN 10 mg/dL CA19-9 1.4 U/mL
Cre 0.72 mg/dL DUPAN-2 1,100 U/mL
AMY 56 U/L
LIP 27 U/L
FPG 116 mg/dL
HbA1c 5.8 %
Although computed tomography (CT) taken eight months earlier because of rib fracture had not revealed any abnormal findings in the pancreas, contrast-enhanced CT showed a rim-enhanced 85×85-mm low-density pancreatic tumor with irregular margins (Fig. 1A). The tumor had spread to the liver, stomach, celiac artery, portal vein and superior mesenteric vein. Endoscopic ultrasound (EUS) revealed a hypoechoic tumor with irregular margins, and EUS-guided fine-needle aspiration (EUS-FNA) was performed (Fig. 1B). The pathological findings showed numerous atypical cells, suggesting poorly differentiated carcinoma (Fig. 1C).
Although there was no distant metastasis, we diagnosed it as unresectable due to invasion to major vessels, including the celiac artery and portal vein. Chemotherapy with gemcitabine and nanovector-albumin-bound paclitaxel was initiated. In October 2018, abdominal CT revealed that the pancreatic tumor had grown to 150 mm in diameter. Distant metastases were detected in the para-aortic lymph nodes, liver and lung (Fig. 2A). In addition, the pancreatic tumor had further spread into the stomach and duodenum. Because an endoscopic examination revealed gastric invasion and gastric outlet obstruction (Fig. 2B), we inserted a self-expanding metallic stent endoscopically (Fig. 2C). Although there were no complications after stent insertion, bloating, anorexia, epigastric and back pain did not improve.
Figure 1. Contrast-enhanced computed tomography images at our hospital on day 1. An 85×85 mm low-density pancreatic tumor with high density area on the periphery of the tumor had spread to organs near the pancreas, such as the liver, stomach, celiac artery, portal vein and superior mesenteric vein (A). Endoscopic ultrasound revealed a hypoechoic mass with irregular margins (B). Pathological findings showed numerous atypical cells, suggesting poorly differentiated carcinoma (C).
Figure 2. Contrast-enhanced computed tomography images at our hospital on day 56. The pancreatic tumor had grown quickly (arrowheads) and liver metastases were detected (A). Endoscopic examination on day 66 revealed gastric invasion and gastric outlet obstruction (B). A self-expanding metallic stent was inserted through the endoscope and deployed in place (C).
The patient fell into a coma following a rapid decrease in blood pressure and died in November 2018. Because of the rapid fatal course, we performed an autopsy with the consent of his family. The autopsy revealed that the tumor had grown to 200 mm in diameter and ruptured with massive bleeding (Fig. 3A). The cause of death was ascertained as hemorrhagic shock as a result of spontaneous rupture of the pancreatic tumor. In addition, the pathological findings of the tumor showed that the tumor consisted of pleomorphic-type anaplastic carcinoma (Fig. 3B) composed of squamoid (Fig. 3C), intermediate (Fig. 3D) and mucinous cells (Fig. 3E). The proportion of mucoepidermoid carcinoma was a little higher than that of anaplastic carcinoma in the tumor. In addition, the metastatic lesions, para-aortic lymph nodes, liver and lung consisted mainly of mucoepidermoid carcinoma, with anaplastic carcinoma comprising only one part. Gene rearrangement and split signal were not detected by fluorescence in situ hybridization (FISH) using an isolated probe of the CTRC-MAML2 gene type.
Figure 3. The autopsy revealed that the pancreatic tumor had grown to 200 mm in diameter and ruptured with massive bleeding (A). Pathological findings showed that the tumor consisted mainly of pleomorphic-type anaplastic carcinoma (B), while part of the tumor was composed of squamoid (C), intermediate (D), and mucinous cells (E).
Our final diagnosis was pleomorphic-type anaplastic carcinoma with mucoepidermoid carcinoma of the pancreas.
Discussion
We experienced a case of anaplastic carcinoma with mucoepidermoid carcinoma of the pancreas showing rapid tumor progression. Anaplastic pancreatic carcinoma is classified as a subtype of PDAC and is reported to potentially be a malignant transformation from PDAC (8). However, given that the present case contained no PDAC, it was possible that the tumor originally developed as an anaplastic carcinoma. Mucoepidermoid carcinoma is classified as a subtype of adenosquamous carcinoma, but little is known about its histonomy.
Both anaplastic carcinoma and mucoepidermoid carcinoma are very rare histologic subtypes of pancreatic carcinoma, and their prognoses are poorer than that of common PDAC (1,3). The reported median survival time from the diagnosis of anaplastic carcinoma of the pancreas ranges from 3.3 months (9) to 12.8 months (10), which is significantly shorter than that of common PDAC. Mucoepidermoid carcinoma is most frequently seen in the salivary glands and is uncommon in the pancreas (11). There have been a few case reports of mucoepidermoid carcinoma of the pancreas, and the survival times were 2-45 months (5-7). The present case was resistant to treatment and had a poor prognosis.
It was reported that five patients underwent EUS-FNA for anaplastic carcinoma of the pancreas, and the cytology demonstrated anaplastic carcinoma in four and ductal carcinoma in one. The accurate diagnosis of anaplastic carcinoma was confirmed after surgical resection (12). The present case was difficult to diagnose using only EUS-FNA, because the amount of the specimen obtained for EUS-FNA was insufficient. Had the EUS-FNA specimen shown numerous atypical cells, suggesting poorly differentiated carcinoma, the pancreatic carcinoma might have been deemed a rare histologic subtype of pancreatic carcinoma, like an anaplastic carcinoma with mucoepidermoid carcinoma.
CTRC-MAML2 translocation-positive mucoepidermoid carcinoma in salivary gland has been associated with good survival rates (13). However, the present patient with mucoepidermoid carcinoma had a rapid fatal course. Although the malignant potential of mucoepidermoid carcinoma in the pancreas is unknown, the CTRC-MAML2 translocation-negative status may have been the reason for the poor prognosis. The carcinoma's pathologic aspects of poorly differentiated anaplastic carcinoma and high-grade mucoepidermoid carcinoma might have been responsible for the rapid fatal course in the present case.
There had been no abnormal findings on CT performed 8 months before admission in the present case, but a pancreatic tumor measuring 85 mm×85 mm was observed in the pancreatic body at the first visit. After 2 months, the tumor had grown to 150 mm in diameter. In a previous report on 9 patients with pancreatic carcinoma, the median doubling time was 144 days (14). Pathologically, the doubling time of pancreatic carcinoma with squamous component is 81.8 days, whereas that with an adenomatous component is 166.3 days (15). In the present case, the doubling time was 25 days, so the tumor grew rapidly and finally ruptured. Although whether or not the previous intratumor hemorrhaging had affected the rapid increase in the tumor size was unclear, the hematoma consisted of previous and new intratumor hemorrhaging. Pancreatic carcinoma with anaplastic carcinoma and mucoepidermoid carcinoma is one of the most lethal malignant neoplasms.
It is difficult to distinguish anaplastic carcinoma and mucoepidermoid carcinoma from the other types of pancreatic carcinoma without referencing the pathological findings. Regarding laboratory findings, some anaplastic carcinoma cases have shown severe anemia (hemoglobin level <10.0 g/dL), elevated white blood cell counts (>12,000 /μL) and elevated serum carbohydrate antigen 19-9 levels (>37 U/mL) (16). The present case had an inflammatory response and anemia, but the carbohydrate antigen 19-9 was within the normal range. Typical CT images of anaplastic carcinoma show a tumor with rim enhancement and central necrosis (17,18). In the present case, the pancreatic tumor appeared as a low-density lesion with peripheral contrast enhancement without central necrosis on contrast-enhanced CT at the first visit. This made it difficult to distinguish anaplastic carcinoma from other types of pancreatic carcinoma. CT is also limited in its ability to distinguish mucoepidermoid carcinoma from other types of pancreatic carcinoma, because of its low specificity (3). EUS findings of anaplastic carcinoma of the pancreas show a hypoechoic and heterogeneous pattern (19), and the findings of mucoepidermoid carcinoma are hypoechoic pattern with slightly high internal echoes (11). In the present case, EUS revealed a hypoechoic mass with irregular margins, findings similar to those of common PDAC. Because it is difficult to distinguish anaplastic carcinoma and mucoepidermoid carcinoma from common PDAC, it is important to consider the possibility of this carcinoma and perform imaging examinations frequently when the pathological findings from EUS-FNA show poorly differentiated carcinoma.
In recent years, anaplastic carcinomas have been pathologically subdivided into three variants: pleomorphic type, spindle cell type and anaplastic carcinomas with osteoclast-like giant cells. The prognosis depends on the tissue type among cases of anaplastic carcinoma (19). Anaplastic carcinoma without osteoclast-like giant cells often cannot benefit from surgery, even if diagnosed in an operable state; however, anaplastic carcinoma with osteoclast-like giant cells may have a good long-term prognosis with surgical treatment (16). However, the effectiveness of chemotherapy for anaplastic carcinoma of the pancreas is still unknown for anaplastic carcinoma of the pancreas. The effectiveness of surgical treatment and chemotherapy for mucoepidermoid carcinoma in pancreas is still unknown. Although we started combination chemotherapy of gemcitabine and nanovector-albumin-bound paclitaxel according to the typical treatment approach for pancreatic carcinoma, the tumor grew in size.
Anaplastic carcinoma with mucoepidermoid carcinoma is a very rare histologic subtype of pancreatic carcinoma. The clinical diagnosis was difficult without pathological findings. Thus, a pathological examination was important for predicting the patient's prognosis in the present case, and an autopsy was necessary to confirm the pathological findings because of the presence of various histological features. We should consider performing an autopsy when a patient has an unusual and rapid fatal clinical course.
Conclusion
We experienced a case of rapidly progressing anaplastic carcinoma with mucoepidermoid carcinoma of the pancreas. We should be aware of this rare fatal disease.
The authors state that they have no Conflict of Interest (COI). | GEMCITABINE, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33612673 | 20,737,963 | 2021-07-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Reversible cerebral vasoconstriction syndrome'. | Reversible Cerebral Vasoconstriction Syndrome without Headache That Was Initially Suspected of Being Primary Angiitis of the Central Nervous System.
A 48-year-old man had convulsions, and magnetic resonance angiography (MRA) showed diffuse constriction of the cerebral arteries. He was suspected of having primary angiitis of the central nervous system (PACNS) and treated with steroid for three days. The MRA abnormality disappeared after a week. After 69 days, he developed dizziness, and MRA revealed recurrence of cerebral artery stenosis. Nevertheless, the symptoms and abnormal MRA findings recovered promptly without treatment. He was diagnosed with reversible cerebral vasoconstriction syndrome (RCVS) without headache. This case suggests that RCVS should be a differential diagnosis in patients without headache whose MRA findings show multiple cerebral artery stenosis.
Introduction
Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical and radiologic syndrome characterized by a severe headache and multifocal segmental vasoconstriction of cerebral arteries that improves spontaneously within three months (1). A wide variety of brain lesions, such as convexity subarachnoid hemorrhaging (cSAH), intracerebral hemorrhaging (ICH), posterior reversible encephalopathy syndrome (PRES), and ischemic stroke (IS), are known to be complicated by RCVS (2). The characteristic headache is a thunderclap headache (TCH) that is hyperacute severe and reaches its maximal intensity in less than a minute (3). TCH is the most common symptom of RCVS, and 78-100% of patients experience TCH as initial manifestation (4-6). Thus, RCVS is typically diagnosed on the basis of the clinical and radiologic presentation by excluding other causes of TCH (7). In contrast, Wolff et al. reported that some patients with RCVS do not have TCH, and a few of them do not have any headache at all (8).
We herein report a patient with RCVS without headache over the course of two attacks whose symptoms were difficult to differentiate from those of primary angiitis of the central nervous system (PACNS).
Case Report
A 48-year-old man was transferred to our hospital due to a convulsion. In the morning of the day when he had the convulsion, he had conversed with his family in a normal healthy state. He was undergoing treatment for psoriasis vulgaris with apremilast and had a history of untreated hypertension.
When arriving at our hospital, his consciousness level was disturbed (Glasgow Coma Scale 4-4-5), and he was vomiting. Therefore, he was unable to follow the instructions of the medical staff. His blood pressure was 169/101 mmHg, pulse was 129 beats per minute, body temperature was 36.1°C, respiratory rate was 36 breaths per minute, and oxygen saturation was 100% (10 L/min reservoir mask). He had red scaly rashes on his limbs and trunk. His pupils were equal in size (3.0 mm in diameter), round, and reactive to light. Although it was difficult to evaluate his strength accurately due to disturbance of consciousness, there was no obvious motor paralysis. The deep tendon reflexes of all four limbs were decreased. He showed no meningeal signs, such as nuchal rigidity, Kernig's sign and Brudzinski's sign. Other physical and neurological examinations were normal.
On laboratory tests, his white blood cell (WBC) count was 20,000 /μL with 89.3% neutrophils. Both D-dimer (＜0.5 μg/mL) and C-reactive protein (＜0.05 mg/dL) levels were within the normal ranges. Immunological tests for rheumatoid factor, antinuclear antibodies, anti SS-A/SS-B antibodies, anti-neutrophil cytoplasmic antibody, anti-cardiolipin antibody, and lupus anticoagulant were negative. A cerebrospinal fluid (CSF) examination showed increased WBC counts (76/3 μL) with 99% lymphocytes, and normal ranges of protein (44 mg/dL), glucose (66 mg/dL), and IgG index (0.58). The CSF culture and herpes simplex virus (HSV)-1/2DNA test were negative.
Whole-body computed tomography (CT) with contrast revealed that there were no organs and blood vessels with poor contrast enhancement. Diffusion-weighted magnetic resonance imaging (MRI) of the head without contrast demonstrated a high signal intensity in the left deep white matter near the splenium of the corpus callosum, without a change in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI showed a high signal intensity in the same area. The lesion was suspected to be a subacute phase or later cerebral infarction (Fig. 1A). FLAIR MRI showed a low-intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhaging (Fig. 1A). FLAIR MRI also revealed multiple high-intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhaging, respectively (Fig. 1A, B). MRA revealed multifocal segmental cerebral artery vasoconstriction, which was most prominent in the bilateral posterior cerebral arteries (Fig. 2A).
Figure 1. Head MRI findings on admission. Upper (A) and lower panels (B) show axial slices at the level of the foramen of Monro and centrum semiovale, respectively. (A) Diffusion-weighted imaging (DWI) demonstrates a high signal intensity in the left deep white matter near the splenium of the corpus callosum; without changes in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI shows a high signal intensity in the same area, suggesting subacute phase or later cerebral infarction (yellow arrows). FLAIR MRI also shows a low intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhage (white arrows). (A, B) FLAIR MRI shows multiple high intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhage, respectively (red arrows).
Figure 2. Time course of the MRA and MRI findings 1 (A), 10 (B), 69 (C), 70 (D), and 295 days (E) after onset. (A) Multifocal segmental cerebral artery vasoconstriction is most prominent in the bilateral posterior cerebral arteries (yellow arrows). (B) Disappearance of the abnormal findings observed on day 1. (C) Multiple cerebral artery stenosis (red arrows). (D) Normalization of cerebral artery stenosis. (E) No new lesions were detected (orange arrows).
After arriving, he was intubated to secure the airway. Midazolam and propofol were used for sedation and to prevent convulsions. Levetiracetam and valproic acid were initiated for convulsion. Because he was suspected of PACNS based on the results of the MRA and CSF analysis, high-dose intravenous methylprednisolone (1,000 mg daily for 3 days) was initiated from the next day of hospitalization. Intravenous acyclovir (10 mg/kg Q8h) was administered until the result of HSV-DNA was confirmed to be negative. Paroxysmal waves were not detected on the electroencephalogram two days after administration. A follow-up CSF examination on day 8 showed normalized WBC counts (2/3 μL). The patient did not develop convulsions after hospitalization, so he was extubated. Follow-up MRA showed that the multifocal segmental cerebral artery vasoconstriction had disappeared (Fig. 2B). There were no neurological abnormalities, and he was discharged on day 26. On day 52, amlodipine was initiated for hypertension.
On day 69, he developed dizziness and consulted another hospital. MRA showed multiple cerebral artery stenosis (Fig. 2C), and he was transferred to our hospital on day 70. On arrival, MRI and CSF examinations were performed. MRI and MRA revealed no new intracranial lesions and cerebral artery stenosis, respectively (Fig. 2D). His CSF contained WBCs (1/3 μL) and protein (34.2 mg/dL) concentrations within the normal range. In addition, a neurological examination revealed no evidence of abnormal findings, and the dizziness had disappeared at arrival. The patient also reported that there was no headache during the course of the two clinical attacks. Finally, these findings led us to exclude PACNS, and he was diagnosed with RCVS without headache. No new lesions were detected on follow up MRI after hospital discharge on day 295 (Fig. 2E).
Discussion
The exact pathogenesis of headache in RCVS remains unclear (9); however, it is inferred that a sudden change in central vascular tone may stretch the vessel walls and result in TCH at the initial stage of RCVS (3). As with TCH, seizures are an early complication of RCVS, and are present in 1-17% of cases (1). Thus, the presence of headache in RCVS cases with seizure may be unclear, as patients with disturbed consciousness cannot describe their symptoms (10,11). Although the possibility that our patient had headache at the first hospitalization cannot be ruled out, he insisted that there was no headache during both the first hospitalization before the convulsion and the second hospitalization. Previous reports have presented detailed information of the clinical and radiological features of 10 patients with RCVS without headache (Table) (12-17). These reports showed several characteristics of RCVS without headache. First, all of the patients had cerebrovascular disease accompanied by RCVS; nine had ischemic stroke, and one had cSAH. In the present case, MRI showed subacute or later phase cerebral infarction and old hemorrhaging. These may have been complications of RCVS, as cerebrovascular disease is often associated with RCVS. Nonetheless, he did not have any symptoms before the day of the hospitalization. We concluded that RCVS did not accompany ischemic stroke at the time when he was hospitalized with the convulsion. This case suggests that RCVS can lead to asymptomatic attack, and it is rare for clinical RCVS attack without headache and cerebrovascular disease to occur together. Regarding the patient's dizziness, stenosis of the basilar artery seemed to result in the symptoms of a transient ischemic attack. Second, the clinical outcomes of almost all previously described patients were good, and all were under 50 years old. Our patient had common features with those patients in that no sequelae remained, and he was 48 years old.
Table. The Characteristics of Patients without Headache Associated with RCVS.
Case Age
(y) Sex Precipitant
factor Neurological symptoms Complications Outcome Reference
1 25 Female None Diplopia, right ataxia IS mRS 0 12
2 35 Male None Left hemiparesis IS mRS 0 12
3 27 Male Cannabis Right paresthesia IS mRS 0 12
4 38 Male Nasal decongestants Right ataxia, dysarthria IS mRS 1 12
5 36 Male None Vertigo, right hemiparesis IS mRS 0 12
6 31 Female Postpartum Serotonergic antidepressant Left hemiparesis IS Persistent deficit 13
7 24 Female Postpartum Generalized tonic-clonic seizure cSAH Asymptomatic 14
8 42 Male Cannabis Transient episodes of right hemiparesis IS Asymptomatic 15
9 32 Female Pregnancy Dizziness, diplopia IS mRS 0 16
10 46 Male None Visual field defect, left lower limb weakness IS NA 17
11 48 Male None First attack; None
Second attack; convulsion
Third attack; dizziness IS, ICH mRS 0 Our case
RCVS: reversible cerebral vasoconstriction syndrome, IS: ischemic stroke, cSAH: convexity subarachnoid hemorrhage, mRS: modified Rankin Scale, NA: not attributable, ICH: intracerebral hematoma
The diagnostic criteria for RCVS proposed by Calabrese in 2007 include the presence of severe acute headache (18). Clinically, RCVS is considered in patients with a hyperacute severe headache (18), whereas radiological aspects are important in cases of RCVS without headache (8). Multiple cerebral artery stenosis is a critical feature of RCVS. Many diseases, such as PACNS, secondary central nervous system vasculitis, infectious disease, multiple embolic cerebral infarcts, anti-phospholipid antibody syndrome, and Moyamoya disease, have the same feature (19). In our case, examinations such as laboratory tests, whole-body CT, and head MRI excluded differential diagnoses other than PACNS.
We initially suspected that PACNS was the cause of his symptoms based on the results of MRA and CSF studies. The classical diagnostic criteria for PACNS proposed by Calabrese and Mallek in 1988 include angiographic and histopathological examinations (20). As with digital subtraction angiography (DSA), MRA can also detect multilocular stenosis, multiple narrowing and dilatation, and other abnormal findings of intracranial vessels that are caused by central nervous system vasculitis (21) and can be implemented in the PACNS diagnostic approach (22). Nevertheless, the limited diagnostic specificity of MRA and DSA leads to difficulty distinguishing between PACNS and RCVS (23). Thus, Beuker et al. proposed considering a CSF profile for the PACNS diagnosis (24). In PACNS, the CSF analysis findings are abnormal (leucocytosis and high total protein concentrations); however, in RCVS, these findings are normal or near normal (protein concentrations ＜100 mg/dL, ＜15 WBC/μL) (18). In our case, PACNS was suspected rather than RCVS initially because the patient's MRA showed multifocal vessel narrowing, and his CSF study showed leucocytosis. DSA was not performed for two reasons. First, we had already detected abnormal MRA findings that were compatible with the diagnosis of PACNS. Second, DSA reportedly sometimes aggravates ischemic lesions of PACNS (25) and vasoconstriction of RCVS (2). In addition, we did not perform a biopsy before initiating corticosteroid therapy because it is highly invasive; however, a biopsy is crucial for a PACNS diagnosis (26). A biopsy is encouraged, especially when considering prolonged immunosuppressant treatment of patients suspected of PACNS (23).
In addition to CSF analyses, it has been reported that the characteristic headache can help distinguish RCVS from PACNS (24); this is also referenced in the diagnostic criteria of RCVS (18). TCHs are typical in RCVS, whereas they are subacute and progressive in PACNS. However, the headache characteristic is not useful when patients do not have headaches. Of note, a CSF analysis of convulsion and cerebral infarcts may show pleocytosis, as seen in our case (27,28). It is thus challenging to differentiate RCVS without headache and PACNS at first consultation, and we may need to initiate corticosteroid therapy because early treatment is indispensable to avoid poor outcomes in PACNS (29). The cerebrovascular abnormality observed in our case normalized completely and rapidly, while that of PACNS is frequently irreversible (30). Thus, our case was correctly diagnosed thanks to careful follow-up.
In conclusion, we experienced a patient with RCVS who presented with convulsion and dizziness. RCVS should be considered as a differential diagnosis for patients without headache whose MRA show multifocal segmental cerebral artery vasoconstriction. At the initial consultation, it is difficult to distinguish RCVS without headache from PACNS. The clinical course after the onset may play a key role in the diagnosis, and a biopsy should be considered according to the clinical course.
The authors state that they have no Conflict of Interest (COI). | ACYCLOVIR, AMLODIPINE BESYLATE, APREMILAST, LEVETIRACETAM, TELMISARTAN | DrugsGivenReaction | CC BY-NC-ND | 33612678 | 19,735,583 | 2021-07-15 |
What was the administration route of drug 'ACYCLOVIR'? | Reversible Cerebral Vasoconstriction Syndrome without Headache That Was Initially Suspected of Being Primary Angiitis of the Central Nervous System.
A 48-year-old man had convulsions, and magnetic resonance angiography (MRA) showed diffuse constriction of the cerebral arteries. He was suspected of having primary angiitis of the central nervous system (PACNS) and treated with steroid for three days. The MRA abnormality disappeared after a week. After 69 days, he developed dizziness, and MRA revealed recurrence of cerebral artery stenosis. Nevertheless, the symptoms and abnormal MRA findings recovered promptly without treatment. He was diagnosed with reversible cerebral vasoconstriction syndrome (RCVS) without headache. This case suggests that RCVS should be a differential diagnosis in patients without headache whose MRA findings show multiple cerebral artery stenosis.
Introduction
Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical and radiologic syndrome characterized by a severe headache and multifocal segmental vasoconstriction of cerebral arteries that improves spontaneously within three months (1). A wide variety of brain lesions, such as convexity subarachnoid hemorrhaging (cSAH), intracerebral hemorrhaging (ICH), posterior reversible encephalopathy syndrome (PRES), and ischemic stroke (IS), are known to be complicated by RCVS (2). The characteristic headache is a thunderclap headache (TCH) that is hyperacute severe and reaches its maximal intensity in less than a minute (3). TCH is the most common symptom of RCVS, and 78-100% of patients experience TCH as initial manifestation (4-6). Thus, RCVS is typically diagnosed on the basis of the clinical and radiologic presentation by excluding other causes of TCH (7). In contrast, Wolff et al. reported that some patients with RCVS do not have TCH, and a few of them do not have any headache at all (8).
We herein report a patient with RCVS without headache over the course of two attacks whose symptoms were difficult to differentiate from those of primary angiitis of the central nervous system (PACNS).
Case Report
A 48-year-old man was transferred to our hospital due to a convulsion. In the morning of the day when he had the convulsion, he had conversed with his family in a normal healthy state. He was undergoing treatment for psoriasis vulgaris with apremilast and had a history of untreated hypertension.
When arriving at our hospital, his consciousness level was disturbed (Glasgow Coma Scale 4-4-5), and he was vomiting. Therefore, he was unable to follow the instructions of the medical staff. His blood pressure was 169/101 mmHg, pulse was 129 beats per minute, body temperature was 36.1°C, respiratory rate was 36 breaths per minute, and oxygen saturation was 100% (10 L/min reservoir mask). He had red scaly rashes on his limbs and trunk. His pupils were equal in size (3.0 mm in diameter), round, and reactive to light. Although it was difficult to evaluate his strength accurately due to disturbance of consciousness, there was no obvious motor paralysis. The deep tendon reflexes of all four limbs were decreased. He showed no meningeal signs, such as nuchal rigidity, Kernig's sign and Brudzinski's sign. Other physical and neurological examinations were normal.
On laboratory tests, his white blood cell (WBC) count was 20,000 /μL with 89.3% neutrophils. Both D-dimer (＜0.5 μg/mL) and C-reactive protein (＜0.05 mg/dL) levels were within the normal ranges. Immunological tests for rheumatoid factor, antinuclear antibodies, anti SS-A/SS-B antibodies, anti-neutrophil cytoplasmic antibody, anti-cardiolipin antibody, and lupus anticoagulant were negative. A cerebrospinal fluid (CSF) examination showed increased WBC counts (76/3 μL) with 99% lymphocytes, and normal ranges of protein (44 mg/dL), glucose (66 mg/dL), and IgG index (0.58). The CSF culture and herpes simplex virus (HSV)-1/2DNA test were negative.
Whole-body computed tomography (CT) with contrast revealed that there were no organs and blood vessels with poor contrast enhancement. Diffusion-weighted magnetic resonance imaging (MRI) of the head without contrast demonstrated a high signal intensity in the left deep white matter near the splenium of the corpus callosum, without a change in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI showed a high signal intensity in the same area. The lesion was suspected to be a subacute phase or later cerebral infarction (Fig. 1A). FLAIR MRI showed a low-intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhaging (Fig. 1A). FLAIR MRI also revealed multiple high-intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhaging, respectively (Fig. 1A, B). MRA revealed multifocal segmental cerebral artery vasoconstriction, which was most prominent in the bilateral posterior cerebral arteries (Fig. 2A).
Figure 1. Head MRI findings on admission. Upper (A) and lower panels (B) show axial slices at the level of the foramen of Monro and centrum semiovale, respectively. (A) Diffusion-weighted imaging (DWI) demonstrates a high signal intensity in the left deep white matter near the splenium of the corpus callosum; without changes in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI shows a high signal intensity in the same area, suggesting subacute phase or later cerebral infarction (yellow arrows). FLAIR MRI also shows a low intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhage (white arrows). (A, B) FLAIR MRI shows multiple high intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhage, respectively (red arrows).
Figure 2. Time course of the MRA and MRI findings 1 (A), 10 (B), 69 (C), 70 (D), and 295 days (E) after onset. (A) Multifocal segmental cerebral artery vasoconstriction is most prominent in the bilateral posterior cerebral arteries (yellow arrows). (B) Disappearance of the abnormal findings observed on day 1. (C) Multiple cerebral artery stenosis (red arrows). (D) Normalization of cerebral artery stenosis. (E) No new lesions were detected (orange arrows).
After arriving, he was intubated to secure the airway. Midazolam and propofol were used for sedation and to prevent convulsions. Levetiracetam and valproic acid were initiated for convulsion. Because he was suspected of PACNS based on the results of the MRA and CSF analysis, high-dose intravenous methylprednisolone (1,000 mg daily for 3 days) was initiated from the next day of hospitalization. Intravenous acyclovir (10 mg/kg Q8h) was administered until the result of HSV-DNA was confirmed to be negative. Paroxysmal waves were not detected on the electroencephalogram two days after administration. A follow-up CSF examination on day 8 showed normalized WBC counts (2/3 μL). The patient did not develop convulsions after hospitalization, so he was extubated. Follow-up MRA showed that the multifocal segmental cerebral artery vasoconstriction had disappeared (Fig. 2B). There were no neurological abnormalities, and he was discharged on day 26. On day 52, amlodipine was initiated for hypertension.
On day 69, he developed dizziness and consulted another hospital. MRA showed multiple cerebral artery stenosis (Fig. 2C), and he was transferred to our hospital on day 70. On arrival, MRI and CSF examinations were performed. MRI and MRA revealed no new intracranial lesions and cerebral artery stenosis, respectively (Fig. 2D). His CSF contained WBCs (1/3 μL) and protein (34.2 mg/dL) concentrations within the normal range. In addition, a neurological examination revealed no evidence of abnormal findings, and the dizziness had disappeared at arrival. The patient also reported that there was no headache during the course of the two clinical attacks. Finally, these findings led us to exclude PACNS, and he was diagnosed with RCVS without headache. No new lesions were detected on follow up MRI after hospital discharge on day 295 (Fig. 2E).
Discussion
The exact pathogenesis of headache in RCVS remains unclear (9); however, it is inferred that a sudden change in central vascular tone may stretch the vessel walls and result in TCH at the initial stage of RCVS (3). As with TCH, seizures are an early complication of RCVS, and are present in 1-17% of cases (1). Thus, the presence of headache in RCVS cases with seizure may be unclear, as patients with disturbed consciousness cannot describe their symptoms (10,11). Although the possibility that our patient had headache at the first hospitalization cannot be ruled out, he insisted that there was no headache during both the first hospitalization before the convulsion and the second hospitalization. Previous reports have presented detailed information of the clinical and radiological features of 10 patients with RCVS without headache (Table) (12-17). These reports showed several characteristics of RCVS without headache. First, all of the patients had cerebrovascular disease accompanied by RCVS; nine had ischemic stroke, and one had cSAH. In the present case, MRI showed subacute or later phase cerebral infarction and old hemorrhaging. These may have been complications of RCVS, as cerebrovascular disease is often associated with RCVS. Nonetheless, he did not have any symptoms before the day of the hospitalization. We concluded that RCVS did not accompany ischemic stroke at the time when he was hospitalized with the convulsion. This case suggests that RCVS can lead to asymptomatic attack, and it is rare for clinical RCVS attack without headache and cerebrovascular disease to occur together. Regarding the patient's dizziness, stenosis of the basilar artery seemed to result in the symptoms of a transient ischemic attack. Second, the clinical outcomes of almost all previously described patients were good, and all were under 50 years old. Our patient had common features with those patients in that no sequelae remained, and he was 48 years old.
Table. The Characteristics of Patients without Headache Associated with RCVS.
Case Age
(y) Sex Precipitant
factor Neurological symptoms Complications Outcome Reference
1 25 Female None Diplopia, right ataxia IS mRS 0 12
2 35 Male None Left hemiparesis IS mRS 0 12
3 27 Male Cannabis Right paresthesia IS mRS 0 12
4 38 Male Nasal decongestants Right ataxia, dysarthria IS mRS 1 12
5 36 Male None Vertigo, right hemiparesis IS mRS 0 12
6 31 Female Postpartum Serotonergic antidepressant Left hemiparesis IS Persistent deficit 13
7 24 Female Postpartum Generalized tonic-clonic seizure cSAH Asymptomatic 14
8 42 Male Cannabis Transient episodes of right hemiparesis IS Asymptomatic 15
9 32 Female Pregnancy Dizziness, diplopia IS mRS 0 16
10 46 Male None Visual field defect, left lower limb weakness IS NA 17
11 48 Male None First attack; None
Second attack; convulsion
Third attack; dizziness IS, ICH mRS 0 Our case
RCVS: reversible cerebral vasoconstriction syndrome, IS: ischemic stroke, cSAH: convexity subarachnoid hemorrhage, mRS: modified Rankin Scale, NA: not attributable, ICH: intracerebral hematoma
The diagnostic criteria for RCVS proposed by Calabrese in 2007 include the presence of severe acute headache (18). Clinically, RCVS is considered in patients with a hyperacute severe headache (18), whereas radiological aspects are important in cases of RCVS without headache (8). Multiple cerebral artery stenosis is a critical feature of RCVS. Many diseases, such as PACNS, secondary central nervous system vasculitis, infectious disease, multiple embolic cerebral infarcts, anti-phospholipid antibody syndrome, and Moyamoya disease, have the same feature (19). In our case, examinations such as laboratory tests, whole-body CT, and head MRI excluded differential diagnoses other than PACNS.
We initially suspected that PACNS was the cause of his symptoms based on the results of MRA and CSF studies. The classical diagnostic criteria for PACNS proposed by Calabrese and Mallek in 1988 include angiographic and histopathological examinations (20). As with digital subtraction angiography (DSA), MRA can also detect multilocular stenosis, multiple narrowing and dilatation, and other abnormal findings of intracranial vessels that are caused by central nervous system vasculitis (21) and can be implemented in the PACNS diagnostic approach (22). Nevertheless, the limited diagnostic specificity of MRA and DSA leads to difficulty distinguishing between PACNS and RCVS (23). Thus, Beuker et al. proposed considering a CSF profile for the PACNS diagnosis (24). In PACNS, the CSF analysis findings are abnormal (leucocytosis and high total protein concentrations); however, in RCVS, these findings are normal or near normal (protein concentrations ＜100 mg/dL, ＜15 WBC/μL) (18). In our case, PACNS was suspected rather than RCVS initially because the patient's MRA showed multifocal vessel narrowing, and his CSF study showed leucocytosis. DSA was not performed for two reasons. First, we had already detected abnormal MRA findings that were compatible with the diagnosis of PACNS. Second, DSA reportedly sometimes aggravates ischemic lesions of PACNS (25) and vasoconstriction of RCVS (2). In addition, we did not perform a biopsy before initiating corticosteroid therapy because it is highly invasive; however, a biopsy is crucial for a PACNS diagnosis (26). A biopsy is encouraged, especially when considering prolonged immunosuppressant treatment of patients suspected of PACNS (23).
In addition to CSF analyses, it has been reported that the characteristic headache can help distinguish RCVS from PACNS (24); this is also referenced in the diagnostic criteria of RCVS (18). TCHs are typical in RCVS, whereas they are subacute and progressive in PACNS. However, the headache characteristic is not useful when patients do not have headaches. Of note, a CSF analysis of convulsion and cerebral infarcts may show pleocytosis, as seen in our case (27,28). It is thus challenging to differentiate RCVS without headache and PACNS at first consultation, and we may need to initiate corticosteroid therapy because early treatment is indispensable to avoid poor outcomes in PACNS (29). The cerebrovascular abnormality observed in our case normalized completely and rapidly, while that of PACNS is frequently irreversible (30). Thus, our case was correctly diagnosed thanks to careful follow-up.
In conclusion, we experienced a patient with RCVS who presented with convulsion and dizziness. RCVS should be considered as a differential diagnosis for patients without headache whose MRA show multifocal segmental cerebral artery vasoconstriction. At the initial consultation, it is difficult to distinguish RCVS without headache from PACNS. The clinical course after the onset may play a key role in the diagnosis, and a biopsy should be considered according to the clinical course.
The authors state that they have no Conflict of Interest (COI). | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33612678 | 19,735,583 | 2021-07-15 |
What was the administration route of drug 'APREMILAST'? | Reversible Cerebral Vasoconstriction Syndrome without Headache That Was Initially Suspected of Being Primary Angiitis of the Central Nervous System.
A 48-year-old man had convulsions, and magnetic resonance angiography (MRA) showed diffuse constriction of the cerebral arteries. He was suspected of having primary angiitis of the central nervous system (PACNS) and treated with steroid for three days. The MRA abnormality disappeared after a week. After 69 days, he developed dizziness, and MRA revealed recurrence of cerebral artery stenosis. Nevertheless, the symptoms and abnormal MRA findings recovered promptly without treatment. He was diagnosed with reversible cerebral vasoconstriction syndrome (RCVS) without headache. This case suggests that RCVS should be a differential diagnosis in patients without headache whose MRA findings show multiple cerebral artery stenosis.
Introduction
Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical and radiologic syndrome characterized by a severe headache and multifocal segmental vasoconstriction of cerebral arteries that improves spontaneously within three months (1). A wide variety of brain lesions, such as convexity subarachnoid hemorrhaging (cSAH), intracerebral hemorrhaging (ICH), posterior reversible encephalopathy syndrome (PRES), and ischemic stroke (IS), are known to be complicated by RCVS (2). The characteristic headache is a thunderclap headache (TCH) that is hyperacute severe and reaches its maximal intensity in less than a minute (3). TCH is the most common symptom of RCVS, and 78-100% of patients experience TCH as initial manifestation (4-6). Thus, RCVS is typically diagnosed on the basis of the clinical and radiologic presentation by excluding other causes of TCH (7). In contrast, Wolff et al. reported that some patients with RCVS do not have TCH, and a few of them do not have any headache at all (8).
We herein report a patient with RCVS without headache over the course of two attacks whose symptoms were difficult to differentiate from those of primary angiitis of the central nervous system (PACNS).
Case Report
A 48-year-old man was transferred to our hospital due to a convulsion. In the morning of the day when he had the convulsion, he had conversed with his family in a normal healthy state. He was undergoing treatment for psoriasis vulgaris with apremilast and had a history of untreated hypertension.
When arriving at our hospital, his consciousness level was disturbed (Glasgow Coma Scale 4-4-5), and he was vomiting. Therefore, he was unable to follow the instructions of the medical staff. His blood pressure was 169/101 mmHg, pulse was 129 beats per minute, body temperature was 36.1°C, respiratory rate was 36 breaths per minute, and oxygen saturation was 100% (10 L/min reservoir mask). He had red scaly rashes on his limbs and trunk. His pupils were equal in size (3.0 mm in diameter), round, and reactive to light. Although it was difficult to evaluate his strength accurately due to disturbance of consciousness, there was no obvious motor paralysis. The deep tendon reflexes of all four limbs were decreased. He showed no meningeal signs, such as nuchal rigidity, Kernig's sign and Brudzinski's sign. Other physical and neurological examinations were normal.
On laboratory tests, his white blood cell (WBC) count was 20,000 /μL with 89.3% neutrophils. Both D-dimer (＜0.5 μg/mL) and C-reactive protein (＜0.05 mg/dL) levels were within the normal ranges. Immunological tests for rheumatoid factor, antinuclear antibodies, anti SS-A/SS-B antibodies, anti-neutrophil cytoplasmic antibody, anti-cardiolipin antibody, and lupus anticoagulant were negative. A cerebrospinal fluid (CSF) examination showed increased WBC counts (76/3 μL) with 99% lymphocytes, and normal ranges of protein (44 mg/dL), glucose (66 mg/dL), and IgG index (0.58). The CSF culture and herpes simplex virus (HSV)-1/2DNA test were negative.
Whole-body computed tomography (CT) with contrast revealed that there were no organs and blood vessels with poor contrast enhancement. Diffusion-weighted magnetic resonance imaging (MRI) of the head without contrast demonstrated a high signal intensity in the left deep white matter near the splenium of the corpus callosum, without a change in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI showed a high signal intensity in the same area. The lesion was suspected to be a subacute phase or later cerebral infarction (Fig. 1A). FLAIR MRI showed a low-intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhaging (Fig. 1A). FLAIR MRI also revealed multiple high-intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhaging, respectively (Fig. 1A, B). MRA revealed multifocal segmental cerebral artery vasoconstriction, which was most prominent in the bilateral posterior cerebral arteries (Fig. 2A).
Figure 1. Head MRI findings on admission. Upper (A) and lower panels (B) show axial slices at the level of the foramen of Monro and centrum semiovale, respectively. (A) Diffusion-weighted imaging (DWI) demonstrates a high signal intensity in the left deep white matter near the splenium of the corpus callosum; without changes in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI shows a high signal intensity in the same area, suggesting subacute phase or later cerebral infarction (yellow arrows). FLAIR MRI also shows a low intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhage (white arrows). (A, B) FLAIR MRI shows multiple high intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhage, respectively (red arrows).
Figure 2. Time course of the MRA and MRI findings 1 (A), 10 (B), 69 (C), 70 (D), and 295 days (E) after onset. (A) Multifocal segmental cerebral artery vasoconstriction is most prominent in the bilateral posterior cerebral arteries (yellow arrows). (B) Disappearance of the abnormal findings observed on day 1. (C) Multiple cerebral artery stenosis (red arrows). (D) Normalization of cerebral artery stenosis. (E) No new lesions were detected (orange arrows).
After arriving, he was intubated to secure the airway. Midazolam and propofol were used for sedation and to prevent convulsions. Levetiracetam and valproic acid were initiated for convulsion. Because he was suspected of PACNS based on the results of the MRA and CSF analysis, high-dose intravenous methylprednisolone (1,000 mg daily for 3 days) was initiated from the next day of hospitalization. Intravenous acyclovir (10 mg/kg Q8h) was administered until the result of HSV-DNA was confirmed to be negative. Paroxysmal waves were not detected on the electroencephalogram two days after administration. A follow-up CSF examination on day 8 showed normalized WBC counts (2/3 μL). The patient did not develop convulsions after hospitalization, so he was extubated. Follow-up MRA showed that the multifocal segmental cerebral artery vasoconstriction had disappeared (Fig. 2B). There were no neurological abnormalities, and he was discharged on day 26. On day 52, amlodipine was initiated for hypertension.
On day 69, he developed dizziness and consulted another hospital. MRA showed multiple cerebral artery stenosis (Fig. 2C), and he was transferred to our hospital on day 70. On arrival, MRI and CSF examinations were performed. MRI and MRA revealed no new intracranial lesions and cerebral artery stenosis, respectively (Fig. 2D). His CSF contained WBCs (1/3 μL) and protein (34.2 mg/dL) concentrations within the normal range. In addition, a neurological examination revealed no evidence of abnormal findings, and the dizziness had disappeared at arrival. The patient also reported that there was no headache during the course of the two clinical attacks. Finally, these findings led us to exclude PACNS, and he was diagnosed with RCVS without headache. No new lesions were detected on follow up MRI after hospital discharge on day 295 (Fig. 2E).
Discussion
The exact pathogenesis of headache in RCVS remains unclear (9); however, it is inferred that a sudden change in central vascular tone may stretch the vessel walls and result in TCH at the initial stage of RCVS (3). As with TCH, seizures are an early complication of RCVS, and are present in 1-17% of cases (1). Thus, the presence of headache in RCVS cases with seizure may be unclear, as patients with disturbed consciousness cannot describe their symptoms (10,11). Although the possibility that our patient had headache at the first hospitalization cannot be ruled out, he insisted that there was no headache during both the first hospitalization before the convulsion and the second hospitalization. Previous reports have presented detailed information of the clinical and radiological features of 10 patients with RCVS without headache (Table) (12-17). These reports showed several characteristics of RCVS without headache. First, all of the patients had cerebrovascular disease accompanied by RCVS; nine had ischemic stroke, and one had cSAH. In the present case, MRI showed subacute or later phase cerebral infarction and old hemorrhaging. These may have been complications of RCVS, as cerebrovascular disease is often associated with RCVS. Nonetheless, he did not have any symptoms before the day of the hospitalization. We concluded that RCVS did not accompany ischemic stroke at the time when he was hospitalized with the convulsion. This case suggests that RCVS can lead to asymptomatic attack, and it is rare for clinical RCVS attack without headache and cerebrovascular disease to occur together. Regarding the patient's dizziness, stenosis of the basilar artery seemed to result in the symptoms of a transient ischemic attack. Second, the clinical outcomes of almost all previously described patients were good, and all were under 50 years old. Our patient had common features with those patients in that no sequelae remained, and he was 48 years old.
Table. The Characteristics of Patients without Headache Associated with RCVS.
Case Age
(y) Sex Precipitant
factor Neurological symptoms Complications Outcome Reference
1 25 Female None Diplopia, right ataxia IS mRS 0 12
2 35 Male None Left hemiparesis IS mRS 0 12
3 27 Male Cannabis Right paresthesia IS mRS 0 12
4 38 Male Nasal decongestants Right ataxia, dysarthria IS mRS 1 12
5 36 Male None Vertigo, right hemiparesis IS mRS 0 12
6 31 Female Postpartum Serotonergic antidepressant Left hemiparesis IS Persistent deficit 13
7 24 Female Postpartum Generalized tonic-clonic seizure cSAH Asymptomatic 14
8 42 Male Cannabis Transient episodes of right hemiparesis IS Asymptomatic 15
9 32 Female Pregnancy Dizziness, diplopia IS mRS 0 16
10 46 Male None Visual field defect, left lower limb weakness IS NA 17
11 48 Male None First attack; None
Second attack; convulsion
Third attack; dizziness IS, ICH mRS 0 Our case
RCVS: reversible cerebral vasoconstriction syndrome, IS: ischemic stroke, cSAH: convexity subarachnoid hemorrhage, mRS: modified Rankin Scale, NA: not attributable, ICH: intracerebral hematoma
The diagnostic criteria for RCVS proposed by Calabrese in 2007 include the presence of severe acute headache (18). Clinically, RCVS is considered in patients with a hyperacute severe headache (18), whereas radiological aspects are important in cases of RCVS without headache (8). Multiple cerebral artery stenosis is a critical feature of RCVS. Many diseases, such as PACNS, secondary central nervous system vasculitis, infectious disease, multiple embolic cerebral infarcts, anti-phospholipid antibody syndrome, and Moyamoya disease, have the same feature (19). In our case, examinations such as laboratory tests, whole-body CT, and head MRI excluded differential diagnoses other than PACNS.
We initially suspected that PACNS was the cause of his symptoms based on the results of MRA and CSF studies. The classical diagnostic criteria for PACNS proposed by Calabrese and Mallek in 1988 include angiographic and histopathological examinations (20). As with digital subtraction angiography (DSA), MRA can also detect multilocular stenosis, multiple narrowing and dilatation, and other abnormal findings of intracranial vessels that are caused by central nervous system vasculitis (21) and can be implemented in the PACNS diagnostic approach (22). Nevertheless, the limited diagnostic specificity of MRA and DSA leads to difficulty distinguishing between PACNS and RCVS (23). Thus, Beuker et al. proposed considering a CSF profile for the PACNS diagnosis (24). In PACNS, the CSF analysis findings are abnormal (leucocytosis and high total protein concentrations); however, in RCVS, these findings are normal or near normal (protein concentrations ＜100 mg/dL, ＜15 WBC/μL) (18). In our case, PACNS was suspected rather than RCVS initially because the patient's MRA showed multifocal vessel narrowing, and his CSF study showed leucocytosis. DSA was not performed for two reasons. First, we had already detected abnormal MRA findings that were compatible with the diagnosis of PACNS. Second, DSA reportedly sometimes aggravates ischemic lesions of PACNS (25) and vasoconstriction of RCVS (2). In addition, we did not perform a biopsy before initiating corticosteroid therapy because it is highly invasive; however, a biopsy is crucial for a PACNS diagnosis (26). A biopsy is encouraged, especially when considering prolonged immunosuppressant treatment of patients suspected of PACNS (23).
In addition to CSF analyses, it has been reported that the characteristic headache can help distinguish RCVS from PACNS (24); this is also referenced in the diagnostic criteria of RCVS (18). TCHs are typical in RCVS, whereas they are subacute and progressive in PACNS. However, the headache characteristic is not useful when patients do not have headaches. Of note, a CSF analysis of convulsion and cerebral infarcts may show pleocytosis, as seen in our case (27,28). It is thus challenging to differentiate RCVS without headache and PACNS at first consultation, and we may need to initiate corticosteroid therapy because early treatment is indispensable to avoid poor outcomes in PACNS (29). The cerebrovascular abnormality observed in our case normalized completely and rapidly, while that of PACNS is frequently irreversible (30). Thus, our case was correctly diagnosed thanks to careful follow-up.
In conclusion, we experienced a patient with RCVS who presented with convulsion and dizziness. RCVS should be considered as a differential diagnosis for patients without headache whose MRA show multifocal segmental cerebral artery vasoconstriction. At the initial consultation, it is difficult to distinguish RCVS without headache from PACNS. The clinical course after the onset may play a key role in the diagnosis, and a biopsy should be considered according to the clinical course.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33612678 | 19,735,583 | 2021-07-15 |
What was the dosage of drug 'ACYCLOVIR'? | Reversible Cerebral Vasoconstriction Syndrome without Headache That Was Initially Suspected of Being Primary Angiitis of the Central Nervous System.
A 48-year-old man had convulsions, and magnetic resonance angiography (MRA) showed diffuse constriction of the cerebral arteries. He was suspected of having primary angiitis of the central nervous system (PACNS) and treated with steroid for three days. The MRA abnormality disappeared after a week. After 69 days, he developed dizziness, and MRA revealed recurrence of cerebral artery stenosis. Nevertheless, the symptoms and abnormal MRA findings recovered promptly without treatment. He was diagnosed with reversible cerebral vasoconstriction syndrome (RCVS) without headache. This case suggests that RCVS should be a differential diagnosis in patients without headache whose MRA findings show multiple cerebral artery stenosis.
Introduction
Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical and radiologic syndrome characterized by a severe headache and multifocal segmental vasoconstriction of cerebral arteries that improves spontaneously within three months (1). A wide variety of brain lesions, such as convexity subarachnoid hemorrhaging (cSAH), intracerebral hemorrhaging (ICH), posterior reversible encephalopathy syndrome (PRES), and ischemic stroke (IS), are known to be complicated by RCVS (2). The characteristic headache is a thunderclap headache (TCH) that is hyperacute severe and reaches its maximal intensity in less than a minute (3). TCH is the most common symptom of RCVS, and 78-100% of patients experience TCH as initial manifestation (4-6). Thus, RCVS is typically diagnosed on the basis of the clinical and radiologic presentation by excluding other causes of TCH (7). In contrast, Wolff et al. reported that some patients with RCVS do not have TCH, and a few of them do not have any headache at all (8).
We herein report a patient with RCVS without headache over the course of two attacks whose symptoms were difficult to differentiate from those of primary angiitis of the central nervous system (PACNS).
Case Report
A 48-year-old man was transferred to our hospital due to a convulsion. In the morning of the day when he had the convulsion, he had conversed with his family in a normal healthy state. He was undergoing treatment for psoriasis vulgaris with apremilast and had a history of untreated hypertension.
When arriving at our hospital, his consciousness level was disturbed (Glasgow Coma Scale 4-4-5), and he was vomiting. Therefore, he was unable to follow the instructions of the medical staff. His blood pressure was 169/101 mmHg, pulse was 129 beats per minute, body temperature was 36.1°C, respiratory rate was 36 breaths per minute, and oxygen saturation was 100% (10 L/min reservoir mask). He had red scaly rashes on his limbs and trunk. His pupils were equal in size (3.0 mm in diameter), round, and reactive to light. Although it was difficult to evaluate his strength accurately due to disturbance of consciousness, there was no obvious motor paralysis. The deep tendon reflexes of all four limbs were decreased. He showed no meningeal signs, such as nuchal rigidity, Kernig's sign and Brudzinski's sign. Other physical and neurological examinations were normal.
On laboratory tests, his white blood cell (WBC) count was 20,000 /μL with 89.3% neutrophils. Both D-dimer (＜0.5 μg/mL) and C-reactive protein (＜0.05 mg/dL) levels were within the normal ranges. Immunological tests for rheumatoid factor, antinuclear antibodies, anti SS-A/SS-B antibodies, anti-neutrophil cytoplasmic antibody, anti-cardiolipin antibody, and lupus anticoagulant were negative. A cerebrospinal fluid (CSF) examination showed increased WBC counts (76/3 μL) with 99% lymphocytes, and normal ranges of protein (44 mg/dL), glucose (66 mg/dL), and IgG index (0.58). The CSF culture and herpes simplex virus (HSV)-1/2DNA test were negative.
Whole-body computed tomography (CT) with contrast revealed that there were no organs and blood vessels with poor contrast enhancement. Diffusion-weighted magnetic resonance imaging (MRI) of the head without contrast demonstrated a high signal intensity in the left deep white matter near the splenium of the corpus callosum, without a change in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI showed a high signal intensity in the same area. The lesion was suspected to be a subacute phase or later cerebral infarction (Fig. 1A). FLAIR MRI showed a low-intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhaging (Fig. 1A). FLAIR MRI also revealed multiple high-intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhaging, respectively (Fig. 1A, B). MRA revealed multifocal segmental cerebral artery vasoconstriction, which was most prominent in the bilateral posterior cerebral arteries (Fig. 2A).
Figure 1. Head MRI findings on admission. Upper (A) and lower panels (B) show axial slices at the level of the foramen of Monro and centrum semiovale, respectively. (A) Diffusion-weighted imaging (DWI) demonstrates a high signal intensity in the left deep white matter near the splenium of the corpus callosum; without changes in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI shows a high signal intensity in the same area, suggesting subacute phase or later cerebral infarction (yellow arrows). FLAIR MRI also shows a low intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhage (white arrows). (A, B) FLAIR MRI shows multiple high intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhage, respectively (red arrows).
Figure 2. Time course of the MRA and MRI findings 1 (A), 10 (B), 69 (C), 70 (D), and 295 days (E) after onset. (A) Multifocal segmental cerebral artery vasoconstriction is most prominent in the bilateral posterior cerebral arteries (yellow arrows). (B) Disappearance of the abnormal findings observed on day 1. (C) Multiple cerebral artery stenosis (red arrows). (D) Normalization of cerebral artery stenosis. (E) No new lesions were detected (orange arrows).
After arriving, he was intubated to secure the airway. Midazolam and propofol were used for sedation and to prevent convulsions. Levetiracetam and valproic acid were initiated for convulsion. Because he was suspected of PACNS based on the results of the MRA and CSF analysis, high-dose intravenous methylprednisolone (1,000 mg daily for 3 days) was initiated from the next day of hospitalization. Intravenous acyclovir (10 mg/kg Q8h) was administered until the result of HSV-DNA was confirmed to be negative. Paroxysmal waves were not detected on the electroencephalogram two days after administration. A follow-up CSF examination on day 8 showed normalized WBC counts (2/3 μL). The patient did not develop convulsions after hospitalization, so he was extubated. Follow-up MRA showed that the multifocal segmental cerebral artery vasoconstriction had disappeared (Fig. 2B). There were no neurological abnormalities, and he was discharged on day 26. On day 52, amlodipine was initiated for hypertension.
On day 69, he developed dizziness and consulted another hospital. MRA showed multiple cerebral artery stenosis (Fig. 2C), and he was transferred to our hospital on day 70. On arrival, MRI and CSF examinations were performed. MRI and MRA revealed no new intracranial lesions and cerebral artery stenosis, respectively (Fig. 2D). His CSF contained WBCs (1/3 μL) and protein (34.2 mg/dL) concentrations within the normal range. In addition, a neurological examination revealed no evidence of abnormal findings, and the dizziness had disappeared at arrival. The patient also reported that there was no headache during the course of the two clinical attacks. Finally, these findings led us to exclude PACNS, and he was diagnosed with RCVS without headache. No new lesions were detected on follow up MRI after hospital discharge on day 295 (Fig. 2E).
Discussion
The exact pathogenesis of headache in RCVS remains unclear (9); however, it is inferred that a sudden change in central vascular tone may stretch the vessel walls and result in TCH at the initial stage of RCVS (3). As with TCH, seizures are an early complication of RCVS, and are present in 1-17% of cases (1). Thus, the presence of headache in RCVS cases with seizure may be unclear, as patients with disturbed consciousness cannot describe their symptoms (10,11). Although the possibility that our patient had headache at the first hospitalization cannot be ruled out, he insisted that there was no headache during both the first hospitalization before the convulsion and the second hospitalization. Previous reports have presented detailed information of the clinical and radiological features of 10 patients with RCVS without headache (Table) (12-17). These reports showed several characteristics of RCVS without headache. First, all of the patients had cerebrovascular disease accompanied by RCVS; nine had ischemic stroke, and one had cSAH. In the present case, MRI showed subacute or later phase cerebral infarction and old hemorrhaging. These may have been complications of RCVS, as cerebrovascular disease is often associated with RCVS. Nonetheless, he did not have any symptoms before the day of the hospitalization. We concluded that RCVS did not accompany ischemic stroke at the time when he was hospitalized with the convulsion. This case suggests that RCVS can lead to asymptomatic attack, and it is rare for clinical RCVS attack without headache and cerebrovascular disease to occur together. Regarding the patient's dizziness, stenosis of the basilar artery seemed to result in the symptoms of a transient ischemic attack. Second, the clinical outcomes of almost all previously described patients were good, and all were under 50 years old. Our patient had common features with those patients in that no sequelae remained, and he was 48 years old.
Table. The Characteristics of Patients without Headache Associated with RCVS.
Case Age
(y) Sex Precipitant
factor Neurological symptoms Complications Outcome Reference
1 25 Female None Diplopia, right ataxia IS mRS 0 12
2 35 Male None Left hemiparesis IS mRS 0 12
3 27 Male Cannabis Right paresthesia IS mRS 0 12
4 38 Male Nasal decongestants Right ataxia, dysarthria IS mRS 1 12
5 36 Male None Vertigo, right hemiparesis IS mRS 0 12
6 31 Female Postpartum Serotonergic antidepressant Left hemiparesis IS Persistent deficit 13
7 24 Female Postpartum Generalized tonic-clonic seizure cSAH Asymptomatic 14
8 42 Male Cannabis Transient episodes of right hemiparesis IS Asymptomatic 15
9 32 Female Pregnancy Dizziness, diplopia IS mRS 0 16
10 46 Male None Visual field defect, left lower limb weakness IS NA 17
11 48 Male None First attack; None
Second attack; convulsion
Third attack; dizziness IS, ICH mRS 0 Our case
RCVS: reversible cerebral vasoconstriction syndrome, IS: ischemic stroke, cSAH: convexity subarachnoid hemorrhage, mRS: modified Rankin Scale, NA: not attributable, ICH: intracerebral hematoma
The diagnostic criteria for RCVS proposed by Calabrese in 2007 include the presence of severe acute headache (18). Clinically, RCVS is considered in patients with a hyperacute severe headache (18), whereas radiological aspects are important in cases of RCVS without headache (8). Multiple cerebral artery stenosis is a critical feature of RCVS. Many diseases, such as PACNS, secondary central nervous system vasculitis, infectious disease, multiple embolic cerebral infarcts, anti-phospholipid antibody syndrome, and Moyamoya disease, have the same feature (19). In our case, examinations such as laboratory tests, whole-body CT, and head MRI excluded differential diagnoses other than PACNS.
We initially suspected that PACNS was the cause of his symptoms based on the results of MRA and CSF studies. The classical diagnostic criteria for PACNS proposed by Calabrese and Mallek in 1988 include angiographic and histopathological examinations (20). As with digital subtraction angiography (DSA), MRA can also detect multilocular stenosis, multiple narrowing and dilatation, and other abnormal findings of intracranial vessels that are caused by central nervous system vasculitis (21) and can be implemented in the PACNS diagnostic approach (22). Nevertheless, the limited diagnostic specificity of MRA and DSA leads to difficulty distinguishing between PACNS and RCVS (23). Thus, Beuker et al. proposed considering a CSF profile for the PACNS diagnosis (24). In PACNS, the CSF analysis findings are abnormal (leucocytosis and high total protein concentrations); however, in RCVS, these findings are normal or near normal (protein concentrations ＜100 mg/dL, ＜15 WBC/μL) (18). In our case, PACNS was suspected rather than RCVS initially because the patient's MRA showed multifocal vessel narrowing, and his CSF study showed leucocytosis. DSA was not performed for two reasons. First, we had already detected abnormal MRA findings that were compatible with the diagnosis of PACNS. Second, DSA reportedly sometimes aggravates ischemic lesions of PACNS (25) and vasoconstriction of RCVS (2). In addition, we did not perform a biopsy before initiating corticosteroid therapy because it is highly invasive; however, a biopsy is crucial for a PACNS diagnosis (26). A biopsy is encouraged, especially when considering prolonged immunosuppressant treatment of patients suspected of PACNS (23).
In addition to CSF analyses, it has been reported that the characteristic headache can help distinguish RCVS from PACNS (24); this is also referenced in the diagnostic criteria of RCVS (18). TCHs are typical in RCVS, whereas they are subacute and progressive in PACNS. However, the headache characteristic is not useful when patients do not have headaches. Of note, a CSF analysis of convulsion and cerebral infarcts may show pleocytosis, as seen in our case (27,28). It is thus challenging to differentiate RCVS without headache and PACNS at first consultation, and we may need to initiate corticosteroid therapy because early treatment is indispensable to avoid poor outcomes in PACNS (29). The cerebrovascular abnormality observed in our case normalized completely and rapidly, while that of PACNS is frequently irreversible (30). Thus, our case was correctly diagnosed thanks to careful follow-up.
In conclusion, we experienced a patient with RCVS who presented with convulsion and dizziness. RCVS should be considered as a differential diagnosis for patients without headache whose MRA show multifocal segmental cerebral artery vasoconstriction. At the initial consultation, it is difficult to distinguish RCVS without headache from PACNS. The clinical course after the onset may play a key role in the diagnosis, and a biopsy should be considered according to the clinical course.
The authors state that they have no Conflict of Interest (COI). | 10 MILLIGRAM/KILOGRAM, Q8H | DrugDosageText | CC BY-NC-ND | 33612678 | 19,735,583 | 2021-07-15 |
What was the dosage of drug 'APREMILAST'? | Reversible Cerebral Vasoconstriction Syndrome without Headache That Was Initially Suspected of Being Primary Angiitis of the Central Nervous System.
A 48-year-old man had convulsions, and magnetic resonance angiography (MRA) showed diffuse constriction of the cerebral arteries. He was suspected of having primary angiitis of the central nervous system (PACNS) and treated with steroid for three days. The MRA abnormality disappeared after a week. After 69 days, he developed dizziness, and MRA revealed recurrence of cerebral artery stenosis. Nevertheless, the symptoms and abnormal MRA findings recovered promptly without treatment. He was diagnosed with reversible cerebral vasoconstriction syndrome (RCVS) without headache. This case suggests that RCVS should be a differential diagnosis in patients without headache whose MRA findings show multiple cerebral artery stenosis.
Introduction
Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical and radiologic syndrome characterized by a severe headache and multifocal segmental vasoconstriction of cerebral arteries that improves spontaneously within three months (1). A wide variety of brain lesions, such as convexity subarachnoid hemorrhaging (cSAH), intracerebral hemorrhaging (ICH), posterior reversible encephalopathy syndrome (PRES), and ischemic stroke (IS), are known to be complicated by RCVS (2). The characteristic headache is a thunderclap headache (TCH) that is hyperacute severe and reaches its maximal intensity in less than a minute (3). TCH is the most common symptom of RCVS, and 78-100% of patients experience TCH as initial manifestation (4-6). Thus, RCVS is typically diagnosed on the basis of the clinical and radiologic presentation by excluding other causes of TCH (7). In contrast, Wolff et al. reported that some patients with RCVS do not have TCH, and a few of them do not have any headache at all (8).
We herein report a patient with RCVS without headache over the course of two attacks whose symptoms were difficult to differentiate from those of primary angiitis of the central nervous system (PACNS).
Case Report
A 48-year-old man was transferred to our hospital due to a convulsion. In the morning of the day when he had the convulsion, he had conversed with his family in a normal healthy state. He was undergoing treatment for psoriasis vulgaris with apremilast and had a history of untreated hypertension.
When arriving at our hospital, his consciousness level was disturbed (Glasgow Coma Scale 4-4-5), and he was vomiting. Therefore, he was unable to follow the instructions of the medical staff. His blood pressure was 169/101 mmHg, pulse was 129 beats per minute, body temperature was 36.1°C, respiratory rate was 36 breaths per minute, and oxygen saturation was 100% (10 L/min reservoir mask). He had red scaly rashes on his limbs and trunk. His pupils were equal in size (3.0 mm in diameter), round, and reactive to light. Although it was difficult to evaluate his strength accurately due to disturbance of consciousness, there was no obvious motor paralysis. The deep tendon reflexes of all four limbs were decreased. He showed no meningeal signs, such as nuchal rigidity, Kernig's sign and Brudzinski's sign. Other physical and neurological examinations were normal.
On laboratory tests, his white blood cell (WBC) count was 20,000 /μL with 89.3% neutrophils. Both D-dimer (＜0.5 μg/mL) and C-reactive protein (＜0.05 mg/dL) levels were within the normal ranges. Immunological tests for rheumatoid factor, antinuclear antibodies, anti SS-A/SS-B antibodies, anti-neutrophil cytoplasmic antibody, anti-cardiolipin antibody, and lupus anticoagulant were negative. A cerebrospinal fluid (CSF) examination showed increased WBC counts (76/3 μL) with 99% lymphocytes, and normal ranges of protein (44 mg/dL), glucose (66 mg/dL), and IgG index (0.58). The CSF culture and herpes simplex virus (HSV)-1/2DNA test were negative.
Whole-body computed tomography (CT) with contrast revealed that there were no organs and blood vessels with poor contrast enhancement. Diffusion-weighted magnetic resonance imaging (MRI) of the head without contrast demonstrated a high signal intensity in the left deep white matter near the splenium of the corpus callosum, without a change in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI showed a high signal intensity in the same area. The lesion was suspected to be a subacute phase or later cerebral infarction (Fig. 1A). FLAIR MRI showed a low-intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhaging (Fig. 1A). FLAIR MRI also revealed multiple high-intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhaging, respectively (Fig. 1A, B). MRA revealed multifocal segmental cerebral artery vasoconstriction, which was most prominent in the bilateral posterior cerebral arteries (Fig. 2A).
Figure 1. Head MRI findings on admission. Upper (A) and lower panels (B) show axial slices at the level of the foramen of Monro and centrum semiovale, respectively. (A) Diffusion-weighted imaging (DWI) demonstrates a high signal intensity in the left deep white matter near the splenium of the corpus callosum; without changes in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI shows a high signal intensity in the same area, suggesting subacute phase or later cerebral infarction (yellow arrows). FLAIR MRI also shows a low intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhage (white arrows). (A, B) FLAIR MRI shows multiple high intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhage, respectively (red arrows).
Figure 2. Time course of the MRA and MRI findings 1 (A), 10 (B), 69 (C), 70 (D), and 295 days (E) after onset. (A) Multifocal segmental cerebral artery vasoconstriction is most prominent in the bilateral posterior cerebral arteries (yellow arrows). (B) Disappearance of the abnormal findings observed on day 1. (C) Multiple cerebral artery stenosis (red arrows). (D) Normalization of cerebral artery stenosis. (E) No new lesions were detected (orange arrows).
After arriving, he was intubated to secure the airway. Midazolam and propofol were used for sedation and to prevent convulsions. Levetiracetam and valproic acid were initiated for convulsion. Because he was suspected of PACNS based on the results of the MRA and CSF analysis, high-dose intravenous methylprednisolone (1,000 mg daily for 3 days) was initiated from the next day of hospitalization. Intravenous acyclovir (10 mg/kg Q8h) was administered until the result of HSV-DNA was confirmed to be negative. Paroxysmal waves were not detected on the electroencephalogram two days after administration. A follow-up CSF examination on day 8 showed normalized WBC counts (2/3 μL). The patient did not develop convulsions after hospitalization, so he was extubated. Follow-up MRA showed that the multifocal segmental cerebral artery vasoconstriction had disappeared (Fig. 2B). There were no neurological abnormalities, and he was discharged on day 26. On day 52, amlodipine was initiated for hypertension.
On day 69, he developed dizziness and consulted another hospital. MRA showed multiple cerebral artery stenosis (Fig. 2C), and he was transferred to our hospital on day 70. On arrival, MRI and CSF examinations were performed. MRI and MRA revealed no new intracranial lesions and cerebral artery stenosis, respectively (Fig. 2D). His CSF contained WBCs (1/3 μL) and protein (34.2 mg/dL) concentrations within the normal range. In addition, a neurological examination revealed no evidence of abnormal findings, and the dizziness had disappeared at arrival. The patient also reported that there was no headache during the course of the two clinical attacks. Finally, these findings led us to exclude PACNS, and he was diagnosed with RCVS without headache. No new lesions were detected on follow up MRI after hospital discharge on day 295 (Fig. 2E).
Discussion
The exact pathogenesis of headache in RCVS remains unclear (9); however, it is inferred that a sudden change in central vascular tone may stretch the vessel walls and result in TCH at the initial stage of RCVS (3). As with TCH, seizures are an early complication of RCVS, and are present in 1-17% of cases (1). Thus, the presence of headache in RCVS cases with seizure may be unclear, as patients with disturbed consciousness cannot describe their symptoms (10,11). Although the possibility that our patient had headache at the first hospitalization cannot be ruled out, he insisted that there was no headache during both the first hospitalization before the convulsion and the second hospitalization. Previous reports have presented detailed information of the clinical and radiological features of 10 patients with RCVS without headache (Table) (12-17). These reports showed several characteristics of RCVS without headache. First, all of the patients had cerebrovascular disease accompanied by RCVS; nine had ischemic stroke, and one had cSAH. In the present case, MRI showed subacute or later phase cerebral infarction and old hemorrhaging. These may have been complications of RCVS, as cerebrovascular disease is often associated with RCVS. Nonetheless, he did not have any symptoms before the day of the hospitalization. We concluded that RCVS did not accompany ischemic stroke at the time when he was hospitalized with the convulsion. This case suggests that RCVS can lead to asymptomatic attack, and it is rare for clinical RCVS attack without headache and cerebrovascular disease to occur together. Regarding the patient's dizziness, stenosis of the basilar artery seemed to result in the symptoms of a transient ischemic attack. Second, the clinical outcomes of almost all previously described patients were good, and all were under 50 years old. Our patient had common features with those patients in that no sequelae remained, and he was 48 years old.
Table. The Characteristics of Patients without Headache Associated with RCVS.
Case Age
(y) Sex Precipitant
factor Neurological symptoms Complications Outcome Reference
1 25 Female None Diplopia, right ataxia IS mRS 0 12
2 35 Male None Left hemiparesis IS mRS 0 12
3 27 Male Cannabis Right paresthesia IS mRS 0 12
4 38 Male Nasal decongestants Right ataxia, dysarthria IS mRS 1 12
5 36 Male None Vertigo, right hemiparesis IS mRS 0 12
6 31 Female Postpartum Serotonergic antidepressant Left hemiparesis IS Persistent deficit 13
7 24 Female Postpartum Generalized tonic-clonic seizure cSAH Asymptomatic 14
8 42 Male Cannabis Transient episodes of right hemiparesis IS Asymptomatic 15
9 32 Female Pregnancy Dizziness, diplopia IS mRS 0 16
10 46 Male None Visual field defect, left lower limb weakness IS NA 17
11 48 Male None First attack; None
Second attack; convulsion
Third attack; dizziness IS, ICH mRS 0 Our case
RCVS: reversible cerebral vasoconstriction syndrome, IS: ischemic stroke, cSAH: convexity subarachnoid hemorrhage, mRS: modified Rankin Scale, NA: not attributable, ICH: intracerebral hematoma
The diagnostic criteria for RCVS proposed by Calabrese in 2007 include the presence of severe acute headache (18). Clinically, RCVS is considered in patients with a hyperacute severe headache (18), whereas radiological aspects are important in cases of RCVS without headache (8). Multiple cerebral artery stenosis is a critical feature of RCVS. Many diseases, such as PACNS, secondary central nervous system vasculitis, infectious disease, multiple embolic cerebral infarcts, anti-phospholipid antibody syndrome, and Moyamoya disease, have the same feature (19). In our case, examinations such as laboratory tests, whole-body CT, and head MRI excluded differential diagnoses other than PACNS.
We initially suspected that PACNS was the cause of his symptoms based on the results of MRA and CSF studies. The classical diagnostic criteria for PACNS proposed by Calabrese and Mallek in 1988 include angiographic and histopathological examinations (20). As with digital subtraction angiography (DSA), MRA can also detect multilocular stenosis, multiple narrowing and dilatation, and other abnormal findings of intracranial vessels that are caused by central nervous system vasculitis (21) and can be implemented in the PACNS diagnostic approach (22). Nevertheless, the limited diagnostic specificity of MRA and DSA leads to difficulty distinguishing between PACNS and RCVS (23). Thus, Beuker et al. proposed considering a CSF profile for the PACNS diagnosis (24). In PACNS, the CSF analysis findings are abnormal (leucocytosis and high total protein concentrations); however, in RCVS, these findings are normal or near normal (protein concentrations ＜100 mg/dL, ＜15 WBC/μL) (18). In our case, PACNS was suspected rather than RCVS initially because the patient's MRA showed multifocal vessel narrowing, and his CSF study showed leucocytosis. DSA was not performed for two reasons. First, we had already detected abnormal MRA findings that were compatible with the diagnosis of PACNS. Second, DSA reportedly sometimes aggravates ischemic lesions of PACNS (25) and vasoconstriction of RCVS (2). In addition, we did not perform a biopsy before initiating corticosteroid therapy because it is highly invasive; however, a biopsy is crucial for a PACNS diagnosis (26). A biopsy is encouraged, especially when considering prolonged immunosuppressant treatment of patients suspected of PACNS (23).
In addition to CSF analyses, it has been reported that the characteristic headache can help distinguish RCVS from PACNS (24); this is also referenced in the diagnostic criteria of RCVS (18). TCHs are typical in RCVS, whereas they are subacute and progressive in PACNS. However, the headache characteristic is not useful when patients do not have headaches. Of note, a CSF analysis of convulsion and cerebral infarcts may show pleocytosis, as seen in our case (27,28). It is thus challenging to differentiate RCVS without headache and PACNS at first consultation, and we may need to initiate corticosteroid therapy because early treatment is indispensable to avoid poor outcomes in PACNS (29). The cerebrovascular abnormality observed in our case normalized completely and rapidly, while that of PACNS is frequently irreversible (30). Thus, our case was correctly diagnosed thanks to careful follow-up.
In conclusion, we experienced a patient with RCVS who presented with convulsion and dizziness. RCVS should be considered as a differential diagnosis for patients without headache whose MRA show multifocal segmental cerebral artery vasoconstriction. At the initial consultation, it is difficult to distinguish RCVS without headache from PACNS. The clinical course after the onset may play a key role in the diagnosis, and a biopsy should be considered according to the clinical course.
The authors state that they have no Conflict of Interest (COI). | 30 MILLIGRAM, BID | DrugDosageText | CC BY-NC-ND | 33612678 | 19,735,583 | 2021-07-15 |
What was the outcome of reaction 'Reversible cerebral vasoconstriction syndrome'? | Reversible Cerebral Vasoconstriction Syndrome without Headache That Was Initially Suspected of Being Primary Angiitis of the Central Nervous System.
A 48-year-old man had convulsions, and magnetic resonance angiography (MRA) showed diffuse constriction of the cerebral arteries. He was suspected of having primary angiitis of the central nervous system (PACNS) and treated with steroid for three days. The MRA abnormality disappeared after a week. After 69 days, he developed dizziness, and MRA revealed recurrence of cerebral artery stenosis. Nevertheless, the symptoms and abnormal MRA findings recovered promptly without treatment. He was diagnosed with reversible cerebral vasoconstriction syndrome (RCVS) without headache. This case suggests that RCVS should be a differential diagnosis in patients without headache whose MRA findings show multiple cerebral artery stenosis.
Introduction
Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical and radiologic syndrome characterized by a severe headache and multifocal segmental vasoconstriction of cerebral arteries that improves spontaneously within three months (1). A wide variety of brain lesions, such as convexity subarachnoid hemorrhaging (cSAH), intracerebral hemorrhaging (ICH), posterior reversible encephalopathy syndrome (PRES), and ischemic stroke (IS), are known to be complicated by RCVS (2). The characteristic headache is a thunderclap headache (TCH) that is hyperacute severe and reaches its maximal intensity in less than a minute (3). TCH is the most common symptom of RCVS, and 78-100% of patients experience TCH as initial manifestation (4-6). Thus, RCVS is typically diagnosed on the basis of the clinical and radiologic presentation by excluding other causes of TCH (7). In contrast, Wolff et al. reported that some patients with RCVS do not have TCH, and a few of them do not have any headache at all (8).
We herein report a patient with RCVS without headache over the course of two attacks whose symptoms were difficult to differentiate from those of primary angiitis of the central nervous system (PACNS).
Case Report
A 48-year-old man was transferred to our hospital due to a convulsion. In the morning of the day when he had the convulsion, he had conversed with his family in a normal healthy state. He was undergoing treatment for psoriasis vulgaris with apremilast and had a history of untreated hypertension.
When arriving at our hospital, his consciousness level was disturbed (Glasgow Coma Scale 4-4-5), and he was vomiting. Therefore, he was unable to follow the instructions of the medical staff. His blood pressure was 169/101 mmHg, pulse was 129 beats per minute, body temperature was 36.1°C, respiratory rate was 36 breaths per minute, and oxygen saturation was 100% (10 L/min reservoir mask). He had red scaly rashes on his limbs and trunk. His pupils were equal in size (3.0 mm in diameter), round, and reactive to light. Although it was difficult to evaluate his strength accurately due to disturbance of consciousness, there was no obvious motor paralysis. The deep tendon reflexes of all four limbs were decreased. He showed no meningeal signs, such as nuchal rigidity, Kernig's sign and Brudzinski's sign. Other physical and neurological examinations were normal.
On laboratory tests, his white blood cell (WBC) count was 20,000 /μL with 89.3% neutrophils. Both D-dimer (＜0.5 μg/mL) and C-reactive protein (＜0.05 mg/dL) levels were within the normal ranges. Immunological tests for rheumatoid factor, antinuclear antibodies, anti SS-A/SS-B antibodies, anti-neutrophil cytoplasmic antibody, anti-cardiolipin antibody, and lupus anticoagulant were negative. A cerebrospinal fluid (CSF) examination showed increased WBC counts (76/3 μL) with 99% lymphocytes, and normal ranges of protein (44 mg/dL), glucose (66 mg/dL), and IgG index (0.58). The CSF culture and herpes simplex virus (HSV)-1/2DNA test were negative.
Whole-body computed tomography (CT) with contrast revealed that there were no organs and blood vessels with poor contrast enhancement. Diffusion-weighted magnetic resonance imaging (MRI) of the head without contrast demonstrated a high signal intensity in the left deep white matter near the splenium of the corpus callosum, without a change in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI showed a high signal intensity in the same area. The lesion was suspected to be a subacute phase or later cerebral infarction (Fig. 1A). FLAIR MRI showed a low-intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhaging (Fig. 1A). FLAIR MRI also revealed multiple high-intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhaging, respectively (Fig. 1A, B). MRA revealed multifocal segmental cerebral artery vasoconstriction, which was most prominent in the bilateral posterior cerebral arteries (Fig. 2A).
Figure 1. Head MRI findings on admission. Upper (A) and lower panels (B) show axial slices at the level of the foramen of Monro and centrum semiovale, respectively. (A) Diffusion-weighted imaging (DWI) demonstrates a high signal intensity in the left deep white matter near the splenium of the corpus callosum; without changes in the apparent diffusion coefficient (ADC). Fluid-attenuated inversion recovery (FLAIR) MRI shows a high signal intensity in the same area, suggesting subacute phase or later cerebral infarction (yellow arrows). FLAIR MRI also shows a low intensity area near the cerebral infarction with a low intensity on T2 star-weighted imaging, indicating old hemorrhage (white arrows). (A, B) FLAIR MRI shows multiple high intensity areas in the left frontal lobe and right deep white matter with or without low intensity on T2 star-weighted imaging, indicating old infarction or hemorrhage, respectively (red arrows).
Figure 2. Time course of the MRA and MRI findings 1 (A), 10 (B), 69 (C), 70 (D), and 295 days (E) after onset. (A) Multifocal segmental cerebral artery vasoconstriction is most prominent in the bilateral posterior cerebral arteries (yellow arrows). (B) Disappearance of the abnormal findings observed on day 1. (C) Multiple cerebral artery stenosis (red arrows). (D) Normalization of cerebral artery stenosis. (E) No new lesions were detected (orange arrows).
After arriving, he was intubated to secure the airway. Midazolam and propofol were used for sedation and to prevent convulsions. Levetiracetam and valproic acid were initiated for convulsion. Because he was suspected of PACNS based on the results of the MRA and CSF analysis, high-dose intravenous methylprednisolone (1,000 mg daily for 3 days) was initiated from the next day of hospitalization. Intravenous acyclovir (10 mg/kg Q8h) was administered until the result of HSV-DNA was confirmed to be negative. Paroxysmal waves were not detected on the electroencephalogram two days after administration. A follow-up CSF examination on day 8 showed normalized WBC counts (2/3 μL). The patient did not develop convulsions after hospitalization, so he was extubated. Follow-up MRA showed that the multifocal segmental cerebral artery vasoconstriction had disappeared (Fig. 2B). There were no neurological abnormalities, and he was discharged on day 26. On day 52, amlodipine was initiated for hypertension.
On day 69, he developed dizziness and consulted another hospital. MRA showed multiple cerebral artery stenosis (Fig. 2C), and he was transferred to our hospital on day 70. On arrival, MRI and CSF examinations were performed. MRI and MRA revealed no new intracranial lesions and cerebral artery stenosis, respectively (Fig. 2D). His CSF contained WBCs (1/3 μL) and protein (34.2 mg/dL) concentrations within the normal range. In addition, a neurological examination revealed no evidence of abnormal findings, and the dizziness had disappeared at arrival. The patient also reported that there was no headache during the course of the two clinical attacks. Finally, these findings led us to exclude PACNS, and he was diagnosed with RCVS without headache. No new lesions were detected on follow up MRI after hospital discharge on day 295 (Fig. 2E).
Discussion
The exact pathogenesis of headache in RCVS remains unclear (9); however, it is inferred that a sudden change in central vascular tone may stretch the vessel walls and result in TCH at the initial stage of RCVS (3). As with TCH, seizures are an early complication of RCVS, and are present in 1-17% of cases (1). Thus, the presence of headache in RCVS cases with seizure may be unclear, as patients with disturbed consciousness cannot describe their symptoms (10,11). Although the possibility that our patient had headache at the first hospitalization cannot be ruled out, he insisted that there was no headache during both the first hospitalization before the convulsion and the second hospitalization. Previous reports have presented detailed information of the clinical and radiological features of 10 patients with RCVS without headache (Table) (12-17). These reports showed several characteristics of RCVS without headache. First, all of the patients had cerebrovascular disease accompanied by RCVS; nine had ischemic stroke, and one had cSAH. In the present case, MRI showed subacute or later phase cerebral infarction and old hemorrhaging. These may have been complications of RCVS, as cerebrovascular disease is often associated with RCVS. Nonetheless, he did not have any symptoms before the day of the hospitalization. We concluded that RCVS did not accompany ischemic stroke at the time when he was hospitalized with the convulsion. This case suggests that RCVS can lead to asymptomatic attack, and it is rare for clinical RCVS attack without headache and cerebrovascular disease to occur together. Regarding the patient's dizziness, stenosis of the basilar artery seemed to result in the symptoms of a transient ischemic attack. Second, the clinical outcomes of almost all previously described patients were good, and all were under 50 years old. Our patient had common features with those patients in that no sequelae remained, and he was 48 years old.
Table. The Characteristics of Patients without Headache Associated with RCVS.
Case Age
(y) Sex Precipitant
factor Neurological symptoms Complications Outcome Reference
1 25 Female None Diplopia, right ataxia IS mRS 0 12
2 35 Male None Left hemiparesis IS mRS 0 12
3 27 Male Cannabis Right paresthesia IS mRS 0 12
4 38 Male Nasal decongestants Right ataxia, dysarthria IS mRS 1 12
5 36 Male None Vertigo, right hemiparesis IS mRS 0 12
6 31 Female Postpartum Serotonergic antidepressant Left hemiparesis IS Persistent deficit 13
7 24 Female Postpartum Generalized tonic-clonic seizure cSAH Asymptomatic 14
8 42 Male Cannabis Transient episodes of right hemiparesis IS Asymptomatic 15
9 32 Female Pregnancy Dizziness, diplopia IS mRS 0 16
10 46 Male None Visual field defect, left lower limb weakness IS NA 17
11 48 Male None First attack; None
Second attack; convulsion
Third attack; dizziness IS, ICH mRS 0 Our case
RCVS: reversible cerebral vasoconstriction syndrome, IS: ischemic stroke, cSAH: convexity subarachnoid hemorrhage, mRS: modified Rankin Scale, NA: not attributable, ICH: intracerebral hematoma
The diagnostic criteria for RCVS proposed by Calabrese in 2007 include the presence of severe acute headache (18). Clinically, RCVS is considered in patients with a hyperacute severe headache (18), whereas radiological aspects are important in cases of RCVS without headache (8). Multiple cerebral artery stenosis is a critical feature of RCVS. Many diseases, such as PACNS, secondary central nervous system vasculitis, infectious disease, multiple embolic cerebral infarcts, anti-phospholipid antibody syndrome, and Moyamoya disease, have the same feature (19). In our case, examinations such as laboratory tests, whole-body CT, and head MRI excluded differential diagnoses other than PACNS.
We initially suspected that PACNS was the cause of his symptoms based on the results of MRA and CSF studies. The classical diagnostic criteria for PACNS proposed by Calabrese and Mallek in 1988 include angiographic and histopathological examinations (20). As with digital subtraction angiography (DSA), MRA can also detect multilocular stenosis, multiple narrowing and dilatation, and other abnormal findings of intracranial vessels that are caused by central nervous system vasculitis (21) and can be implemented in the PACNS diagnostic approach (22). Nevertheless, the limited diagnostic specificity of MRA and DSA leads to difficulty distinguishing between PACNS and RCVS (23). Thus, Beuker et al. proposed considering a CSF profile for the PACNS diagnosis (24). In PACNS, the CSF analysis findings are abnormal (leucocytosis and high total protein concentrations); however, in RCVS, these findings are normal or near normal (protein concentrations ＜100 mg/dL, ＜15 WBC/μL) (18). In our case, PACNS was suspected rather than RCVS initially because the patient's MRA showed multifocal vessel narrowing, and his CSF study showed leucocytosis. DSA was not performed for two reasons. First, we had already detected abnormal MRA findings that were compatible with the diagnosis of PACNS. Second, DSA reportedly sometimes aggravates ischemic lesions of PACNS (25) and vasoconstriction of RCVS (2). In addition, we did not perform a biopsy before initiating corticosteroid therapy because it is highly invasive; however, a biopsy is crucial for a PACNS diagnosis (26). A biopsy is encouraged, especially when considering prolonged immunosuppressant treatment of patients suspected of PACNS (23).
In addition to CSF analyses, it has been reported that the characteristic headache can help distinguish RCVS from PACNS (24); this is also referenced in the diagnostic criteria of RCVS (18). TCHs are typical in RCVS, whereas they are subacute and progressive in PACNS. However, the headache characteristic is not useful when patients do not have headaches. Of note, a CSF analysis of convulsion and cerebral infarcts may show pleocytosis, as seen in our case (27,28). It is thus challenging to differentiate RCVS without headache and PACNS at first consultation, and we may need to initiate corticosteroid therapy because early treatment is indispensable to avoid poor outcomes in PACNS (29). The cerebrovascular abnormality observed in our case normalized completely and rapidly, while that of PACNS is frequently irreversible (30). Thus, our case was correctly diagnosed thanks to careful follow-up.
In conclusion, we experienced a patient with RCVS who presented with convulsion and dizziness. RCVS should be considered as a differential diagnosis for patients without headache whose MRA show multifocal segmental cerebral artery vasoconstriction. At the initial consultation, it is difficult to distinguish RCVS without headache from PACNS. The clinical course after the onset may play a key role in the diagnosis, and a biopsy should be considered according to the clinical course.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33612678 | 19,735,583 | 2021-07-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug-induced liver injury'. | Severe Liver Injury Associated with Glecaprevir Plus Pibrentasvir Therapy in a Patient with Treatment-naïve Hepatitis C Virus Infection.
A 49-year-old man underwent treatment with glecaprevir plus pibrentasvir (G/P) for chronic hepatitis C infection. Six weeks later, he was admitted to our hospital because of jaundice and fatigue with no accompanying skin rash. A laboratory examination and evaluation of the patient's history resulted in a diagnosis of acute liver injury. Discontinuation of G/P and a rigorous medical protocol, including plasma exchange and hemodiafiltration, successfully mitigated the liver damage. The patient was also found to be allergic to two drugs other than the G/P therapy. In such cases with a history of drug allergy, careful observation may be required to detect serious adverse events.
Introduction
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (1). With the introduction of direct-acting antiviral agents (DAAs), the efficacy and safety of the treatment of chronic hepatitis C infection has improved significantly (2). Glecaprevir [nonstructural protein 3/4A (NS3/4A) protease inhibitor] plus pibrentasvir [nonstructural protein 5A (NS5A) inhibitor] (G/P) therapy comprises ribavirin-free treatment with a DAA and has the advantage of a shorter treatment duration than other regimens; furthermore, the treatment is pan-genotypic and thus recommended for all genotypes of HCV infection (3).
G/P has been reported to exhibit a strong antiviral effect with a good safety profile and a low rate of side effects (4-6). However, we observed one instance of severe liver injury that occurred during the administration of G/P in a patient with treatment-naïve genotype 1b HCV infection. The individual risk of drug-induced liver injury (DILI) and its associated clinical phenotype are likely to be determined by the complex interplay between the physiochemical and toxicological properties of drugs, host factors, and the resulting interactions between them (7).
We herein report a rare case of an adverse event caused by interplay between G/P therapy and host risk factors.
Case Report
The patient was a 49-year-old man (height: 175.0 cm; weight: 77.2 kg; body mass index: 25.2) with a tattoo and a history of allergy with isopropylantipyrine. He was first referred to our hospital due to liver dysfunction at the age of 48. He had underlying conditions of insomnia and reflux esophagitis, for which he had been taking etizolam, brotizolam, and esomeprazole.
His workup revealed co-infection with HCV (genotype 1b, 5.8 log IU/mL) and hepatitis B virus (HBV) (genotype C, quantity undetectable). Since the level of serum HBV DNA level was negative, and the level of hepatitis B surface antigen (HBs-Ag) was low (33.7 IU/mL), he was diagnosed as an inactive HBV carrier. Although the patient had stopped consuming alcohol, he had previously consumed ethanol equivalent to 60 g a day. Six months after he stopped, he started treatment with an 8-week course for HCV with 3 tablets of glecaprevir (100 mg)/ pibrentasvir (40 mg) once a day. The patient’s laboratory data at the treatment initiation are shown in Table 1.
Table 1. Laboratory Data at the Start of Glecaprevir Plus Pibrentasvir Therapy.
Variable Variable
White blood cells (/µL) 5,880 Total protein (g/dL) 7.3
Neutrophils (%) 50.0 Albumin (g/dL) 3.9
Eosinophils (%) 1.7 Total bilirubin (mg/dL) 1.1
Basophils (%) 0.7 AST (IU/L) 100
Monocytes (%) 11.4 ALT (IU/L) 51
Lymphocytes (%) 36.2 LDH (IU/L) 185
Red blood cells (104/µL) 409 ALP (IU/L) 436
Hematocrit (%) 41.4 GGT (IU/L) 125
Hemoglobin (g/dL) 14.0 BUN (mg/dL) 10
Platelets (104/µL) 19.2 Creatinine (mg/dL) 0.66
C-reactive protein (mg/dL) 0.05
Glucose (mg/dL) 162 HCV-RNA (log IU/mL) 1.4
HBsAg (IU/mL) 18.2
PT-INR 1.21 HBV-DNA (log IU/mL) negative
PT (%) 67.8 HBcrAg (log U/mL) ≤2.9
FIB-4 index 3.57 HBV genotype C
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, FIB-4 index: fibrosis-4 index, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, BUN: blood urea nitrogen, HCV-RNA: hepatitis C virus RNA, HBsAg: hepatitis B surface antigen, HBV-DNA: hepatitis B virus DNA, HBcrAg: hepatitis B core-related antigen
After 6 weeks of G/P, the patient complained of vomiting, abdominal pain, and jaundice. He visited our hospital 3 days later and was found to have severe liver injury with a total bilirubin (T-Bil) level of 20.6 mg/dL. The patient’s data with regard to laboratory parameters and antibodies to other possible viral infections are summarized in Table 2. HBV reactivation was excluded from the causes of liver injury, as the level of serum HBV DNA remained negative, and the level of HBs-Ag was low (7.8 IU/mL). Since there was no history of recent ingestion of other drugs or alcohol, we considered the possibility of DILI due to the G/P therapy, and G/P was immediately discontinued. During treatment with G/P, the patient had complained of fatigue, although he did not experience skin rash or a fever. The results of a drug-induced lymphocyte stimulation test (DLST) for G/P were negative. Based on the Digestive Disease Week Japan 2004 (DDW-J) scale (8), this type of liver damage was classified as cholestatic liver injury, and an association between G/P and liver injury was deemed possible (score of 4).
Table 2. Laboratory Data on Admission.
Variable Variable
White blood cells (/µL) 10,260 Total protein (g/dL) 7.2
Neutrophils (%) 78.4 Albumin (g/dL) 3.6
Eosinophils (%) 0.5 Total bilirubin (mg/dL) 20.6
Basophils (%) 0.1 Direct bilirubin (mg/dL) 15.4
Monocytes (%) 7.0 AST (IU/L) 205
Lymphocytes (%) 14.0 ALT (IU/L) 65
Red blood cells (104/µL) 372 LDH (IU/L) 246
Hematocrit (%) 34.1 ALP (IU/L) 442
Hemoglobin (g/dL) 12.3 GGT (IU/L) 124
Platelets (104/µL) 11.7 BUN (mg/dL) 4
C-reactive protein (mg/dL) 0.65 Creatinine (mg/dL) 0.88
Glucose (mg/dL) 178 NH3(mg/dL) 55
HbA1c (N) (%) 6.8 HCV-RNA (log IU/mL) negative
HBsAg (IU/mL) 7.8
PT-INR 1.21 IgM anti-HBc (-)
PT (%) 67.8 HBV-DNA (log IU/mL) negative
FIB-4 index 10.65 HBeAg (-)
HBeAb (%) (+)
IgG (mg/dL) 1,462 HBcrAg (log U/mL) ≤2.9
IgA (mg/dL) 421 IgM anti-HAV (-)
IgM (mg/dL) 101 IgA anti-HEV (-)
IgE (IU/mL) 18 IgM anti-EBV VCA (-)
Anti-nuclear antibody <40 IgG anti-EBV VCA (+)
Anti-mitochondria M2 1.4 EBNA (-)
Anti-smooth muscle <20 IgM anti-CMV (-)
Anti-LKM1 <5.0 IgM anti-HSV (-)
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, FIB-4 index: fibrosis-4 index, HbA1c (N): glycated hemoglobin, Ig: immunoglobulin, Anti-LKM1: anti-liver-kidney microsome type 1 antibody, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, BUN: blood urea nitrogen, HCV-RNA: hepatitis C virus RNA, HBsAg: hepatitis B surface antigen, anti-HBc: hepatitis B virus core antibody, HBV-DNA: hepatitis B virus DNA, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen, anti-HAV: anti-hepatitis A virus antibody, HEV: hepatitis E virus, anti-EBV VCA: anti-Epstein-Barr virus capsid antigen antibody, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, HSV: herpes simplex virus
A physical examination on admission showed neither ascites nor signs of hepatic encephalopathy. The clinical course is summarized in Fig. 1 (date of hospitalization was labeled as day 0). In addition, serial changes in liver function tests and viral markers are shown in Table 3. After hospitalization, the serum T-Bil level gradually improved without any treatment, but the prothrombin time (PT) level worsened. On day 9, the patient developed asterixis and was diagnosed with grade II hepatic encephalopathy. Although the observed PT (54.7%) did not meet the criteria for acute liver failure (9), since the patient was developing hepatic encephalopathy, plasma exchange (PE) and hemodiafiltration (HDF) procedures were initiated along with oral treatment of lactulose and rifaximin. After three PE sessions, and one HDF session, his liver function improved, and he recovered from hepatic encephalopathy. Each PE session included the administration of 40 units of fresh-frozen plasma (FFP). One hour after initiating the first PE session, the patient developed an anaphylactic reaction (skin rashes with slight dyspnea), and was treated with methylprednisolone (125 mg). Consequently, he was started on tenofovir alafenamide fumarate (TAF) to prevent HBV reactivation. However, no side effects were observed when FFP was administered on day 8.
Figure 1. Clinical course. Days indicate days from admission. CEZ: cefazolin, FFP: fresh-frozen plasma, G/P: glecaprevir plus pibrentasvir, HDF: hemodiafiltration, mPSL: methylprednisolone, PE: plasma exchange, TAF: tenofovir alafenamide fumarate, VCM: vancomycin
Table 3. Serial Changes in Liver Function Tests, and Viral Markers during the Clinical Course.
Diagnosis of HCV Base line Hospital admission H.E. H.E. H.E.
Date from admission 1 year ago -45 -31 -17 0 9 14 22 23 33 41
Treatment contents G/P
started G/P
stopped PE mPSL PE mPSL PE mPSL HDF Liver biopsy
T.Bil (mg/dL) 1.5 1.1 0.7 1.1 20.6 11.9 5.5 3 2.4 2 1.4
AST (IU/L) 224 100 112 100 205 133 86 48 33 63 36
ALT (IU/L) 107 51 63 51 65 56 45 27 22 30 15
ALP (IU/L) 295 436 490 436 442 676 1,039 1,020 620 879 560
GGT (IU/L) 659 125 83 125 124 138 207 274 131 141 84
NH3 (mg/dL) N.E. N.E. N.E. N.E. 73 81 118 113 87 N.E. 71
PT (%) 92.0 87.4 97.0 83.7 67.8 54.7 58.3 62.3 72.9 75.1 77.4
HCV-RNA (log IU/mL) 5.8 1.4 negative N.E. N.E. N.E. N.E. N.E. N.E. negative N.E.
HBV-DNA (log IU/mL) negative negative negative N.E. negative N.E. N.E. N.E. N.E. negative N.E.
HBsAg (IU/mL) 33.7 18.2 12.0 N.E. 7.8 N.E. N.E. N.E. N.E. 11.5 N.E.
AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, G/P: glecaprevir plus pibrentasvir, HBsAg: hepatitis B surface antigen, HBV-DNA: hepatitis B virus DNA, HCV-RNA: hepatitis C virus RNA, HDF: hemodiafiltration, H.E.: hepatic encephalopathy, mPSL: methylprednisolone, N.E.: not examined, PE: plasma exchange, PT: prothrombin time
The patient developed a fever with a body temperature of 39°C on day 24. The results of a subsequent catheter tip culture revealed growth of Staphylococcus capitis subsp. ureolyticus; therefore, we prioritized treatment for sepsis. Empirical antibiotic therapy with vancomycin was initiated, and it was de-escalated to cefazolin (CEZ) on day 32. However, drug eruption appeared 4 days after the switch to CEZ (after approximately 2 weeks of antibiotic treatment), so treatment was discontinued. The drug eruption consequently resolved within a few days. The results of a DLST for CEZ were negative. On day 33, an ultrasound-guided percutaneous liver biopsy was performed. Subsequently, on day 42, the patient was discharged from the hospital. At this point, 12 weeks after the end of G/P, HCV RNA was not detected.
Histological findings of the liver biopsy
The biopsy specimen revealed cross-linked fibrosis between the portal veins, and lymphocyte and plasma cell infiltrate in the portal vein area, with slight interface hepatitis observed. There was no noticeable liver steatosis. Ductular proliferation, ballooning hepatocytes, and cholestasis, which are consistent with DILI, were observed (Fig. 2). Although a liver biopsy showed no cirrhosis, stage 3 fibrosis (F3) was observed; fibrosis develops in patients with chronic liver damage due to viral hepatitis or a history of alcohol consumption. The lobular inflammation observed within the existing viral hepatitis and DILI was difficult to distinguish. These pathological findings indicated that DILI developed after the chronic liver injury.
Figure 2. Histological findings from the liver biopsy specimen. (a) Portal inflammation with slight interface hepatitis [Hematoxylin and Eosin (H&E) staining; magnification: ×100]. (b) Fibrosis with portal-to-portal bridging (Masson’s trichrome staining; magnification: ×100). (c) Mixed lymphocyte and plasma cell infiltration and rare eosinophils in the portal area with ductular proliferation (H&E staining; magnification: ×200). (d) Mild cholestasis and ballooning hepatocytes (H&E staining; magnification: ×200).
Discussion
The details of this case show that the interaction between G/P therapy and host risk factors may induce serious adverse events. The excellent safety profile of G/P has been demonstrated in several trials and studies (4-6). Although there have been reports of a transient elevation in serum bilirubin levels among patients treated with G/P (10,11), severe liver injury associated with this treatment has not previously been reported.
NS3/4A protease inhibitors such as glecaprevir are primarily metabolized by P4503A and are contraindicated in decompensated cirrhosis due to significantly elevated protease inhibitor concentrations and an increased risk of liver toxicity (12-14). In terms of pharmacokinetics, the glecaprevir exposure was shown to be higher in patients with compensated cirrhosis than in those without cirrhosis, inducing possible hepatotoxicity (15,16). Thus, variations in the safety and efficacy profile of G/P therapy in patients with compensated cirrhosis have been well-documented. In our patient, a liver biopsy indicated the absence of liver cirrhosis. NS5A inhibitors, such as pibrentasvir should also be considered to carry a risk of causing hepatoxicity. In the present patient, hyperbilirubinemia was assumed to be the result of drug- or metabolite-mediated inhibition of hepatobiliary transporters, but further research will be needed to determine the mechanism.
The reported incidence and severity of DILI varies among drugs (17-19), suggesting that drug properties play a role in determining the risk of DILI. On the other hand, only a small population of patients develop DILI, even after taking drugs with the potential to cause DILI, indicating that host factors play a major role in DILI development. Known host risk factors include an increased age, female sex, presence of underlying liver disease, and heavy alcohol intake; in addition, several genetic variants in the human leukocyte antigen (HLA) regions have been identified as risk factors for idiosyncratic DILI (7). Heavy alcohol consumption is a risk factor for DILI because the direct hepatotoxicity induced by ethanol and indirect hepatotoxicity induced by its metabolite (acetaldehyde) result in hepatocellular damage (20). Our patient had a habit of heavy alcohol consumption six months earlier, although it had not caused the present DILI. Among patients receiving antiviral treatment for viral hepatitis, our patient had no particular risk factor for DILI.
HBV reactivation during or after DAA therapy is frequent among HBV/HCV-coinfected patients (21). In our case, HBV reactivation was excluded from the potential causes of liver injury, as the level of serum HBV DNA remained negative, and the level of HBs-Ag was low during DAA therapy. Since it was necessary to use an immunosuppressive drug to manage anaphylaxis during the clinical course, TAF treatment was initiated to prevent HBV reactivation. Regarding the relationship between HBV/HCV-coinfection and DILI, the inflammation and altered cytokine milieu caused by a chronic viral disease may influence drug hepatotoxicity (22).
Our patient also had a history of drug allergy against two drugs other than the G/P. Laboratory findings related to the presence of allergies included a negative result of DLST for G/P, and low levels of serum eosinophils. According to previous reports, DLST was positive in 48% of patient with DILI, and eosinophilia was greater than 6% in 27% of patients with DILI (23). Thus, the sensitivity of these factors is not high, and these findings are useless for diagnosing drug allergy.
Factors causing immune allergic response are involved in the mechanism underlying cellular injury in idiosyncratic DILI (7,22). For example, allergies are caused by excessively strong immune functions, and patients with an allergic constitution are often more sensitive to drugs and show a higher incidence of DILI than patients without allergic constitution (20). At present, a history of drug allergy is not listed as a risk factor for DILI (7,7-19). Although the overall incidence of drug allergy is unknown, it accounts for 1-2% of all admissions and 3-5% of hospitalized patients (24). According to a report by the Drug-induced Liver Injury Network, patients with DILI frequently (>40%) have a history of drug allergy (19). Therefore, the history of drug allergy may have been a host risk factor for DILI in this case.
DILI is a leading cause of acute liver failure (7,9,17,19,23), with 1% of cases being subjected to PE (23). In Japan, artificial liver support, consisting of PE and HDF, is performed as treatment for patients with acute liver failure, especially in those with hepatic encephalopathy to stabilize the patient’s condition until recovery of the native liver or performance of liver transplantation (9,25). Disaccharides and the nonabsorbable antibiotic rifaximin are also recommended for the treatment of hepatic encephalopathy for patients with cirrhosis (26). In our patient, the PT did not meet the criteria for acute liver failure (9); however, he suffered from severe liver injury, hyperbilirubinemia, deterioration of PT over time, and the development of grade II hepatic encephalopathy. The results of a liver biopsy showed sever liver injury with jaundice, mixed lymphocyte and plasma cell infiltration in the portal vein area, ductular proliferation, ballooning hepatocytes, and cholestasis. Oral treatment of lactulose and rifaximin for hepatic encephalopathy, and artificial liver support were useful for maintaining the minimal liver function required to sustain the life of this patient.
Recently, it was reported that the recovery rate from hepatic encephalopathy is higher in patients with PE and HDF than in those with PE alone (25). This is because HDF removes low- to middle-sized molecules, including ammonia, decreasing the side-effects of PE. In the present case, hepatic encephalopathy was not observed after the combined use of PE and HDF. Although anaphylaxis and catheter infection occurred as a complication of plasmapheresis, with appropriate treatment, the patient eventually recovered from his severe liver injury.
In conclusion, we encountered a case of a severe liver injury caused by G/P therapy. Host factors should be considered in order to prevent DILI during treatment with this regimen.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors thank Drs. S. Hosoi and Y. Okumura for their cooperation in the management of the reported case. | BROTIZOLAM, ESOMEPRAZOLE MAGNESIUM, ETIZOLAM, GLECAPREVIR\PIBRENTASVIR | DrugsGivenReaction | CC BY-NC-ND | 33612683 | 19,682,017 | 2021-08-01 |
What is the weight of the patient? | Severe Liver Injury Associated with Glecaprevir Plus Pibrentasvir Therapy in a Patient with Treatment-naïve Hepatitis C Virus Infection.
A 49-year-old man underwent treatment with glecaprevir plus pibrentasvir (G/P) for chronic hepatitis C infection. Six weeks later, he was admitted to our hospital because of jaundice and fatigue with no accompanying skin rash. A laboratory examination and evaluation of the patient's history resulted in a diagnosis of acute liver injury. Discontinuation of G/P and a rigorous medical protocol, including plasma exchange and hemodiafiltration, successfully mitigated the liver damage. The patient was also found to be allergic to two drugs other than the G/P therapy. In such cases with a history of drug allergy, careful observation may be required to detect serious adverse events.
Introduction
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (1). With the introduction of direct-acting antiviral agents (DAAs), the efficacy and safety of the treatment of chronic hepatitis C infection has improved significantly (2). Glecaprevir [nonstructural protein 3/4A (NS3/4A) protease inhibitor] plus pibrentasvir [nonstructural protein 5A (NS5A) inhibitor] (G/P) therapy comprises ribavirin-free treatment with a DAA and has the advantage of a shorter treatment duration than other regimens; furthermore, the treatment is pan-genotypic and thus recommended for all genotypes of HCV infection (3).
G/P has been reported to exhibit a strong antiviral effect with a good safety profile and a low rate of side effects (4-6). However, we observed one instance of severe liver injury that occurred during the administration of G/P in a patient with treatment-naïve genotype 1b HCV infection. The individual risk of drug-induced liver injury (DILI) and its associated clinical phenotype are likely to be determined by the complex interplay between the physiochemical and toxicological properties of drugs, host factors, and the resulting interactions between them (7).
We herein report a rare case of an adverse event caused by interplay between G/P therapy and host risk factors.
Case Report
The patient was a 49-year-old man (height: 175.0 cm; weight: 77.2 kg; body mass index: 25.2) with a tattoo and a history of allergy with isopropylantipyrine. He was first referred to our hospital due to liver dysfunction at the age of 48. He had underlying conditions of insomnia and reflux esophagitis, for which he had been taking etizolam, brotizolam, and esomeprazole.
His workup revealed co-infection with HCV (genotype 1b, 5.8 log IU/mL) and hepatitis B virus (HBV) (genotype C, quantity undetectable). Since the level of serum HBV DNA level was negative, and the level of hepatitis B surface antigen (HBs-Ag) was low (33.7 IU/mL), he was diagnosed as an inactive HBV carrier. Although the patient had stopped consuming alcohol, he had previously consumed ethanol equivalent to 60 g a day. Six months after he stopped, he started treatment with an 8-week course for HCV with 3 tablets of glecaprevir (100 mg)/ pibrentasvir (40 mg) once a day. The patient’s laboratory data at the treatment initiation are shown in Table 1.
Table 1. Laboratory Data at the Start of Glecaprevir Plus Pibrentasvir Therapy.
Variable Variable
White blood cells (/µL) 5,880 Total protein (g/dL) 7.3
Neutrophils (%) 50.0 Albumin (g/dL) 3.9
Eosinophils (%) 1.7 Total bilirubin (mg/dL) 1.1
Basophils (%) 0.7 AST (IU/L) 100
Monocytes (%) 11.4 ALT (IU/L) 51
Lymphocytes (%) 36.2 LDH (IU/L) 185
Red blood cells (104/µL) 409 ALP (IU/L) 436
Hematocrit (%) 41.4 GGT (IU/L) 125
Hemoglobin (g/dL) 14.0 BUN (mg/dL) 10
Platelets (104/µL) 19.2 Creatinine (mg/dL) 0.66
C-reactive protein (mg/dL) 0.05
Glucose (mg/dL) 162 HCV-RNA (log IU/mL) 1.4
HBsAg (IU/mL) 18.2
PT-INR 1.21 HBV-DNA (log IU/mL) negative
PT (%) 67.8 HBcrAg (log U/mL) ≤2.9
FIB-4 index 3.57 HBV genotype C
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, FIB-4 index: fibrosis-4 index, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, BUN: blood urea nitrogen, HCV-RNA: hepatitis C virus RNA, HBsAg: hepatitis B surface antigen, HBV-DNA: hepatitis B virus DNA, HBcrAg: hepatitis B core-related antigen
After 6 weeks of G/P, the patient complained of vomiting, abdominal pain, and jaundice. He visited our hospital 3 days later and was found to have severe liver injury with a total bilirubin (T-Bil) level of 20.6 mg/dL. The patient’s data with regard to laboratory parameters and antibodies to other possible viral infections are summarized in Table 2. HBV reactivation was excluded from the causes of liver injury, as the level of serum HBV DNA remained negative, and the level of HBs-Ag was low (7.8 IU/mL). Since there was no history of recent ingestion of other drugs or alcohol, we considered the possibility of DILI due to the G/P therapy, and G/P was immediately discontinued. During treatment with G/P, the patient had complained of fatigue, although he did not experience skin rash or a fever. The results of a drug-induced lymphocyte stimulation test (DLST) for G/P were negative. Based on the Digestive Disease Week Japan 2004 (DDW-J) scale (8), this type of liver damage was classified as cholestatic liver injury, and an association between G/P and liver injury was deemed possible (score of 4).
Table 2. Laboratory Data on Admission.
Variable Variable
White blood cells (/µL) 10,260 Total protein (g/dL) 7.2
Neutrophils (%) 78.4 Albumin (g/dL) 3.6
Eosinophils (%) 0.5 Total bilirubin (mg/dL) 20.6
Basophils (%) 0.1 Direct bilirubin (mg/dL) 15.4
Monocytes (%) 7.0 AST (IU/L) 205
Lymphocytes (%) 14.0 ALT (IU/L) 65
Red blood cells (104/µL) 372 LDH (IU/L) 246
Hematocrit (%) 34.1 ALP (IU/L) 442
Hemoglobin (g/dL) 12.3 GGT (IU/L) 124
Platelets (104/µL) 11.7 BUN (mg/dL) 4
C-reactive protein (mg/dL) 0.65 Creatinine (mg/dL) 0.88
Glucose (mg/dL) 178 NH3(mg/dL) 55
HbA1c (N) (%) 6.8 HCV-RNA (log IU/mL) negative
HBsAg (IU/mL) 7.8
PT-INR 1.21 IgM anti-HBc (-)
PT (%) 67.8 HBV-DNA (log IU/mL) negative
FIB-4 index 10.65 HBeAg (-)
HBeAb (%) (+)
IgG (mg/dL) 1,462 HBcrAg (log U/mL) ≤2.9
IgA (mg/dL) 421 IgM anti-HAV (-)
IgM (mg/dL) 101 IgA anti-HEV (-)
IgE (IU/mL) 18 IgM anti-EBV VCA (-)
Anti-nuclear antibody <40 IgG anti-EBV VCA (+)
Anti-mitochondria M2 1.4 EBNA (-)
Anti-smooth muscle <20 IgM anti-CMV (-)
Anti-LKM1 <5.0 IgM anti-HSV (-)
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, FIB-4 index: fibrosis-4 index, HbA1c (N): glycated hemoglobin, Ig: immunoglobulin, Anti-LKM1: anti-liver-kidney microsome type 1 antibody, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, BUN: blood urea nitrogen, HCV-RNA: hepatitis C virus RNA, HBsAg: hepatitis B surface antigen, anti-HBc: hepatitis B virus core antibody, HBV-DNA: hepatitis B virus DNA, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen, anti-HAV: anti-hepatitis A virus antibody, HEV: hepatitis E virus, anti-EBV VCA: anti-Epstein-Barr virus capsid antigen antibody, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, HSV: herpes simplex virus
A physical examination on admission showed neither ascites nor signs of hepatic encephalopathy. The clinical course is summarized in Fig. 1 (date of hospitalization was labeled as day 0). In addition, serial changes in liver function tests and viral markers are shown in Table 3. After hospitalization, the serum T-Bil level gradually improved without any treatment, but the prothrombin time (PT) level worsened. On day 9, the patient developed asterixis and was diagnosed with grade II hepatic encephalopathy. Although the observed PT (54.7%) did not meet the criteria for acute liver failure (9), since the patient was developing hepatic encephalopathy, plasma exchange (PE) and hemodiafiltration (HDF) procedures were initiated along with oral treatment of lactulose and rifaximin. After three PE sessions, and one HDF session, his liver function improved, and he recovered from hepatic encephalopathy. Each PE session included the administration of 40 units of fresh-frozen plasma (FFP). One hour after initiating the first PE session, the patient developed an anaphylactic reaction (skin rashes with slight dyspnea), and was treated with methylprednisolone (125 mg). Consequently, he was started on tenofovir alafenamide fumarate (TAF) to prevent HBV reactivation. However, no side effects were observed when FFP was administered on day 8.
Figure 1. Clinical course. Days indicate days from admission. CEZ: cefazolin, FFP: fresh-frozen plasma, G/P: glecaprevir plus pibrentasvir, HDF: hemodiafiltration, mPSL: methylprednisolone, PE: plasma exchange, TAF: tenofovir alafenamide fumarate, VCM: vancomycin
Table 3. Serial Changes in Liver Function Tests, and Viral Markers during the Clinical Course.
Diagnosis of HCV Base line Hospital admission H.E. H.E. H.E.
Date from admission 1 year ago -45 -31 -17 0 9 14 22 23 33 41
Treatment contents G/P
started G/P
stopped PE mPSL PE mPSL PE mPSL HDF Liver biopsy
T.Bil (mg/dL) 1.5 1.1 0.7 1.1 20.6 11.9 5.5 3 2.4 2 1.4
AST (IU/L) 224 100 112 100 205 133 86 48 33 63 36
ALT (IU/L) 107 51 63 51 65 56 45 27 22 30 15
ALP (IU/L) 295 436 490 436 442 676 1,039 1,020 620 879 560
GGT (IU/L) 659 125 83 125 124 138 207 274 131 141 84
NH3 (mg/dL) N.E. N.E. N.E. N.E. 73 81 118 113 87 N.E. 71
PT (%) 92.0 87.4 97.0 83.7 67.8 54.7 58.3 62.3 72.9 75.1 77.4
HCV-RNA (log IU/mL) 5.8 1.4 negative N.E. N.E. N.E. N.E. N.E. N.E. negative N.E.
HBV-DNA (log IU/mL) negative negative negative N.E. negative N.E. N.E. N.E. N.E. negative N.E.
HBsAg (IU/mL) 33.7 18.2 12.0 N.E. 7.8 N.E. N.E. N.E. N.E. 11.5 N.E.
AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, G/P: glecaprevir plus pibrentasvir, HBsAg: hepatitis B surface antigen, HBV-DNA: hepatitis B virus DNA, HCV-RNA: hepatitis C virus RNA, HDF: hemodiafiltration, H.E.: hepatic encephalopathy, mPSL: methylprednisolone, N.E.: not examined, PE: plasma exchange, PT: prothrombin time
The patient developed a fever with a body temperature of 39°C on day 24. The results of a subsequent catheter tip culture revealed growth of Staphylococcus capitis subsp. ureolyticus; therefore, we prioritized treatment for sepsis. Empirical antibiotic therapy with vancomycin was initiated, and it was de-escalated to cefazolin (CEZ) on day 32. However, drug eruption appeared 4 days after the switch to CEZ (after approximately 2 weeks of antibiotic treatment), so treatment was discontinued. The drug eruption consequently resolved within a few days. The results of a DLST for CEZ were negative. On day 33, an ultrasound-guided percutaneous liver biopsy was performed. Subsequently, on day 42, the patient was discharged from the hospital. At this point, 12 weeks after the end of G/P, HCV RNA was not detected.
Histological findings of the liver biopsy
The biopsy specimen revealed cross-linked fibrosis between the portal veins, and lymphocyte and plasma cell infiltrate in the portal vein area, with slight interface hepatitis observed. There was no noticeable liver steatosis. Ductular proliferation, ballooning hepatocytes, and cholestasis, which are consistent with DILI, were observed (Fig. 2). Although a liver biopsy showed no cirrhosis, stage 3 fibrosis (F3) was observed; fibrosis develops in patients with chronic liver damage due to viral hepatitis or a history of alcohol consumption. The lobular inflammation observed within the existing viral hepatitis and DILI was difficult to distinguish. These pathological findings indicated that DILI developed after the chronic liver injury.
Figure 2. Histological findings from the liver biopsy specimen. (a) Portal inflammation with slight interface hepatitis [Hematoxylin and Eosin (H&E) staining; magnification: ×100]. (b) Fibrosis with portal-to-portal bridging (Masson’s trichrome staining; magnification: ×100). (c) Mixed lymphocyte and plasma cell infiltration and rare eosinophils in the portal area with ductular proliferation (H&E staining; magnification: ×200). (d) Mild cholestasis and ballooning hepatocytes (H&E staining; magnification: ×200).
Discussion
The details of this case show that the interaction between G/P therapy and host risk factors may induce serious adverse events. The excellent safety profile of G/P has been demonstrated in several trials and studies (4-6). Although there have been reports of a transient elevation in serum bilirubin levels among patients treated with G/P (10,11), severe liver injury associated with this treatment has not previously been reported.
NS3/4A protease inhibitors such as glecaprevir are primarily metabolized by P4503A and are contraindicated in decompensated cirrhosis due to significantly elevated protease inhibitor concentrations and an increased risk of liver toxicity (12-14). In terms of pharmacokinetics, the glecaprevir exposure was shown to be higher in patients with compensated cirrhosis than in those without cirrhosis, inducing possible hepatotoxicity (15,16). Thus, variations in the safety and efficacy profile of G/P therapy in patients with compensated cirrhosis have been well-documented. In our patient, a liver biopsy indicated the absence of liver cirrhosis. NS5A inhibitors, such as pibrentasvir should also be considered to carry a risk of causing hepatoxicity. In the present patient, hyperbilirubinemia was assumed to be the result of drug- or metabolite-mediated inhibition of hepatobiliary transporters, but further research will be needed to determine the mechanism.
The reported incidence and severity of DILI varies among drugs (17-19), suggesting that drug properties play a role in determining the risk of DILI. On the other hand, only a small population of patients develop DILI, even after taking drugs with the potential to cause DILI, indicating that host factors play a major role in DILI development. Known host risk factors include an increased age, female sex, presence of underlying liver disease, and heavy alcohol intake; in addition, several genetic variants in the human leukocyte antigen (HLA) regions have been identified as risk factors for idiosyncratic DILI (7). Heavy alcohol consumption is a risk factor for DILI because the direct hepatotoxicity induced by ethanol and indirect hepatotoxicity induced by its metabolite (acetaldehyde) result in hepatocellular damage (20). Our patient had a habit of heavy alcohol consumption six months earlier, although it had not caused the present DILI. Among patients receiving antiviral treatment for viral hepatitis, our patient had no particular risk factor for DILI.
HBV reactivation during or after DAA therapy is frequent among HBV/HCV-coinfected patients (21). In our case, HBV reactivation was excluded from the potential causes of liver injury, as the level of serum HBV DNA remained negative, and the level of HBs-Ag was low during DAA therapy. Since it was necessary to use an immunosuppressive drug to manage anaphylaxis during the clinical course, TAF treatment was initiated to prevent HBV reactivation. Regarding the relationship between HBV/HCV-coinfection and DILI, the inflammation and altered cytokine milieu caused by a chronic viral disease may influence drug hepatotoxicity (22).
Our patient also had a history of drug allergy against two drugs other than the G/P. Laboratory findings related to the presence of allergies included a negative result of DLST for G/P, and low levels of serum eosinophils. According to previous reports, DLST was positive in 48% of patient with DILI, and eosinophilia was greater than 6% in 27% of patients with DILI (23). Thus, the sensitivity of these factors is not high, and these findings are useless for diagnosing drug allergy.
Factors causing immune allergic response are involved in the mechanism underlying cellular injury in idiosyncratic DILI (7,22). For example, allergies are caused by excessively strong immune functions, and patients with an allergic constitution are often more sensitive to drugs and show a higher incidence of DILI than patients without allergic constitution (20). At present, a history of drug allergy is not listed as a risk factor for DILI (7,7-19). Although the overall incidence of drug allergy is unknown, it accounts for 1-2% of all admissions and 3-5% of hospitalized patients (24). According to a report by the Drug-induced Liver Injury Network, patients with DILI frequently (>40%) have a history of drug allergy (19). Therefore, the history of drug allergy may have been a host risk factor for DILI in this case.
DILI is a leading cause of acute liver failure (7,9,17,19,23), with 1% of cases being subjected to PE (23). In Japan, artificial liver support, consisting of PE and HDF, is performed as treatment for patients with acute liver failure, especially in those with hepatic encephalopathy to stabilize the patient’s condition until recovery of the native liver or performance of liver transplantation (9,25). Disaccharides and the nonabsorbable antibiotic rifaximin are also recommended for the treatment of hepatic encephalopathy for patients with cirrhosis (26). In our patient, the PT did not meet the criteria for acute liver failure (9); however, he suffered from severe liver injury, hyperbilirubinemia, deterioration of PT over time, and the development of grade II hepatic encephalopathy. The results of a liver biopsy showed sever liver injury with jaundice, mixed lymphocyte and plasma cell infiltration in the portal vein area, ductular proliferation, ballooning hepatocytes, and cholestasis. Oral treatment of lactulose and rifaximin for hepatic encephalopathy, and artificial liver support were useful for maintaining the minimal liver function required to sustain the life of this patient.
Recently, it was reported that the recovery rate from hepatic encephalopathy is higher in patients with PE and HDF than in those with PE alone (25). This is because HDF removes low- to middle-sized molecules, including ammonia, decreasing the side-effects of PE. In the present case, hepatic encephalopathy was not observed after the combined use of PE and HDF. Although anaphylaxis and catheter infection occurred as a complication of plasmapheresis, with appropriate treatment, the patient eventually recovered from his severe liver injury.
In conclusion, we encountered a case of a severe liver injury caused by G/P therapy. Host factors should be considered in order to prevent DILI during treatment with this regimen.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors thank Drs. S. Hosoi and Y. Okumura for their cooperation in the management of the reported case. | 77.2 kg. | Weight | CC BY-NC-ND | 33612683 | 19,682,017 | 2021-08-01 |
What was the administration route of drug 'GLECAPREVIR\PIBRENTASVIR'? | Severe Liver Injury Associated with Glecaprevir Plus Pibrentasvir Therapy in a Patient with Treatment-naïve Hepatitis C Virus Infection.
A 49-year-old man underwent treatment with glecaprevir plus pibrentasvir (G/P) for chronic hepatitis C infection. Six weeks later, he was admitted to our hospital because of jaundice and fatigue with no accompanying skin rash. A laboratory examination and evaluation of the patient's history resulted in a diagnosis of acute liver injury. Discontinuation of G/P and a rigorous medical protocol, including plasma exchange and hemodiafiltration, successfully mitigated the liver damage. The patient was also found to be allergic to two drugs other than the G/P therapy. In such cases with a history of drug allergy, careful observation may be required to detect serious adverse events.
Introduction
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (1). With the introduction of direct-acting antiviral agents (DAAs), the efficacy and safety of the treatment of chronic hepatitis C infection has improved significantly (2). Glecaprevir [nonstructural protein 3/4A (NS3/4A) protease inhibitor] plus pibrentasvir [nonstructural protein 5A (NS5A) inhibitor] (G/P) therapy comprises ribavirin-free treatment with a DAA and has the advantage of a shorter treatment duration than other regimens; furthermore, the treatment is pan-genotypic and thus recommended for all genotypes of HCV infection (3).
G/P has been reported to exhibit a strong antiviral effect with a good safety profile and a low rate of side effects (4-6). However, we observed one instance of severe liver injury that occurred during the administration of G/P in a patient with treatment-naïve genotype 1b HCV infection. The individual risk of drug-induced liver injury (DILI) and its associated clinical phenotype are likely to be determined by the complex interplay between the physiochemical and toxicological properties of drugs, host factors, and the resulting interactions between them (7).
We herein report a rare case of an adverse event caused by interplay between G/P therapy and host risk factors.
Case Report
The patient was a 49-year-old man (height: 175.0 cm; weight: 77.2 kg; body mass index: 25.2) with a tattoo and a history of allergy with isopropylantipyrine. He was first referred to our hospital due to liver dysfunction at the age of 48. He had underlying conditions of insomnia and reflux esophagitis, for which he had been taking etizolam, brotizolam, and esomeprazole.
His workup revealed co-infection with HCV (genotype 1b, 5.8 log IU/mL) and hepatitis B virus (HBV) (genotype C, quantity undetectable). Since the level of serum HBV DNA level was negative, and the level of hepatitis B surface antigen (HBs-Ag) was low (33.7 IU/mL), he was diagnosed as an inactive HBV carrier. Although the patient had stopped consuming alcohol, he had previously consumed ethanol equivalent to 60 g a day. Six months after he stopped, he started treatment with an 8-week course for HCV with 3 tablets of glecaprevir (100 mg)/ pibrentasvir (40 mg) once a day. The patient’s laboratory data at the treatment initiation are shown in Table 1.
Table 1. Laboratory Data at the Start of Glecaprevir Plus Pibrentasvir Therapy.
Variable Variable
White blood cells (/µL) 5,880 Total protein (g/dL) 7.3
Neutrophils (%) 50.0 Albumin (g/dL) 3.9
Eosinophils (%) 1.7 Total bilirubin (mg/dL) 1.1
Basophils (%) 0.7 AST (IU/L) 100
Monocytes (%) 11.4 ALT (IU/L) 51
Lymphocytes (%) 36.2 LDH (IU/L) 185
Red blood cells (104/µL) 409 ALP (IU/L) 436
Hematocrit (%) 41.4 GGT (IU/L) 125
Hemoglobin (g/dL) 14.0 BUN (mg/dL) 10
Platelets (104/µL) 19.2 Creatinine (mg/dL) 0.66
C-reactive protein (mg/dL) 0.05
Glucose (mg/dL) 162 HCV-RNA (log IU/mL) 1.4
HBsAg (IU/mL) 18.2
PT-INR 1.21 HBV-DNA (log IU/mL) negative
PT (%) 67.8 HBcrAg (log U/mL) ≤2.9
FIB-4 index 3.57 HBV genotype C
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, FIB-4 index: fibrosis-4 index, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, BUN: blood urea nitrogen, HCV-RNA: hepatitis C virus RNA, HBsAg: hepatitis B surface antigen, HBV-DNA: hepatitis B virus DNA, HBcrAg: hepatitis B core-related antigen
After 6 weeks of G/P, the patient complained of vomiting, abdominal pain, and jaundice. He visited our hospital 3 days later and was found to have severe liver injury with a total bilirubin (T-Bil) level of 20.6 mg/dL. The patient’s data with regard to laboratory parameters and antibodies to other possible viral infections are summarized in Table 2. HBV reactivation was excluded from the causes of liver injury, as the level of serum HBV DNA remained negative, and the level of HBs-Ag was low (7.8 IU/mL). Since there was no history of recent ingestion of other drugs or alcohol, we considered the possibility of DILI due to the G/P therapy, and G/P was immediately discontinued. During treatment with G/P, the patient had complained of fatigue, although he did not experience skin rash or a fever. The results of a drug-induced lymphocyte stimulation test (DLST) for G/P were negative. Based on the Digestive Disease Week Japan 2004 (DDW-J) scale (8), this type of liver damage was classified as cholestatic liver injury, and an association between G/P and liver injury was deemed possible (score of 4).
Table 2. Laboratory Data on Admission.
Variable Variable
White blood cells (/µL) 10,260 Total protein (g/dL) 7.2
Neutrophils (%) 78.4 Albumin (g/dL) 3.6
Eosinophils (%) 0.5 Total bilirubin (mg/dL) 20.6
Basophils (%) 0.1 Direct bilirubin (mg/dL) 15.4
Monocytes (%) 7.0 AST (IU/L) 205
Lymphocytes (%) 14.0 ALT (IU/L) 65
Red blood cells (104/µL) 372 LDH (IU/L) 246
Hematocrit (%) 34.1 ALP (IU/L) 442
Hemoglobin (g/dL) 12.3 GGT (IU/L) 124
Platelets (104/µL) 11.7 BUN (mg/dL) 4
C-reactive protein (mg/dL) 0.65 Creatinine (mg/dL) 0.88
Glucose (mg/dL) 178 NH3(mg/dL) 55
HbA1c (N) (%) 6.8 HCV-RNA (log IU/mL) negative
HBsAg (IU/mL) 7.8
PT-INR 1.21 IgM anti-HBc (-)
PT (%) 67.8 HBV-DNA (log IU/mL) negative
FIB-4 index 10.65 HBeAg (-)
HBeAb (%) (+)
IgG (mg/dL) 1,462 HBcrAg (log U/mL) ≤2.9
IgA (mg/dL) 421 IgM anti-HAV (-)
IgM (mg/dL) 101 IgA anti-HEV (-)
IgE (IU/mL) 18 IgM anti-EBV VCA (-)
Anti-nuclear antibody <40 IgG anti-EBV VCA (+)
Anti-mitochondria M2 1.4 EBNA (-)
Anti-smooth muscle <20 IgM anti-CMV (-)
Anti-LKM1 <5.0 IgM anti-HSV (-)
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, FIB-4 index: fibrosis-4 index, HbA1c (N): glycated hemoglobin, Ig: immunoglobulin, Anti-LKM1: anti-liver-kidney microsome type 1 antibody, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, BUN: blood urea nitrogen, HCV-RNA: hepatitis C virus RNA, HBsAg: hepatitis B surface antigen, anti-HBc: hepatitis B virus core antibody, HBV-DNA: hepatitis B virus DNA, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen, anti-HAV: anti-hepatitis A virus antibody, HEV: hepatitis E virus, anti-EBV VCA: anti-Epstein-Barr virus capsid antigen antibody, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, HSV: herpes simplex virus
A physical examination on admission showed neither ascites nor signs of hepatic encephalopathy. The clinical course is summarized in Fig. 1 (date of hospitalization was labeled as day 0). In addition, serial changes in liver function tests and viral markers are shown in Table 3. After hospitalization, the serum T-Bil level gradually improved without any treatment, but the prothrombin time (PT) level worsened. On day 9, the patient developed asterixis and was diagnosed with grade II hepatic encephalopathy. Although the observed PT (54.7%) did not meet the criteria for acute liver failure (9), since the patient was developing hepatic encephalopathy, plasma exchange (PE) and hemodiafiltration (HDF) procedures were initiated along with oral treatment of lactulose and rifaximin. After three PE sessions, and one HDF session, his liver function improved, and he recovered from hepatic encephalopathy. Each PE session included the administration of 40 units of fresh-frozen plasma (FFP). One hour after initiating the first PE session, the patient developed an anaphylactic reaction (skin rashes with slight dyspnea), and was treated with methylprednisolone (125 mg). Consequently, he was started on tenofovir alafenamide fumarate (TAF) to prevent HBV reactivation. However, no side effects were observed when FFP was administered on day 8.
Figure 1. Clinical course. Days indicate days from admission. CEZ: cefazolin, FFP: fresh-frozen plasma, G/P: glecaprevir plus pibrentasvir, HDF: hemodiafiltration, mPSL: methylprednisolone, PE: plasma exchange, TAF: tenofovir alafenamide fumarate, VCM: vancomycin
Table 3. Serial Changes in Liver Function Tests, and Viral Markers during the Clinical Course.
Diagnosis of HCV Base line Hospital admission H.E. H.E. H.E.
Date from admission 1 year ago -45 -31 -17 0 9 14 22 23 33 41
Treatment contents G/P
started G/P
stopped PE mPSL PE mPSL PE mPSL HDF Liver biopsy
T.Bil (mg/dL) 1.5 1.1 0.7 1.1 20.6 11.9 5.5 3 2.4 2 1.4
AST (IU/L) 224 100 112 100 205 133 86 48 33 63 36
ALT (IU/L) 107 51 63 51 65 56 45 27 22 30 15
ALP (IU/L) 295 436 490 436 442 676 1,039 1,020 620 879 560
GGT (IU/L) 659 125 83 125 124 138 207 274 131 141 84
NH3 (mg/dL) N.E. N.E. N.E. N.E. 73 81 118 113 87 N.E. 71
PT (%) 92.0 87.4 97.0 83.7 67.8 54.7 58.3 62.3 72.9 75.1 77.4
HCV-RNA (log IU/mL) 5.8 1.4 negative N.E. N.E. N.E. N.E. N.E. N.E. negative N.E.
HBV-DNA (log IU/mL) negative negative negative N.E. negative N.E. N.E. N.E. N.E. negative N.E.
HBsAg (IU/mL) 33.7 18.2 12.0 N.E. 7.8 N.E. N.E. N.E. N.E. 11.5 N.E.
AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, G/P: glecaprevir plus pibrentasvir, HBsAg: hepatitis B surface antigen, HBV-DNA: hepatitis B virus DNA, HCV-RNA: hepatitis C virus RNA, HDF: hemodiafiltration, H.E.: hepatic encephalopathy, mPSL: methylprednisolone, N.E.: not examined, PE: plasma exchange, PT: prothrombin time
The patient developed a fever with a body temperature of 39°C on day 24. The results of a subsequent catheter tip culture revealed growth of Staphylococcus capitis subsp. ureolyticus; therefore, we prioritized treatment for sepsis. Empirical antibiotic therapy with vancomycin was initiated, and it was de-escalated to cefazolin (CEZ) on day 32. However, drug eruption appeared 4 days after the switch to CEZ (after approximately 2 weeks of antibiotic treatment), so treatment was discontinued. The drug eruption consequently resolved within a few days. The results of a DLST for CEZ were negative. On day 33, an ultrasound-guided percutaneous liver biopsy was performed. Subsequently, on day 42, the patient was discharged from the hospital. At this point, 12 weeks after the end of G/P, HCV RNA was not detected.
Histological findings of the liver biopsy
The biopsy specimen revealed cross-linked fibrosis between the portal veins, and lymphocyte and plasma cell infiltrate in the portal vein area, with slight interface hepatitis observed. There was no noticeable liver steatosis. Ductular proliferation, ballooning hepatocytes, and cholestasis, which are consistent with DILI, were observed (Fig. 2). Although a liver biopsy showed no cirrhosis, stage 3 fibrosis (F3) was observed; fibrosis develops in patients with chronic liver damage due to viral hepatitis or a history of alcohol consumption. The lobular inflammation observed within the existing viral hepatitis and DILI was difficult to distinguish. These pathological findings indicated that DILI developed after the chronic liver injury.
Figure 2. Histological findings from the liver biopsy specimen. (a) Portal inflammation with slight interface hepatitis [Hematoxylin and Eosin (H&E) staining; magnification: ×100]. (b) Fibrosis with portal-to-portal bridging (Masson’s trichrome staining; magnification: ×100). (c) Mixed lymphocyte and plasma cell infiltration and rare eosinophils in the portal area with ductular proliferation (H&E staining; magnification: ×200). (d) Mild cholestasis and ballooning hepatocytes (H&E staining; magnification: ×200).
Discussion
The details of this case show that the interaction between G/P therapy and host risk factors may induce serious adverse events. The excellent safety profile of G/P has been demonstrated in several trials and studies (4-6). Although there have been reports of a transient elevation in serum bilirubin levels among patients treated with G/P (10,11), severe liver injury associated with this treatment has not previously been reported.
NS3/4A protease inhibitors such as glecaprevir are primarily metabolized by P4503A and are contraindicated in decompensated cirrhosis due to significantly elevated protease inhibitor concentrations and an increased risk of liver toxicity (12-14). In terms of pharmacokinetics, the glecaprevir exposure was shown to be higher in patients with compensated cirrhosis than in those without cirrhosis, inducing possible hepatotoxicity (15,16). Thus, variations in the safety and efficacy profile of G/P therapy in patients with compensated cirrhosis have been well-documented. In our patient, a liver biopsy indicated the absence of liver cirrhosis. NS5A inhibitors, such as pibrentasvir should also be considered to carry a risk of causing hepatoxicity. In the present patient, hyperbilirubinemia was assumed to be the result of drug- or metabolite-mediated inhibition of hepatobiliary transporters, but further research will be needed to determine the mechanism.
The reported incidence and severity of DILI varies among drugs (17-19), suggesting that drug properties play a role in determining the risk of DILI. On the other hand, only a small population of patients develop DILI, even after taking drugs with the potential to cause DILI, indicating that host factors play a major role in DILI development. Known host risk factors include an increased age, female sex, presence of underlying liver disease, and heavy alcohol intake; in addition, several genetic variants in the human leukocyte antigen (HLA) regions have been identified as risk factors for idiosyncratic DILI (7). Heavy alcohol consumption is a risk factor for DILI because the direct hepatotoxicity induced by ethanol and indirect hepatotoxicity induced by its metabolite (acetaldehyde) result in hepatocellular damage (20). Our patient had a habit of heavy alcohol consumption six months earlier, although it had not caused the present DILI. Among patients receiving antiviral treatment for viral hepatitis, our patient had no particular risk factor for DILI.
HBV reactivation during or after DAA therapy is frequent among HBV/HCV-coinfected patients (21). In our case, HBV reactivation was excluded from the potential causes of liver injury, as the level of serum HBV DNA remained negative, and the level of HBs-Ag was low during DAA therapy. Since it was necessary to use an immunosuppressive drug to manage anaphylaxis during the clinical course, TAF treatment was initiated to prevent HBV reactivation. Regarding the relationship between HBV/HCV-coinfection and DILI, the inflammation and altered cytokine milieu caused by a chronic viral disease may influence drug hepatotoxicity (22).
Our patient also had a history of drug allergy against two drugs other than the G/P. Laboratory findings related to the presence of allergies included a negative result of DLST for G/P, and low levels of serum eosinophils. According to previous reports, DLST was positive in 48% of patient with DILI, and eosinophilia was greater than 6% in 27% of patients with DILI (23). Thus, the sensitivity of these factors is not high, and these findings are useless for diagnosing drug allergy.
Factors causing immune allergic response are involved in the mechanism underlying cellular injury in idiosyncratic DILI (7,22). For example, allergies are caused by excessively strong immune functions, and patients with an allergic constitution are often more sensitive to drugs and show a higher incidence of DILI than patients without allergic constitution (20). At present, a history of drug allergy is not listed as a risk factor for DILI (7,7-19). Although the overall incidence of drug allergy is unknown, it accounts for 1-2% of all admissions and 3-5% of hospitalized patients (24). According to a report by the Drug-induced Liver Injury Network, patients with DILI frequently (>40%) have a history of drug allergy (19). Therefore, the history of drug allergy may have been a host risk factor for DILI in this case.
DILI is a leading cause of acute liver failure (7,9,17,19,23), with 1% of cases being subjected to PE (23). In Japan, artificial liver support, consisting of PE and HDF, is performed as treatment for patients with acute liver failure, especially in those with hepatic encephalopathy to stabilize the patient’s condition until recovery of the native liver or performance of liver transplantation (9,25). Disaccharides and the nonabsorbable antibiotic rifaximin are also recommended for the treatment of hepatic encephalopathy for patients with cirrhosis (26). In our patient, the PT did not meet the criteria for acute liver failure (9); however, he suffered from severe liver injury, hyperbilirubinemia, deterioration of PT over time, and the development of grade II hepatic encephalopathy. The results of a liver biopsy showed sever liver injury with jaundice, mixed lymphocyte and plasma cell infiltration in the portal vein area, ductular proliferation, ballooning hepatocytes, and cholestasis. Oral treatment of lactulose and rifaximin for hepatic encephalopathy, and artificial liver support were useful for maintaining the minimal liver function required to sustain the life of this patient.
Recently, it was reported that the recovery rate from hepatic encephalopathy is higher in patients with PE and HDF than in those with PE alone (25). This is because HDF removes low- to middle-sized molecules, including ammonia, decreasing the side-effects of PE. In the present case, hepatic encephalopathy was not observed after the combined use of PE and HDF. Although anaphylaxis and catheter infection occurred as a complication of plasmapheresis, with appropriate treatment, the patient eventually recovered from his severe liver injury.
In conclusion, we encountered a case of a severe liver injury caused by G/P therapy. Host factors should be considered in order to prevent DILI during treatment with this regimen.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors thank Drs. S. Hosoi and Y. Okumura for their cooperation in the management of the reported case. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33612683 | 19,682,017 | 2021-08-01 |
What was the dosage of drug 'GLECAPREVIR\PIBRENTASVIR'? | Severe Liver Injury Associated with Glecaprevir Plus Pibrentasvir Therapy in a Patient with Treatment-naïve Hepatitis C Virus Infection.
A 49-year-old man underwent treatment with glecaprevir plus pibrentasvir (G/P) for chronic hepatitis C infection. Six weeks later, he was admitted to our hospital because of jaundice and fatigue with no accompanying skin rash. A laboratory examination and evaluation of the patient's history resulted in a diagnosis of acute liver injury. Discontinuation of G/P and a rigorous medical protocol, including plasma exchange and hemodiafiltration, successfully mitigated the liver damage. The patient was also found to be allergic to two drugs other than the G/P therapy. In such cases with a history of drug allergy, careful observation may be required to detect serious adverse events.
Introduction
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (1). With the introduction of direct-acting antiviral agents (DAAs), the efficacy and safety of the treatment of chronic hepatitis C infection has improved significantly (2). Glecaprevir [nonstructural protein 3/4A (NS3/4A) protease inhibitor] plus pibrentasvir [nonstructural protein 5A (NS5A) inhibitor] (G/P) therapy comprises ribavirin-free treatment with a DAA and has the advantage of a shorter treatment duration than other regimens; furthermore, the treatment is pan-genotypic and thus recommended for all genotypes of HCV infection (3).
G/P has been reported to exhibit a strong antiviral effect with a good safety profile and a low rate of side effects (4-6). However, we observed one instance of severe liver injury that occurred during the administration of G/P in a patient with treatment-naïve genotype 1b HCV infection. The individual risk of drug-induced liver injury (DILI) and its associated clinical phenotype are likely to be determined by the complex interplay between the physiochemical and toxicological properties of drugs, host factors, and the resulting interactions between them (7).
We herein report a rare case of an adverse event caused by interplay between G/P therapy and host risk factors.
Case Report
The patient was a 49-year-old man (height: 175.0 cm; weight: 77.2 kg; body mass index: 25.2) with a tattoo and a history of allergy with isopropylantipyrine. He was first referred to our hospital due to liver dysfunction at the age of 48. He had underlying conditions of insomnia and reflux esophagitis, for which he had been taking etizolam, brotizolam, and esomeprazole.
His workup revealed co-infection with HCV (genotype 1b, 5.8 log IU/mL) and hepatitis B virus (HBV) (genotype C, quantity undetectable). Since the level of serum HBV DNA level was negative, and the level of hepatitis B surface antigen (HBs-Ag) was low (33.7 IU/mL), he was diagnosed as an inactive HBV carrier. Although the patient had stopped consuming alcohol, he had previously consumed ethanol equivalent to 60 g a day. Six months after he stopped, he started treatment with an 8-week course for HCV with 3 tablets of glecaprevir (100 mg)/ pibrentasvir (40 mg) once a day. The patient’s laboratory data at the treatment initiation are shown in Table 1.
Table 1. Laboratory Data at the Start of Glecaprevir Plus Pibrentasvir Therapy.
Variable Variable
White blood cells (/µL) 5,880 Total protein (g/dL) 7.3
Neutrophils (%) 50.0 Albumin (g/dL) 3.9
Eosinophils (%) 1.7 Total bilirubin (mg/dL) 1.1
Basophils (%) 0.7 AST (IU/L) 100
Monocytes (%) 11.4 ALT (IU/L) 51
Lymphocytes (%) 36.2 LDH (IU/L) 185
Red blood cells (104/µL) 409 ALP (IU/L) 436
Hematocrit (%) 41.4 GGT (IU/L) 125
Hemoglobin (g/dL) 14.0 BUN (mg/dL) 10
Platelets (104/µL) 19.2 Creatinine (mg/dL) 0.66
C-reactive protein (mg/dL) 0.05
Glucose (mg/dL) 162 HCV-RNA (log IU/mL) 1.4
HBsAg (IU/mL) 18.2
PT-INR 1.21 HBV-DNA (log IU/mL) negative
PT (%) 67.8 HBcrAg (log U/mL) ≤2.9
FIB-4 index 3.57 HBV genotype C
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, FIB-4 index: fibrosis-4 index, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, BUN: blood urea nitrogen, HCV-RNA: hepatitis C virus RNA, HBsAg: hepatitis B surface antigen, HBV-DNA: hepatitis B virus DNA, HBcrAg: hepatitis B core-related antigen
After 6 weeks of G/P, the patient complained of vomiting, abdominal pain, and jaundice. He visited our hospital 3 days later and was found to have severe liver injury with a total bilirubin (T-Bil) level of 20.6 mg/dL. The patient’s data with regard to laboratory parameters and antibodies to other possible viral infections are summarized in Table 2. HBV reactivation was excluded from the causes of liver injury, as the level of serum HBV DNA remained negative, and the level of HBs-Ag was low (7.8 IU/mL). Since there was no history of recent ingestion of other drugs or alcohol, we considered the possibility of DILI due to the G/P therapy, and G/P was immediately discontinued. During treatment with G/P, the patient had complained of fatigue, although he did not experience skin rash or a fever. The results of a drug-induced lymphocyte stimulation test (DLST) for G/P were negative. Based on the Digestive Disease Week Japan 2004 (DDW-J) scale (8), this type of liver damage was classified as cholestatic liver injury, and an association between G/P and liver injury was deemed possible (score of 4).
Table 2. Laboratory Data on Admission.
Variable Variable
White blood cells (/µL) 10,260 Total protein (g/dL) 7.2
Neutrophils (%) 78.4 Albumin (g/dL) 3.6
Eosinophils (%) 0.5 Total bilirubin (mg/dL) 20.6
Basophils (%) 0.1 Direct bilirubin (mg/dL) 15.4
Monocytes (%) 7.0 AST (IU/L) 205
Lymphocytes (%) 14.0 ALT (IU/L) 65
Red blood cells (104/µL) 372 LDH (IU/L) 246
Hematocrit (%) 34.1 ALP (IU/L) 442
Hemoglobin (g/dL) 12.3 GGT (IU/L) 124
Platelets (104/µL) 11.7 BUN (mg/dL) 4
C-reactive protein (mg/dL) 0.65 Creatinine (mg/dL) 0.88
Glucose (mg/dL) 178 NH3(mg/dL) 55
HbA1c (N) (%) 6.8 HCV-RNA (log IU/mL) negative
HBsAg (IU/mL) 7.8
PT-INR 1.21 IgM anti-HBc (-)
PT (%) 67.8 HBV-DNA (log IU/mL) negative
FIB-4 index 10.65 HBeAg (-)
HBeAb (%) (+)
IgG (mg/dL) 1,462 HBcrAg (log U/mL) ≤2.9
IgA (mg/dL) 421 IgM anti-HAV (-)
IgM (mg/dL) 101 IgA anti-HEV (-)
IgE (IU/mL) 18 IgM anti-EBV VCA (-)
Anti-nuclear antibody <40 IgG anti-EBV VCA (+)
Anti-mitochondria M2 1.4 EBNA (-)
Anti-smooth muscle <20 IgM anti-CMV (-)
Anti-LKM1 <5.0 IgM anti-HSV (-)
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, FIB-4 index: fibrosis-4 index, HbA1c (N): glycated hemoglobin, Ig: immunoglobulin, Anti-LKM1: anti-liver-kidney microsome type 1 antibody, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, BUN: blood urea nitrogen, HCV-RNA: hepatitis C virus RNA, HBsAg: hepatitis B surface antigen, anti-HBc: hepatitis B virus core antibody, HBV-DNA: hepatitis B virus DNA, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen, anti-HAV: anti-hepatitis A virus antibody, HEV: hepatitis E virus, anti-EBV VCA: anti-Epstein-Barr virus capsid antigen antibody, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, HSV: herpes simplex virus
A physical examination on admission showed neither ascites nor signs of hepatic encephalopathy. The clinical course is summarized in Fig. 1 (date of hospitalization was labeled as day 0). In addition, serial changes in liver function tests and viral markers are shown in Table 3. After hospitalization, the serum T-Bil level gradually improved without any treatment, but the prothrombin time (PT) level worsened. On day 9, the patient developed asterixis and was diagnosed with grade II hepatic encephalopathy. Although the observed PT (54.7%) did not meet the criteria for acute liver failure (9), since the patient was developing hepatic encephalopathy, plasma exchange (PE) and hemodiafiltration (HDF) procedures were initiated along with oral treatment of lactulose and rifaximin. After three PE sessions, and one HDF session, his liver function improved, and he recovered from hepatic encephalopathy. Each PE session included the administration of 40 units of fresh-frozen plasma (FFP). One hour after initiating the first PE session, the patient developed an anaphylactic reaction (skin rashes with slight dyspnea), and was treated with methylprednisolone (125 mg). Consequently, he was started on tenofovir alafenamide fumarate (TAF) to prevent HBV reactivation. However, no side effects were observed when FFP was administered on day 8.
Figure 1. Clinical course. Days indicate days from admission. CEZ: cefazolin, FFP: fresh-frozen plasma, G/P: glecaprevir plus pibrentasvir, HDF: hemodiafiltration, mPSL: methylprednisolone, PE: plasma exchange, TAF: tenofovir alafenamide fumarate, VCM: vancomycin
Table 3. Serial Changes in Liver Function Tests, and Viral Markers during the Clinical Course.
Diagnosis of HCV Base line Hospital admission H.E. H.E. H.E.
Date from admission 1 year ago -45 -31 -17 0 9 14 22 23 33 41
Treatment contents G/P
started G/P
stopped PE mPSL PE mPSL PE mPSL HDF Liver biopsy
T.Bil (mg/dL) 1.5 1.1 0.7 1.1 20.6 11.9 5.5 3 2.4 2 1.4
AST (IU/L) 224 100 112 100 205 133 86 48 33 63 36
ALT (IU/L) 107 51 63 51 65 56 45 27 22 30 15
ALP (IU/L) 295 436 490 436 442 676 1,039 1,020 620 879 560
GGT (IU/L) 659 125 83 125 124 138 207 274 131 141 84
NH3 (mg/dL) N.E. N.E. N.E. N.E. 73 81 118 113 87 N.E. 71
PT (%) 92.0 87.4 97.0 83.7 67.8 54.7 58.3 62.3 72.9 75.1 77.4
HCV-RNA (log IU/mL) 5.8 1.4 negative N.E. N.E. N.E. N.E. N.E. N.E. negative N.E.
HBV-DNA (log IU/mL) negative negative negative N.E. negative N.E. N.E. N.E. N.E. negative N.E.
HBsAg (IU/mL) 33.7 18.2 12.0 N.E. 7.8 N.E. N.E. N.E. N.E. 11.5 N.E.
AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, G/P: glecaprevir plus pibrentasvir, HBsAg: hepatitis B surface antigen, HBV-DNA: hepatitis B virus DNA, HCV-RNA: hepatitis C virus RNA, HDF: hemodiafiltration, H.E.: hepatic encephalopathy, mPSL: methylprednisolone, N.E.: not examined, PE: plasma exchange, PT: prothrombin time
The patient developed a fever with a body temperature of 39°C on day 24. The results of a subsequent catheter tip culture revealed growth of Staphylococcus capitis subsp. ureolyticus; therefore, we prioritized treatment for sepsis. Empirical antibiotic therapy with vancomycin was initiated, and it was de-escalated to cefazolin (CEZ) on day 32. However, drug eruption appeared 4 days after the switch to CEZ (after approximately 2 weeks of antibiotic treatment), so treatment was discontinued. The drug eruption consequently resolved within a few days. The results of a DLST for CEZ were negative. On day 33, an ultrasound-guided percutaneous liver biopsy was performed. Subsequently, on day 42, the patient was discharged from the hospital. At this point, 12 weeks after the end of G/P, HCV RNA was not detected.
Histological findings of the liver biopsy
The biopsy specimen revealed cross-linked fibrosis between the portal veins, and lymphocyte and plasma cell infiltrate in the portal vein area, with slight interface hepatitis observed. There was no noticeable liver steatosis. Ductular proliferation, ballooning hepatocytes, and cholestasis, which are consistent with DILI, were observed (Fig. 2). Although a liver biopsy showed no cirrhosis, stage 3 fibrosis (F3) was observed; fibrosis develops in patients with chronic liver damage due to viral hepatitis or a history of alcohol consumption. The lobular inflammation observed within the existing viral hepatitis and DILI was difficult to distinguish. These pathological findings indicated that DILI developed after the chronic liver injury.
Figure 2. Histological findings from the liver biopsy specimen. (a) Portal inflammation with slight interface hepatitis [Hematoxylin and Eosin (H&E) staining; magnification: ×100]. (b) Fibrosis with portal-to-portal bridging (Masson’s trichrome staining; magnification: ×100). (c) Mixed lymphocyte and plasma cell infiltration and rare eosinophils in the portal area with ductular proliferation (H&E staining; magnification: ×200). (d) Mild cholestasis and ballooning hepatocytes (H&E staining; magnification: ×200).
Discussion
The details of this case show that the interaction between G/P therapy and host risk factors may induce serious adverse events. The excellent safety profile of G/P has been demonstrated in several trials and studies (4-6). Although there have been reports of a transient elevation in serum bilirubin levels among patients treated with G/P (10,11), severe liver injury associated with this treatment has not previously been reported.
NS3/4A protease inhibitors such as glecaprevir are primarily metabolized by P4503A and are contraindicated in decompensated cirrhosis due to significantly elevated protease inhibitor concentrations and an increased risk of liver toxicity (12-14). In terms of pharmacokinetics, the glecaprevir exposure was shown to be higher in patients with compensated cirrhosis than in those without cirrhosis, inducing possible hepatotoxicity (15,16). Thus, variations in the safety and efficacy profile of G/P therapy in patients with compensated cirrhosis have been well-documented. In our patient, a liver biopsy indicated the absence of liver cirrhosis. NS5A inhibitors, such as pibrentasvir should also be considered to carry a risk of causing hepatoxicity. In the present patient, hyperbilirubinemia was assumed to be the result of drug- or metabolite-mediated inhibition of hepatobiliary transporters, but further research will be needed to determine the mechanism.
The reported incidence and severity of DILI varies among drugs (17-19), suggesting that drug properties play a role in determining the risk of DILI. On the other hand, only a small population of patients develop DILI, even after taking drugs with the potential to cause DILI, indicating that host factors play a major role in DILI development. Known host risk factors include an increased age, female sex, presence of underlying liver disease, and heavy alcohol intake; in addition, several genetic variants in the human leukocyte antigen (HLA) regions have been identified as risk factors for idiosyncratic DILI (7). Heavy alcohol consumption is a risk factor for DILI because the direct hepatotoxicity induced by ethanol and indirect hepatotoxicity induced by its metabolite (acetaldehyde) result in hepatocellular damage (20). Our patient had a habit of heavy alcohol consumption six months earlier, although it had not caused the present DILI. Among patients receiving antiviral treatment for viral hepatitis, our patient had no particular risk factor for DILI.
HBV reactivation during or after DAA therapy is frequent among HBV/HCV-coinfected patients (21). In our case, HBV reactivation was excluded from the potential causes of liver injury, as the level of serum HBV DNA remained negative, and the level of HBs-Ag was low during DAA therapy. Since it was necessary to use an immunosuppressive drug to manage anaphylaxis during the clinical course, TAF treatment was initiated to prevent HBV reactivation. Regarding the relationship between HBV/HCV-coinfection and DILI, the inflammation and altered cytokine milieu caused by a chronic viral disease may influence drug hepatotoxicity (22).
Our patient also had a history of drug allergy against two drugs other than the G/P. Laboratory findings related to the presence of allergies included a negative result of DLST for G/P, and low levels of serum eosinophils. According to previous reports, DLST was positive in 48% of patient with DILI, and eosinophilia was greater than 6% in 27% of patients with DILI (23). Thus, the sensitivity of these factors is not high, and these findings are useless for diagnosing drug allergy.
Factors causing immune allergic response are involved in the mechanism underlying cellular injury in idiosyncratic DILI (7,22). For example, allergies are caused by excessively strong immune functions, and patients with an allergic constitution are often more sensitive to drugs and show a higher incidence of DILI than patients without allergic constitution (20). At present, a history of drug allergy is not listed as a risk factor for DILI (7,7-19). Although the overall incidence of drug allergy is unknown, it accounts for 1-2% of all admissions and 3-5% of hospitalized patients (24). According to a report by the Drug-induced Liver Injury Network, patients with DILI frequently (>40%) have a history of drug allergy (19). Therefore, the history of drug allergy may have been a host risk factor for DILI in this case.
DILI is a leading cause of acute liver failure (7,9,17,19,23), with 1% of cases being subjected to PE (23). In Japan, artificial liver support, consisting of PE and HDF, is performed as treatment for patients with acute liver failure, especially in those with hepatic encephalopathy to stabilize the patient’s condition until recovery of the native liver or performance of liver transplantation (9,25). Disaccharides and the nonabsorbable antibiotic rifaximin are also recommended for the treatment of hepatic encephalopathy for patients with cirrhosis (26). In our patient, the PT did not meet the criteria for acute liver failure (9); however, he suffered from severe liver injury, hyperbilirubinemia, deterioration of PT over time, and the development of grade II hepatic encephalopathy. The results of a liver biopsy showed sever liver injury with jaundice, mixed lymphocyte and plasma cell infiltration in the portal vein area, ductular proliferation, ballooning hepatocytes, and cholestasis. Oral treatment of lactulose and rifaximin for hepatic encephalopathy, and artificial liver support were useful for maintaining the minimal liver function required to sustain the life of this patient.
Recently, it was reported that the recovery rate from hepatic encephalopathy is higher in patients with PE and HDF than in those with PE alone (25). This is because HDF removes low- to middle-sized molecules, including ammonia, decreasing the side-effects of PE. In the present case, hepatic encephalopathy was not observed after the combined use of PE and HDF. Although anaphylaxis and catheter infection occurred as a complication of plasmapheresis, with appropriate treatment, the patient eventually recovered from his severe liver injury.
In conclusion, we encountered a case of a severe liver injury caused by G/P therapy. Host factors should be considered in order to prevent DILI during treatment with this regimen.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors thank Drs. S. Hosoi and Y. Okumura for their cooperation in the management of the reported case. | 100/40 MG | DrugDosageText | CC BY-NC-ND | 33612683 | 19,682,017 | 2021-08-01 |
What was the outcome of reaction 'Drug-induced liver injury'? | Severe Liver Injury Associated with Glecaprevir Plus Pibrentasvir Therapy in a Patient with Treatment-naïve Hepatitis C Virus Infection.
A 49-year-old man underwent treatment with glecaprevir plus pibrentasvir (G/P) for chronic hepatitis C infection. Six weeks later, he was admitted to our hospital because of jaundice and fatigue with no accompanying skin rash. A laboratory examination and evaluation of the patient's history resulted in a diagnosis of acute liver injury. Discontinuation of G/P and a rigorous medical protocol, including plasma exchange and hemodiafiltration, successfully mitigated the liver damage. The patient was also found to be allergic to two drugs other than the G/P therapy. In such cases with a history of drug allergy, careful observation may be required to detect serious adverse events.
Introduction
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (1). With the introduction of direct-acting antiviral agents (DAAs), the efficacy and safety of the treatment of chronic hepatitis C infection has improved significantly (2). Glecaprevir [nonstructural protein 3/4A (NS3/4A) protease inhibitor] plus pibrentasvir [nonstructural protein 5A (NS5A) inhibitor] (G/P) therapy comprises ribavirin-free treatment with a DAA and has the advantage of a shorter treatment duration than other regimens; furthermore, the treatment is pan-genotypic and thus recommended for all genotypes of HCV infection (3).
G/P has been reported to exhibit a strong antiviral effect with a good safety profile and a low rate of side effects (4-6). However, we observed one instance of severe liver injury that occurred during the administration of G/P in a patient with treatment-naïve genotype 1b HCV infection. The individual risk of drug-induced liver injury (DILI) and its associated clinical phenotype are likely to be determined by the complex interplay between the physiochemical and toxicological properties of drugs, host factors, and the resulting interactions between them (7).
We herein report a rare case of an adverse event caused by interplay between G/P therapy and host risk factors.
Case Report
The patient was a 49-year-old man (height: 175.0 cm; weight: 77.2 kg; body mass index: 25.2) with a tattoo and a history of allergy with isopropylantipyrine. He was first referred to our hospital due to liver dysfunction at the age of 48. He had underlying conditions of insomnia and reflux esophagitis, for which he had been taking etizolam, brotizolam, and esomeprazole.
His workup revealed co-infection with HCV (genotype 1b, 5.8 log IU/mL) and hepatitis B virus (HBV) (genotype C, quantity undetectable). Since the level of serum HBV DNA level was negative, and the level of hepatitis B surface antigen (HBs-Ag) was low (33.7 IU/mL), he was diagnosed as an inactive HBV carrier. Although the patient had stopped consuming alcohol, he had previously consumed ethanol equivalent to 60 g a day. Six months after he stopped, he started treatment with an 8-week course for HCV with 3 tablets of glecaprevir (100 mg)/ pibrentasvir (40 mg) once a day. The patient’s laboratory data at the treatment initiation are shown in Table 1.
Table 1. Laboratory Data at the Start of Glecaprevir Plus Pibrentasvir Therapy.
Variable Variable
White blood cells (/µL) 5,880 Total protein (g/dL) 7.3
Neutrophils (%) 50.0 Albumin (g/dL) 3.9
Eosinophils (%) 1.7 Total bilirubin (mg/dL) 1.1
Basophils (%) 0.7 AST (IU/L) 100
Monocytes (%) 11.4 ALT (IU/L) 51
Lymphocytes (%) 36.2 LDH (IU/L) 185
Red blood cells (104/µL) 409 ALP (IU/L) 436
Hematocrit (%) 41.4 GGT (IU/L) 125
Hemoglobin (g/dL) 14.0 BUN (mg/dL) 10
Platelets (104/µL) 19.2 Creatinine (mg/dL) 0.66
C-reactive protein (mg/dL) 0.05
Glucose (mg/dL) 162 HCV-RNA (log IU/mL) 1.4
HBsAg (IU/mL) 18.2
PT-INR 1.21 HBV-DNA (log IU/mL) negative
PT (%) 67.8 HBcrAg (log U/mL) ≤2.9
FIB-4 index 3.57 HBV genotype C
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, FIB-4 index: fibrosis-4 index, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, BUN: blood urea nitrogen, HCV-RNA: hepatitis C virus RNA, HBsAg: hepatitis B surface antigen, HBV-DNA: hepatitis B virus DNA, HBcrAg: hepatitis B core-related antigen
After 6 weeks of G/P, the patient complained of vomiting, abdominal pain, and jaundice. He visited our hospital 3 days later and was found to have severe liver injury with a total bilirubin (T-Bil) level of 20.6 mg/dL. The patient’s data with regard to laboratory parameters and antibodies to other possible viral infections are summarized in Table 2. HBV reactivation was excluded from the causes of liver injury, as the level of serum HBV DNA remained negative, and the level of HBs-Ag was low (7.8 IU/mL). Since there was no history of recent ingestion of other drugs or alcohol, we considered the possibility of DILI due to the G/P therapy, and G/P was immediately discontinued. During treatment with G/P, the patient had complained of fatigue, although he did not experience skin rash or a fever. The results of a drug-induced lymphocyte stimulation test (DLST) for G/P were negative. Based on the Digestive Disease Week Japan 2004 (DDW-J) scale (8), this type of liver damage was classified as cholestatic liver injury, and an association between G/P and liver injury was deemed possible (score of 4).
Table 2. Laboratory Data on Admission.
Variable Variable
White blood cells (/µL) 10,260 Total protein (g/dL) 7.2
Neutrophils (%) 78.4 Albumin (g/dL) 3.6
Eosinophils (%) 0.5 Total bilirubin (mg/dL) 20.6
Basophils (%) 0.1 Direct bilirubin (mg/dL) 15.4
Monocytes (%) 7.0 AST (IU/L) 205
Lymphocytes (%) 14.0 ALT (IU/L) 65
Red blood cells (104/µL) 372 LDH (IU/L) 246
Hematocrit (%) 34.1 ALP (IU/L) 442
Hemoglobin (g/dL) 12.3 GGT (IU/L) 124
Platelets (104/µL) 11.7 BUN (mg/dL) 4
C-reactive protein (mg/dL) 0.65 Creatinine (mg/dL) 0.88
Glucose (mg/dL) 178 NH3(mg/dL) 55
HbA1c (N) (%) 6.8 HCV-RNA (log IU/mL) negative
HBsAg (IU/mL) 7.8
PT-INR 1.21 IgM anti-HBc (-)
PT (%) 67.8 HBV-DNA (log IU/mL) negative
FIB-4 index 10.65 HBeAg (-)
HBeAb (%) (+)
IgG (mg/dL) 1,462 HBcrAg (log U/mL) ≤2.9
IgA (mg/dL) 421 IgM anti-HAV (-)
IgM (mg/dL) 101 IgA anti-HEV (-)
IgE (IU/mL) 18 IgM anti-EBV VCA (-)
Anti-nuclear antibody <40 IgG anti-EBV VCA (+)
Anti-mitochondria M2 1.4 EBNA (-)
Anti-smooth muscle <20 IgM anti-CMV (-)
Anti-LKM1 <5.0 IgM anti-HSV (-)
PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, FIB-4 index: fibrosis-4 index, HbA1c (N): glycated hemoglobin, Ig: immunoglobulin, Anti-LKM1: anti-liver-kidney microsome type 1 antibody, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, BUN: blood urea nitrogen, HCV-RNA: hepatitis C virus RNA, HBsAg: hepatitis B surface antigen, anti-HBc: hepatitis B virus core antibody, HBV-DNA: hepatitis B virus DNA, HBeAg: hepatitis B envelope antigen, HBeAb: anti-HBe antibody, HBcrAg: hepatitis B core-related antigen, anti-HAV: anti-hepatitis A virus antibody, HEV: hepatitis E virus, anti-EBV VCA: anti-Epstein-Barr virus capsid antigen antibody, EBNA: Epstein-Barr virus nuclear antigen, CMV: cytomegalovirus, HSV: herpes simplex virus
A physical examination on admission showed neither ascites nor signs of hepatic encephalopathy. The clinical course is summarized in Fig. 1 (date of hospitalization was labeled as day 0). In addition, serial changes in liver function tests and viral markers are shown in Table 3. After hospitalization, the serum T-Bil level gradually improved without any treatment, but the prothrombin time (PT) level worsened. On day 9, the patient developed asterixis and was diagnosed with grade II hepatic encephalopathy. Although the observed PT (54.7%) did not meet the criteria for acute liver failure (9), since the patient was developing hepatic encephalopathy, plasma exchange (PE) and hemodiafiltration (HDF) procedures were initiated along with oral treatment of lactulose and rifaximin. After three PE sessions, and one HDF session, his liver function improved, and he recovered from hepatic encephalopathy. Each PE session included the administration of 40 units of fresh-frozen plasma (FFP). One hour after initiating the first PE session, the patient developed an anaphylactic reaction (skin rashes with slight dyspnea), and was treated with methylprednisolone (125 mg). Consequently, he was started on tenofovir alafenamide fumarate (TAF) to prevent HBV reactivation. However, no side effects were observed when FFP was administered on day 8.
Figure 1. Clinical course. Days indicate days from admission. CEZ: cefazolin, FFP: fresh-frozen plasma, G/P: glecaprevir plus pibrentasvir, HDF: hemodiafiltration, mPSL: methylprednisolone, PE: plasma exchange, TAF: tenofovir alafenamide fumarate, VCM: vancomycin
Table 3. Serial Changes in Liver Function Tests, and Viral Markers during the Clinical Course.
Diagnosis of HCV Base line Hospital admission H.E. H.E. H.E.
Date from admission 1 year ago -45 -31 -17 0 9 14 22 23 33 41
Treatment contents G/P
started G/P
stopped PE mPSL PE mPSL PE mPSL HDF Liver biopsy
T.Bil (mg/dL) 1.5 1.1 0.7 1.1 20.6 11.9 5.5 3 2.4 2 1.4
AST (IU/L) 224 100 112 100 205 133 86 48 33 63 36
ALT (IU/L) 107 51 63 51 65 56 45 27 22 30 15
ALP (IU/L) 295 436 490 436 442 676 1,039 1,020 620 879 560
GGT (IU/L) 659 125 83 125 124 138 207 274 131 141 84
NH3 (mg/dL) N.E. N.E. N.E. N.E. 73 81 118 113 87 N.E. 71
PT (%) 92.0 87.4 97.0 83.7 67.8 54.7 58.3 62.3 72.9 75.1 77.4
HCV-RNA (log IU/mL) 5.8 1.4 negative N.E. N.E. N.E. N.E. N.E. N.E. negative N.E.
HBV-DNA (log IU/mL) negative negative negative N.E. negative N.E. N.E. N.E. N.E. negative N.E.
HBsAg (IU/mL) 33.7 18.2 12.0 N.E. 7.8 N.E. N.E. N.E. N.E. 11.5 N.E.
AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, GGT: gamma-glutamyl transpeptidase, G/P: glecaprevir plus pibrentasvir, HBsAg: hepatitis B surface antigen, HBV-DNA: hepatitis B virus DNA, HCV-RNA: hepatitis C virus RNA, HDF: hemodiafiltration, H.E.: hepatic encephalopathy, mPSL: methylprednisolone, N.E.: not examined, PE: plasma exchange, PT: prothrombin time
The patient developed a fever with a body temperature of 39°C on day 24. The results of a subsequent catheter tip culture revealed growth of Staphylococcus capitis subsp. ureolyticus; therefore, we prioritized treatment for sepsis. Empirical antibiotic therapy with vancomycin was initiated, and it was de-escalated to cefazolin (CEZ) on day 32. However, drug eruption appeared 4 days after the switch to CEZ (after approximately 2 weeks of antibiotic treatment), so treatment was discontinued. The drug eruption consequently resolved within a few days. The results of a DLST for CEZ were negative. On day 33, an ultrasound-guided percutaneous liver biopsy was performed. Subsequently, on day 42, the patient was discharged from the hospital. At this point, 12 weeks after the end of G/P, HCV RNA was not detected.
Histological findings of the liver biopsy
The biopsy specimen revealed cross-linked fibrosis between the portal veins, and lymphocyte and plasma cell infiltrate in the portal vein area, with slight interface hepatitis observed. There was no noticeable liver steatosis. Ductular proliferation, ballooning hepatocytes, and cholestasis, which are consistent with DILI, were observed (Fig. 2). Although a liver biopsy showed no cirrhosis, stage 3 fibrosis (F3) was observed; fibrosis develops in patients with chronic liver damage due to viral hepatitis or a history of alcohol consumption. The lobular inflammation observed within the existing viral hepatitis and DILI was difficult to distinguish. These pathological findings indicated that DILI developed after the chronic liver injury.
Figure 2. Histological findings from the liver biopsy specimen. (a) Portal inflammation with slight interface hepatitis [Hematoxylin and Eosin (H&E) staining; magnification: ×100]. (b) Fibrosis with portal-to-portal bridging (Masson’s trichrome staining; magnification: ×100). (c) Mixed lymphocyte and plasma cell infiltration and rare eosinophils in the portal area with ductular proliferation (H&E staining; magnification: ×200). (d) Mild cholestasis and ballooning hepatocytes (H&E staining; magnification: ×200).
Discussion
The details of this case show that the interaction between G/P therapy and host risk factors may induce serious adverse events. The excellent safety profile of G/P has been demonstrated in several trials and studies (4-6). Although there have been reports of a transient elevation in serum bilirubin levels among patients treated with G/P (10,11), severe liver injury associated with this treatment has not previously been reported.
NS3/4A protease inhibitors such as glecaprevir are primarily metabolized by P4503A and are contraindicated in decompensated cirrhosis due to significantly elevated protease inhibitor concentrations and an increased risk of liver toxicity (12-14). In terms of pharmacokinetics, the glecaprevir exposure was shown to be higher in patients with compensated cirrhosis than in those without cirrhosis, inducing possible hepatotoxicity (15,16). Thus, variations in the safety and efficacy profile of G/P therapy in patients with compensated cirrhosis have been well-documented. In our patient, a liver biopsy indicated the absence of liver cirrhosis. NS5A inhibitors, such as pibrentasvir should also be considered to carry a risk of causing hepatoxicity. In the present patient, hyperbilirubinemia was assumed to be the result of drug- or metabolite-mediated inhibition of hepatobiliary transporters, but further research will be needed to determine the mechanism.
The reported incidence and severity of DILI varies among drugs (17-19), suggesting that drug properties play a role in determining the risk of DILI. On the other hand, only a small population of patients develop DILI, even after taking drugs with the potential to cause DILI, indicating that host factors play a major role in DILI development. Known host risk factors include an increased age, female sex, presence of underlying liver disease, and heavy alcohol intake; in addition, several genetic variants in the human leukocyte antigen (HLA) regions have been identified as risk factors for idiosyncratic DILI (7). Heavy alcohol consumption is a risk factor for DILI because the direct hepatotoxicity induced by ethanol and indirect hepatotoxicity induced by its metabolite (acetaldehyde) result in hepatocellular damage (20). Our patient had a habit of heavy alcohol consumption six months earlier, although it had not caused the present DILI. Among patients receiving antiviral treatment for viral hepatitis, our patient had no particular risk factor for DILI.
HBV reactivation during or after DAA therapy is frequent among HBV/HCV-coinfected patients (21). In our case, HBV reactivation was excluded from the potential causes of liver injury, as the level of serum HBV DNA remained negative, and the level of HBs-Ag was low during DAA therapy. Since it was necessary to use an immunosuppressive drug to manage anaphylaxis during the clinical course, TAF treatment was initiated to prevent HBV reactivation. Regarding the relationship between HBV/HCV-coinfection and DILI, the inflammation and altered cytokine milieu caused by a chronic viral disease may influence drug hepatotoxicity (22).
Our patient also had a history of drug allergy against two drugs other than the G/P. Laboratory findings related to the presence of allergies included a negative result of DLST for G/P, and low levels of serum eosinophils. According to previous reports, DLST was positive in 48% of patient with DILI, and eosinophilia was greater than 6% in 27% of patients with DILI (23). Thus, the sensitivity of these factors is not high, and these findings are useless for diagnosing drug allergy.
Factors causing immune allergic response are involved in the mechanism underlying cellular injury in idiosyncratic DILI (7,22). For example, allergies are caused by excessively strong immune functions, and patients with an allergic constitution are often more sensitive to drugs and show a higher incidence of DILI than patients without allergic constitution (20). At present, a history of drug allergy is not listed as a risk factor for DILI (7,7-19). Although the overall incidence of drug allergy is unknown, it accounts for 1-2% of all admissions and 3-5% of hospitalized patients (24). According to a report by the Drug-induced Liver Injury Network, patients with DILI frequently (>40%) have a history of drug allergy (19). Therefore, the history of drug allergy may have been a host risk factor for DILI in this case.
DILI is a leading cause of acute liver failure (7,9,17,19,23), with 1% of cases being subjected to PE (23). In Japan, artificial liver support, consisting of PE and HDF, is performed as treatment for patients with acute liver failure, especially in those with hepatic encephalopathy to stabilize the patient’s condition until recovery of the native liver or performance of liver transplantation (9,25). Disaccharides and the nonabsorbable antibiotic rifaximin are also recommended for the treatment of hepatic encephalopathy for patients with cirrhosis (26). In our patient, the PT did not meet the criteria for acute liver failure (9); however, he suffered from severe liver injury, hyperbilirubinemia, deterioration of PT over time, and the development of grade II hepatic encephalopathy. The results of a liver biopsy showed sever liver injury with jaundice, mixed lymphocyte and plasma cell infiltration in the portal vein area, ductular proliferation, ballooning hepatocytes, and cholestasis. Oral treatment of lactulose and rifaximin for hepatic encephalopathy, and artificial liver support were useful for maintaining the minimal liver function required to sustain the life of this patient.
Recently, it was reported that the recovery rate from hepatic encephalopathy is higher in patients with PE and HDF than in those with PE alone (25). This is because HDF removes low- to middle-sized molecules, including ammonia, decreasing the side-effects of PE. In the present case, hepatic encephalopathy was not observed after the combined use of PE and HDF. Although anaphylaxis and catheter infection occurred as a complication of plasmapheresis, with appropriate treatment, the patient eventually recovered from his severe liver injury.
In conclusion, we encountered a case of a severe liver injury caused by G/P therapy. Host factors should be considered in order to prevent DILI during treatment with this regimen.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors thank Drs. S. Hosoi and Y. Okumura for their cooperation in the management of the reported case. | Recovering | ReactionOutcome | CC BY-NC-ND | 33612683 | 19,682,017 | 2021-08-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Granulocyte and Monocyte Adsorptive Apheresis for Ulcerative Colitis in a Patient with Low Bone Mineral Density Due to Fanconi-Bickel Syndrome.
Systemic steroid is required for the exacerbation of ulcerative colitis (UC), although its administration should be avoided in patients with a low bone mineral density (BMD) exacerbated by side effects of steroids. We herein report the successful induction of remission in an UC case with a low BMD due to Fanconi-Bickel syndrome-or glycogen storage disease type XI-using granulocyte and monocyte adsorptive apheresis (GMA). For a 43-year-old woman with a BMD of 50% the young adult mean, GMA was performed 2 times a week for a total of 10 times. GMA might be a steroid-free treatment option for UC patients with a low BMD.
Introduction
Fanconi-Bickel syndrome (FBS), also known as glycogen storage disease type Ⅺ, is a special form of liver-type glycogen storage disease. It is a rare autosomal recessive metabolic disorder characterized by an impaired metabolism of glucose and galactose and the accumulation of glycogen in the liver and kidneys (Fanconi nephropathy), leading to decreases in bone mineral density (BMD) and proximal renal tubular dysfunction (1). The disease was first reported by Fanconi and Bickel in 1949 (2). In 1997, the gene for the transport protein glucose transporter 2 (GLUT2) was identified as the gene responsible for this disease (3).
Ulcerative colitis (UC) is a refractory, chronic inflammatory bowel disease of unknown origin that forms a chronic inflammatory lesion in the large intestine. Systemic steroid play important roles as the first-line drug in induction therapy at the time of UC exacerbation (4). However, the first-line drug for use in induction therapy is unclear in cases of UC developing in patients who have difficulty receiving steroid administration because of underlying conditions, such as glycogenosis, that result in a low BMD and impaired metabolism.
We herein report a patient with UC complicated with FBS. The patient had a markedly decreased BMD. We selected granulocyte and monocyte adsorptive apheresis (GMA) with AdacolumnⓇ as our first choice of treatment and successfully performed remission induction therapy. This patient had mild renal dysfunction in addition to a low BMD. Salazosulfapyridine was useful without inducing the further exacerbation of renal dysfunction. To our knowledge, there have been no reports of remission induction therapy in UC cases with FBS.
Case Report
We conducted this study in compliance with the principles of the Declaration of Helsinki. The study was approved by the Ethics Committee of Saiseikai Shigaken Hospital. Written informed consent was obtained.
A 43-year-old woman was admitted to our hospital due to hematochezia, lower abdominal pain, and diarrhea. She had been diagnosed with FBS at seven years old. She had no family history, and no other family members had glycogen storage disease. At the initial assessment upon admission, she had an apparent growth disorder. Her height and weight were 117 cm and 28 kg, respectively.
Plain abdominal computed tomography showed marked wall thickening from the rectum to the transverse colon (Fig. 1). Her blood examinations also revealed high levels of inflammatory response markers [erythrocyte sedimentation rate (ESR), 66 mm/h; C-reactive protein (CRP), 0.44 mg/dL]. The nutritional status was poor, and the serum albumin level was 2.5 g/dL. The creatinine value was 1.02 mg/dL. Mild renal impairment was confirmed with an estimated glomerular filtration rate of 47.7 mL/min/1.73 m2. Several days after hospitalization, the patient was found to be positive for cytomegalovirus (CMV) antigens (Table). However, the number of positive cells was 1/50,000 white blood cells (WBCs), and no CMV-positive cells were observed by CMV immunohistochemistry staining (Fig. 2).
Figure 1. Findings of plain abdominal computed tomography of the patient on admission. The wall of the intestinal tract thickened from the rectum to the transverse colon. (A) Transverse colon, (B) sigmoid colon, and (C) rectum.
Table. Blood Test and Fecal Culture Results on Admission.
List Standard value Value
WBC (×103/μL) (3.2-8.5) 6.0
RBC (×104/μL) (370-490) 293
Hemoglobin (g/dL) (11.3-14.8) 9.3
Hematocrit (%) (34-45) 29.3
Plt (×103/μL) (160-370) 374
ESR (mm/h) (3-15) 66
CRP (mg/dL) (less than 0.30) 0.44
TP (g/dL) (6.1-8.2) 6.2
Albumin (g/dL) (3.9-5.0) 2.5
TB (mg/dL) (0.05-1.15) 0.26
AST (IU/L) (5-46) 12
ALT (IU/L) (4-51) 6
LDH (IU/L) (100-225) 160
Glu (mg/dL) (76-110) 76
BUN (mg/dL) (5.5-23.1) 6.2
Creatinine (mg/dL) (0.6-0.9) 1.02
eGFR (mL/min/1.73 m2) (90 or more) 47.7
Na (mEq/L) (136-146) 136
K (mEq/L) (3.5-4.9) 3.8
Cl (mEq/L) (96-110) 102
IP (mg/dL) (2.4-4.3) 2.2
C7-HRP Positive
The number of positive counts 1/50,000WBC
Fecal culture
Common bacterium Negative
Acid-fast bacterium Negative
WBC: white blood cell, RBC: red blood cell, Plt: platelets, LD: lactate dehydrogenase, TB: total bilirubin, TP: total protein, Glu: glucose, eGFR: estimated glomerular filtration rate, IP: inorganic phosphorus, C7-HRP: cytomegalovirus antigenemia
Figure 2. The histological images of (A) Hematoxylin and Eosin staining and (B) immunohistochemistry staining of the large intestine (Scale bars represent 100 μm). No CMV-positive cells were observed by CMV immunohistochemical staining. CMV: cytomegalovirus
Colonoscopy revealed a continuously inflamed mucosa from the rectum to the transverse colon (Fig. 3). The ulcerative colitis endoscopic index of severity (UCEIS) (5) was 5, and the Mayo endoscopic score for ulcerative colitis (MES) (6) was 2.
Figure 3. Endoscopic findings of the patient on admission. Total colonoscopy was performed, and the patient was diagnosed with UC. (A) Transverse colon, (B) sigmoid colon, and (C) rectum. UC: ulcerative colitis
The biopsy specimens taken during colonoscopy showed pathologic findings specific to UC. UC was considered based on the pathologic and endoscopic findings. However, infectious colitis and CMV colitis associated with UC could not be ruled out, although the possibility was deemed low based on the number of CMV antigen-positive cells and the results of immunohistochemistry staining. Thus, the patient was initially treated with both antibiotics and antivirals. Unfortunately, she continued to have frequent diarrhea.
The patient was started on salazosulfapyridine (3,000 mg/day), which can be used regardless of the renal disorder while preventing further deterioration of the renal function. The UC was categorized as total colitis type [Lichtiger Clinical Activity Index (CAI)=11 (7)]. Although the administration of mesalazine was initiated, the frequency of bloody stools and diarrhea did not improve. The patient was started on GMA therapy using AdacolumnⓇ. Steroid therapy was discouraged because of the patient's low BMD. Her BMD of the greater trochanter of the femur measured by dual energy X-ray absorptiometry was 0.377 g/cm2, which was 50% of the young adult mean. GMA therapy was performed twice weekly. It was important for remission induction to succeed as quickly as possible because a patient with FBS syndrome can easily develop hypoglycemia when meal quantities and caloric intakes are decreased. In fact, the patient manifested hypoglycemic symptoms whenever the meal quantities were limited (when the daily dietary calorie intake was ≤1,200 kcal).
After GMA therapy was administered 4 times, the levels of her inflammatory response markers improved markedly (CRP, 0.01 mg/dL; ESR, 7.0 mm/h; CAI 3). She tested negative for CMV antigenemia after the fourth GMA. To evaluate the healing of the intestinal mucosa, colonoscopy was performed after the eighth GMA. The endoscopic findings showed that intestinal mucosal healing had almost been achieved (Fig. 4). UCEIS did not go down to 0 but did decrease to 1 (8), and in MES, it was 1 or 0. After receiving GMA therapy a total of 10 times, the patient's serum albumin levels rose to 3.9 g/dL, and she was discharged with improvement (Fig. 5). One year has passed since the completion of GMA therapy and salazosulfapyridine therapy alone; this patient has had no recurrence.
Figure 4. Endoscopic findings of the patient after the eighth GMA. Total colonoscopy was performed, and intestinal mucosal healing had almost been achieved. (A) Transverse colon, (B) sigmoid colon, and (C) rectum. GMA: granulocyte and monocyte adsorptive apheresis
Figure 5. Clinical course from hospitalization to discharge. GMA: granulocyte and monocyte adsorptive apheresis, eGFR: estimated glomerular filtration rate, ESR: erythrocyte sedimentation rate, ALB: albumin
Discussion
GMA was found to be useful as remission induction therapy for patients with underlying disorders who have a low BMD and cannot be treated with steroids. In addition, GMA and salazosulfapyridine were useful without causing the further exacerbation of renal dysfunction.
GMA was found to be useful for the present UC patient with a low BMD. There have been no reports of GMA exacerbating BMD. Furthermore, we have found no reports of GMA affecting glycogen storage disease in adults. The use of glucocorticoids is known to be a risk factor for a low BMD in patients with UC (9).
Patients with inflammatory bowel disease (IBD) are reported to have a higher frequency of osteoporosis and bone loss than healthy subjects. Furthermore, osteoporosis is recognized as an extraintestinal complication experienced by patients with IBD (10,11,12). Therefore, it is important to treat UC while considering patients' BMD.
A multicenter, retrospective study was recently conducted to identify patients who responded well to adsorptive granulomonocytapheresis (13). The authors found that the predictors of a favorable response to GMA were age ≤60 years old, UC duration <1 year, Mayo endoscopic sub score 2 (vs. 3), and steroid- and biological agent-naïve UC.
At present, there is no consensus concerning the treatment of choice for UC patients with glycogen storage disease. The patient in this case report was <60 years old. Her UC duration was also <1 year. Her Mayo endoscopic sub score was 2 (vs. 3), and her UC was considered to be steroid- and biological agent-naïve. Thus, in patients with a low BMD, GMA may be an effective treatment, especially when steroid therapy must be avoided.
GMA and salazosulfapyridine were useful for treating this case without causing further exacerbation of renal dysfunction. Mesalazine is frequently prescribed for remission therapy and for maintenance therapy in patients with UC. Its careful administration is required for patients with moderate renal dysfunction. In addition, the administration of mesalazine is contraindicated in patients with severe renal dysfunction. We were concerned about further renal dysfunction; therefore, we administered salazosulfapyridine, although the renal dysfunction did not worsen. According to the Japanese CKD guidelines (14), there is no need to reduce the dose of salazosulfapyridine, even when it is administered to patients with an impaired renal function; therefore, salazosulfapyridine was used in this case.
CMV reactivation is also an important issue for UC. The present patient was positive for CMV antigens. The CMV antigenemia assay has a high specificity and low sensitivity for moderate-to-severe UC. It must be recognized that peripheral blood reactivation does not necessarily reflect CMV reactivation in the intestinal tract (15). The gold standard for diagnosing CMV infections is a histological examination in combination with hematoxylin and eosin staining and immunohistochemical staining. However, the CMV positivity rate depends on the number of biopsy tests performed and the location where the biopsy was performed (16). We must therefore be careful when interpreting the results.
In this case, whether or not CMV colitis was present was unclear. GMA has been reported to have little effect on CMV reactivation, as it has no direct effect on the local immune system (17,18). Therefore, GMA is effective as remission induction therapy for UC patients with a history of CMV infection. Even if it is not possible to determine if CMV infection is present or not at the onset of UC, GMA may be effective as remission induction therapy for UC patients.
Although it is rare to treat UC patients with a low BMD and a renal function that has been impaired by a special underlying disease, as in the present case, the chances of encountering cases similar to this case are expected to increase in the future.
The above reasons are why UC has been considered a disease that develops at a young age, although in recent years, the number of cases that develop at an older age has been increasing (19-22), and the number of cases with exacerbation in old age is expected to increase with the aging of the population. There will thus likely be more opportunities to select and administer appropriate remission induction therapy when the symptoms in UC patients with a low BMD due to old age or underlying disease or with renal function worsen.
GMA was found to be useful as remission induction therapy for patients with underlying disorders with a low BMD who cannot be treated with steroids. In addition, GMA and salazosulfapyridine were useful for treating UC without inducing further exacerbation of renal dysfunction.
Our findings may be applicable to not only UC patients with FBS as the underlying disease, similar to the present case, but also to those with other glycogen storage diseases as the underlying disease or with diseases other than glycogen storage diseases that induce a reduction in the BMD. However, our findings are from a single case, so it is necessary to accumulate more cases to investigate whether or not GMA is a suitable first choice for remission induction therapy in UC patients with a low BMD.
In conclusion, our experience with the current case suggests that GMA may be useful as remission induction therapy for patients with underlying disorders who have a low BMD and who cannot be treated with steroids. We recommend further investigations be conducted to establish a detailed consensus concerning the appropriate timing and patient selection for GMA therapy.
The authors state that they have no Conflict of Interest (COI). | MESALAMINE, SULFASALAZINE | DrugsGivenReaction | CC BY-NC-ND | 33612684 | 19,785,330 | 2021-08-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Intralymphatic Histiocytosis: An Unusual Presentation.
Intralymphatic histiocytosis (ILH) is a rare cutaneous condition initially described in 1994 by O'Grady et al. It often appears as a red to violaceous, livedoid patch or plaque usually on the extremities. We present a 71-year-old female with a history of psoriasis, 50 pack years smoking and recent Legionnaires disease who came to us complaining of a red to violaceous, blanching, edematous, mildly tender lesion covering the left lower lip and extending to the chin and anterior neck. After multiple biopsies, ILH was confirmed and the patient was initially started on tacrolimus 0.1% ointment b.i.d., but there was no response. Then, she was started on oral pentoxifylline and intermittent topical steroids, as well as continuing the topical tacrolimus. There was again no response, so now she is taking a TNF-ɑ inhibitor as it appears to be a granulomatous process. These ILH cases are very rare and there is limited literature that describes one treatment as a cure. Treatment of ILH is very difficult, but several different therapies have been reported with varying success. If the disease is secondary to an underlying inflammatory disease or malignancy, then treatment of the primary disorder can lead to resolution of the ILH.
Introduction
Intralymphatic histiocytosis (ILH) is a rare cutaneous condition initially described in 1994 by O'Grady et al. [1]. It often appears as a red to violaceous, livedoid patch or plaque usually on the extremities. The condition is most commonly seen in association with rheumatoid arthritis. Other associations have been identified such as orthopedic implants, chronic inflammation, and underlying malignancy [2, 3]. Interestingly, it has also been described as a histologic feature of granulomatous cheilitis and Melkersson-Rosenthal syndrome (MRS) [4]. We present the case of a 71-year-old female with cutaneous intralymphatic histiocytosis of the lower face with uncertain etiology.
Case Presentation
A 71-year-old female initially presented to another dermatologist complaining of a bright red, warm and tender plaque on the left lower lip. Her past medical history was significant for 50 pack years of smoking, psoriasis, and a hospitalization 1 year prior from Legionnaire's disease. She was initially treated for a presumed infection without improvement. She was also referred to ENT, who recommended CT of the face and sinuses, which was negative for any significant findings.
Six months after initial presentation to a dermatologist, the patient presented to our clinic with a 7-month history of a red to violaceous, blanching, edematous, mildly tender lesion covering the left lower lip and now extending to the chin and anterior neck (Fig. 1, 2). Intraoral exam was negative for any changes. On this visit, there was concern for possible malignancy, and a 3-mm punch biopsy of involved skin on the left lower cutaneous lip was performed. This was interpreted as having “features most consistent with glomeruloid hemangioma.” In light of this pathology report, a workup for POEMS syndrome was initiated, although clinically the lesion did not appear to be consistent with this diagnosis.
Three weeks later, a repeat biopsy was performed and sent to a different laboratory for evaluation. The initial 3-mm punch biopsy was also sent for a second opinion. These two biopsies were found to be most consistent with intravascular/intralymphatic histiocytosis with features of granulomatous vasculitis (Fig. 3, 4). The patient was also sent for a second opinion, and a third and confirmatory biopsy of the left chin again showed intralymphatic histiocytosis. Initial bloodwork showed hemoglobin of 16.6 and hematocrit of 49.7, CEA of 6.4 (ref: 0–4.7), with ANA and ANCA negative. Age-appropriate cancer screening was also recommended and is still pending at this time. The patient had an MRI done which showed asymmetric prominence of the subcutaneous fat over the left face with no abnormal soft tissue mass or lymphadenopathy.
As the diagnosis was not immediately evident, treatment was initiated with tacrolimus 0.1% ointment b.i.d. While this treatment did not shrink the lesion, it prevented the lesion from growing in size. Once the final diagnosis was made, it was decided to start oral pentoxyfylline and intermittent topical steroids, as well as continuing the topical tacrolimus. The patient was on this treatment regimen for 1 month with no improvement. As this appears to be a granulomatous process, our current plan is to pursue treatment with a TNF-ɑ inhibitor.
Discussion/Conclusion
Intralymphatic histiocytosis (ILH) is an extremely rare disease that most often affects elderly women [5]. This disease has an inconsistent presentation ranging from a single erythematous plaque to multiple papules or nodules [6]. The lesions can also be seen as poorly demarcated and irregularly shaped patches or plaques with a livedo-reticularis like pattern [7]. There is a strong association with rheumatoid arthritis with other less common associations such as Rosai-Dorfman disease and orthopedic metal implants. Of the 34 patients in the literature with ILH, 18 patients had rheumatoid arthritis and two additional patients had a positive rheumatoid factor [7]. There is some uncertainty about the pathogenesis of intralymphatic histiocytosis. It is widely accepted that chronic inflammation leads to obstruction and dilation of lymphatic vessels. Lymphostasis leads to poor antigen clearance, constant stimulation of the immune system, and proliferation of histiocytes. This proliferation perpetuates the obstruction as it leads to further adhesion of histiocytes [8].
In a review of 16 cases of ILH, the majority of the lesions were seen on the extremities and breast region [7, 8]. The most common morphology is a pink to violaceous plaque which is then followed by papules and nodules. One lesion on the upper eyelid in this review was associated with MRS [6]. Another case report described ILH in an 8-year-old boy with MRS of the upper lip [9]. In our case, the patient presented with a warm, tender, erythematous plaque of the lower lip which then spread to the chin and neck. The morphology was consistent with previously reported cases of ILH; however, the location of the lesion, and other histologic features not usually seen in orofacial granulomatosis, made it difficult to establish that specific diagnosis.
One review of 16 case reports of ILH identified some common characteristics of the disease. It was found that the epidermis and papillary dermis were unchanged, but the reticular dermis showed dilated vascular and lymphatic structures. Within these dilated vessels, some retained an empty lumen, while some contained histiocytes both singly and in aggregates [7]. The histiocytes within the lumen of the lymphatic system positively stain for CD31,34 and the vessel itself stains positive for D2–40 [8].
Treatment of ILH is very difficult, but several different therapies have been reported with varying success. If the disease is secondary to an underlying inflammatory disease or malignancy, then treatment of the primary disorder can lead to resolution of the ILH. One example is the treatment of rheumatoid arthritis with infliximab, which lead to resolution of ILH. Another example is the treatment of lung adenocarcinoma with pembrolizumab leading to improvement of ILH [10]. One case that was associated with tonsillitis showed response to antibiotic therapy and tonsillectomy [11]. Other reported treatment options include: electron beam therapy, cyclophosphamide, topical and systemic steroids, amoxicillin and acetylsalicylic acid, pentoxifylline, NSAIDs, excision, pressure bandages, topical tacrolimus, and methotrexate [11].
In summary, this is a very unique case that for now has been diagnosed based on its predominant pathologic feature: intralymphatic histiocytosis. This may represent a case of MRS with unusual pathologic features. However, two separate pathology labs confirmed the diagnosis of intralymphatic histiocytosis. Further discussion and research is needed to more fully understand the pathogenesis and treatment of this uncommon disease.
Statement of Ethics
The authors received written informed consent from this patient to publish this case (including images). The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Information revealing the subject's identity has been avoided and all patients were identified by aliases and not by their real names.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding sources were used for this project.
Author Contributions
Timothy J. Blackwell: manuscript contributor, author of discussion and case presentation. Zac Ingersoll: manuscript contributor, author of introduction and case presentation. Martin Blackwell: treating physician, consent of patient, manuscript contributor/author of introduction.
Fig. 1 Clinical presentation showing an ill-defined erythematous to violaceous plaque of the left lower face and chin.
Fig. 2 Clinical presentation showing an ill-defined erythematous to violaceous plaque of the left lower face and chin.
Fig. 3 Low power.
Fig. 4 Granulomatous and lymphoid aggregates. | PENTOXIFYLLINE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33613226 | 19,720,171 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Intralymphatic Histiocytosis: An Unusual Presentation.
Intralymphatic histiocytosis (ILH) is a rare cutaneous condition initially described in 1994 by O'Grady et al. It often appears as a red to violaceous, livedoid patch or plaque usually on the extremities. We present a 71-year-old female with a history of psoriasis, 50 pack years smoking and recent Legionnaires disease who came to us complaining of a red to violaceous, blanching, edematous, mildly tender lesion covering the left lower lip and extending to the chin and anterior neck. After multiple biopsies, ILH was confirmed and the patient was initially started on tacrolimus 0.1% ointment b.i.d., but there was no response. Then, she was started on oral pentoxifylline and intermittent topical steroids, as well as continuing the topical tacrolimus. There was again no response, so now she is taking a TNF-ɑ inhibitor as it appears to be a granulomatous process. These ILH cases are very rare and there is limited literature that describes one treatment as a cure. Treatment of ILH is very difficult, but several different therapies have been reported with varying success. If the disease is secondary to an underlying inflammatory disease or malignancy, then treatment of the primary disorder can lead to resolution of the ILH.
Introduction
Intralymphatic histiocytosis (ILH) is a rare cutaneous condition initially described in 1994 by O'Grady et al. [1]. It often appears as a red to violaceous, livedoid patch or plaque usually on the extremities. The condition is most commonly seen in association with rheumatoid arthritis. Other associations have been identified such as orthopedic implants, chronic inflammation, and underlying malignancy [2, 3]. Interestingly, it has also been described as a histologic feature of granulomatous cheilitis and Melkersson-Rosenthal syndrome (MRS) [4]. We present the case of a 71-year-old female with cutaneous intralymphatic histiocytosis of the lower face with uncertain etiology.
Case Presentation
A 71-year-old female initially presented to another dermatologist complaining of a bright red, warm and tender plaque on the left lower lip. Her past medical history was significant for 50 pack years of smoking, psoriasis, and a hospitalization 1 year prior from Legionnaire's disease. She was initially treated for a presumed infection without improvement. She was also referred to ENT, who recommended CT of the face and sinuses, which was negative for any significant findings.
Six months after initial presentation to a dermatologist, the patient presented to our clinic with a 7-month history of a red to violaceous, blanching, edematous, mildly tender lesion covering the left lower lip and now extending to the chin and anterior neck (Fig. 1, 2). Intraoral exam was negative for any changes. On this visit, there was concern for possible malignancy, and a 3-mm punch biopsy of involved skin on the left lower cutaneous lip was performed. This was interpreted as having “features most consistent with glomeruloid hemangioma.” In light of this pathology report, a workup for POEMS syndrome was initiated, although clinically the lesion did not appear to be consistent with this diagnosis.
Three weeks later, a repeat biopsy was performed and sent to a different laboratory for evaluation. The initial 3-mm punch biopsy was also sent for a second opinion. These two biopsies were found to be most consistent with intravascular/intralymphatic histiocytosis with features of granulomatous vasculitis (Fig. 3, 4). The patient was also sent for a second opinion, and a third and confirmatory biopsy of the left chin again showed intralymphatic histiocytosis. Initial bloodwork showed hemoglobin of 16.6 and hematocrit of 49.7, CEA of 6.4 (ref: 0–4.7), with ANA and ANCA negative. Age-appropriate cancer screening was also recommended and is still pending at this time. The patient had an MRI done which showed asymmetric prominence of the subcutaneous fat over the left face with no abnormal soft tissue mass or lymphadenopathy.
As the diagnosis was not immediately evident, treatment was initiated with tacrolimus 0.1% ointment b.i.d. While this treatment did not shrink the lesion, it prevented the lesion from growing in size. Once the final diagnosis was made, it was decided to start oral pentoxyfylline and intermittent topical steroids, as well as continuing the topical tacrolimus. The patient was on this treatment regimen for 1 month with no improvement. As this appears to be a granulomatous process, our current plan is to pursue treatment with a TNF-ɑ inhibitor.
Discussion/Conclusion
Intralymphatic histiocytosis (ILH) is an extremely rare disease that most often affects elderly women [5]. This disease has an inconsistent presentation ranging from a single erythematous plaque to multiple papules or nodules [6]. The lesions can also be seen as poorly demarcated and irregularly shaped patches or plaques with a livedo-reticularis like pattern [7]. There is a strong association with rheumatoid arthritis with other less common associations such as Rosai-Dorfman disease and orthopedic metal implants. Of the 34 patients in the literature with ILH, 18 patients had rheumatoid arthritis and two additional patients had a positive rheumatoid factor [7]. There is some uncertainty about the pathogenesis of intralymphatic histiocytosis. It is widely accepted that chronic inflammation leads to obstruction and dilation of lymphatic vessels. Lymphostasis leads to poor antigen clearance, constant stimulation of the immune system, and proliferation of histiocytes. This proliferation perpetuates the obstruction as it leads to further adhesion of histiocytes [8].
In a review of 16 cases of ILH, the majority of the lesions were seen on the extremities and breast region [7, 8]. The most common morphology is a pink to violaceous plaque which is then followed by papules and nodules. One lesion on the upper eyelid in this review was associated with MRS [6]. Another case report described ILH in an 8-year-old boy with MRS of the upper lip [9]. In our case, the patient presented with a warm, tender, erythematous plaque of the lower lip which then spread to the chin and neck. The morphology was consistent with previously reported cases of ILH; however, the location of the lesion, and other histologic features not usually seen in orofacial granulomatosis, made it difficult to establish that specific diagnosis.
One review of 16 case reports of ILH identified some common characteristics of the disease. It was found that the epidermis and papillary dermis were unchanged, but the reticular dermis showed dilated vascular and lymphatic structures. Within these dilated vessels, some retained an empty lumen, while some contained histiocytes both singly and in aggregates [7]. The histiocytes within the lumen of the lymphatic system positively stain for CD31,34 and the vessel itself stains positive for D2–40 [8].
Treatment of ILH is very difficult, but several different therapies have been reported with varying success. If the disease is secondary to an underlying inflammatory disease or malignancy, then treatment of the primary disorder can lead to resolution of the ILH. One example is the treatment of rheumatoid arthritis with infliximab, which lead to resolution of ILH. Another example is the treatment of lung adenocarcinoma with pembrolizumab leading to improvement of ILH [10]. One case that was associated with tonsillitis showed response to antibiotic therapy and tonsillectomy [11]. Other reported treatment options include: electron beam therapy, cyclophosphamide, topical and systemic steroids, amoxicillin and acetylsalicylic acid, pentoxifylline, NSAIDs, excision, pressure bandages, topical tacrolimus, and methotrexate [11].
In summary, this is a very unique case that for now has been diagnosed based on its predominant pathologic feature: intralymphatic histiocytosis. This may represent a case of MRS with unusual pathologic features. However, two separate pathology labs confirmed the diagnosis of intralymphatic histiocytosis. Further discussion and research is needed to more fully understand the pathogenesis and treatment of this uncommon disease.
Statement of Ethics
The authors received written informed consent from this patient to publish this case (including images). The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Information revealing the subject's identity has been avoided and all patients were identified by aliases and not by their real names.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding sources were used for this project.
Author Contributions
Timothy J. Blackwell: manuscript contributor, author of discussion and case presentation. Zac Ingersoll: manuscript contributor, author of introduction and case presentation. Martin Blackwell: treating physician, consent of patient, manuscript contributor/author of introduction.
Fig. 1 Clinical presentation showing an ill-defined erythematous to violaceous plaque of the left lower face and chin.
Fig. 2 Clinical presentation showing an ill-defined erythematous to violaceous plaque of the left lower face and chin.
Fig. 3 Low power.
Fig. 4 Granulomatous and lymphoid aggregates. | PENTOXIFYLLINE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33613226 | 19,720,171 | 2021 |
What was the administration route of drug 'PENTOXIFYLLINE'? | Intralymphatic Histiocytosis: An Unusual Presentation.
Intralymphatic histiocytosis (ILH) is a rare cutaneous condition initially described in 1994 by O'Grady et al. It often appears as a red to violaceous, livedoid patch or plaque usually on the extremities. We present a 71-year-old female with a history of psoriasis, 50 pack years smoking and recent Legionnaires disease who came to us complaining of a red to violaceous, blanching, edematous, mildly tender lesion covering the left lower lip and extending to the chin and anterior neck. After multiple biopsies, ILH was confirmed and the patient was initially started on tacrolimus 0.1% ointment b.i.d., but there was no response. Then, she was started on oral pentoxifylline and intermittent topical steroids, as well as continuing the topical tacrolimus. There was again no response, so now she is taking a TNF-ɑ inhibitor as it appears to be a granulomatous process. These ILH cases are very rare and there is limited literature that describes one treatment as a cure. Treatment of ILH is very difficult, but several different therapies have been reported with varying success. If the disease is secondary to an underlying inflammatory disease or malignancy, then treatment of the primary disorder can lead to resolution of the ILH.
Introduction
Intralymphatic histiocytosis (ILH) is a rare cutaneous condition initially described in 1994 by O'Grady et al. [1]. It often appears as a red to violaceous, livedoid patch or plaque usually on the extremities. The condition is most commonly seen in association with rheumatoid arthritis. Other associations have been identified such as orthopedic implants, chronic inflammation, and underlying malignancy [2, 3]. Interestingly, it has also been described as a histologic feature of granulomatous cheilitis and Melkersson-Rosenthal syndrome (MRS) [4]. We present the case of a 71-year-old female with cutaneous intralymphatic histiocytosis of the lower face with uncertain etiology.
Case Presentation
A 71-year-old female initially presented to another dermatologist complaining of a bright red, warm and tender plaque on the left lower lip. Her past medical history was significant for 50 pack years of smoking, psoriasis, and a hospitalization 1 year prior from Legionnaire's disease. She was initially treated for a presumed infection without improvement. She was also referred to ENT, who recommended CT of the face and sinuses, which was negative for any significant findings.
Six months after initial presentation to a dermatologist, the patient presented to our clinic with a 7-month history of a red to violaceous, blanching, edematous, mildly tender lesion covering the left lower lip and now extending to the chin and anterior neck (Fig. 1, 2). Intraoral exam was negative for any changes. On this visit, there was concern for possible malignancy, and a 3-mm punch biopsy of involved skin on the left lower cutaneous lip was performed. This was interpreted as having “features most consistent with glomeruloid hemangioma.” In light of this pathology report, a workup for POEMS syndrome was initiated, although clinically the lesion did not appear to be consistent with this diagnosis.
Three weeks later, a repeat biopsy was performed and sent to a different laboratory for evaluation. The initial 3-mm punch biopsy was also sent for a second opinion. These two biopsies were found to be most consistent with intravascular/intralymphatic histiocytosis with features of granulomatous vasculitis (Fig. 3, 4). The patient was also sent for a second opinion, and a third and confirmatory biopsy of the left chin again showed intralymphatic histiocytosis. Initial bloodwork showed hemoglobin of 16.6 and hematocrit of 49.7, CEA of 6.4 (ref: 0–4.7), with ANA and ANCA negative. Age-appropriate cancer screening was also recommended and is still pending at this time. The patient had an MRI done which showed asymmetric prominence of the subcutaneous fat over the left face with no abnormal soft tissue mass or lymphadenopathy.
As the diagnosis was not immediately evident, treatment was initiated with tacrolimus 0.1% ointment b.i.d. While this treatment did not shrink the lesion, it prevented the lesion from growing in size. Once the final diagnosis was made, it was decided to start oral pentoxyfylline and intermittent topical steroids, as well as continuing the topical tacrolimus. The patient was on this treatment regimen for 1 month with no improvement. As this appears to be a granulomatous process, our current plan is to pursue treatment with a TNF-ɑ inhibitor.
Discussion/Conclusion
Intralymphatic histiocytosis (ILH) is an extremely rare disease that most often affects elderly women [5]. This disease has an inconsistent presentation ranging from a single erythematous plaque to multiple papules or nodules [6]. The lesions can also be seen as poorly demarcated and irregularly shaped patches or plaques with a livedo-reticularis like pattern [7]. There is a strong association with rheumatoid arthritis with other less common associations such as Rosai-Dorfman disease and orthopedic metal implants. Of the 34 patients in the literature with ILH, 18 patients had rheumatoid arthritis and two additional patients had a positive rheumatoid factor [7]. There is some uncertainty about the pathogenesis of intralymphatic histiocytosis. It is widely accepted that chronic inflammation leads to obstruction and dilation of lymphatic vessels. Lymphostasis leads to poor antigen clearance, constant stimulation of the immune system, and proliferation of histiocytes. This proliferation perpetuates the obstruction as it leads to further adhesion of histiocytes [8].
In a review of 16 cases of ILH, the majority of the lesions were seen on the extremities and breast region [7, 8]. The most common morphology is a pink to violaceous plaque which is then followed by papules and nodules. One lesion on the upper eyelid in this review was associated with MRS [6]. Another case report described ILH in an 8-year-old boy with MRS of the upper lip [9]. In our case, the patient presented with a warm, tender, erythematous plaque of the lower lip which then spread to the chin and neck. The morphology was consistent with previously reported cases of ILH; however, the location of the lesion, and other histologic features not usually seen in orofacial granulomatosis, made it difficult to establish that specific diagnosis.
One review of 16 case reports of ILH identified some common characteristics of the disease. It was found that the epidermis and papillary dermis were unchanged, but the reticular dermis showed dilated vascular and lymphatic structures. Within these dilated vessels, some retained an empty lumen, while some contained histiocytes both singly and in aggregates [7]. The histiocytes within the lumen of the lymphatic system positively stain for CD31,34 and the vessel itself stains positive for D2–40 [8].
Treatment of ILH is very difficult, but several different therapies have been reported with varying success. If the disease is secondary to an underlying inflammatory disease or malignancy, then treatment of the primary disorder can lead to resolution of the ILH. One example is the treatment of rheumatoid arthritis with infliximab, which lead to resolution of ILH. Another example is the treatment of lung adenocarcinoma with pembrolizumab leading to improvement of ILH [10]. One case that was associated with tonsillitis showed response to antibiotic therapy and tonsillectomy [11]. Other reported treatment options include: electron beam therapy, cyclophosphamide, topical and systemic steroids, amoxicillin and acetylsalicylic acid, pentoxifylline, NSAIDs, excision, pressure bandages, topical tacrolimus, and methotrexate [11].
In summary, this is a very unique case that for now has been diagnosed based on its predominant pathologic feature: intralymphatic histiocytosis. This may represent a case of MRS with unusual pathologic features. However, two separate pathology labs confirmed the diagnosis of intralymphatic histiocytosis. Further discussion and research is needed to more fully understand the pathogenesis and treatment of this uncommon disease.
Statement of Ethics
The authors received written informed consent from this patient to publish this case (including images). The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Information revealing the subject's identity has been avoided and all patients were identified by aliases and not by their real names.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding sources were used for this project.
Author Contributions
Timothy J. Blackwell: manuscript contributor, author of discussion and case presentation. Zac Ingersoll: manuscript contributor, author of introduction and case presentation. Martin Blackwell: treating physician, consent of patient, manuscript contributor/author of introduction.
Fig. 1 Clinical presentation showing an ill-defined erythematous to violaceous plaque of the left lower face and chin.
Fig. 2 Clinical presentation showing an ill-defined erythematous to violaceous plaque of the left lower face and chin.
Fig. 3 Low power.
Fig. 4 Granulomatous and lymphoid aggregates. | Oral | DrugAdministrationRoute | CC BY-NC | 33613226 | 19,720,171 | 2021 |
What was the administration route of drug 'TACROLIMUS'? | Intralymphatic Histiocytosis: An Unusual Presentation.
Intralymphatic histiocytosis (ILH) is a rare cutaneous condition initially described in 1994 by O'Grady et al. It often appears as a red to violaceous, livedoid patch or plaque usually on the extremities. We present a 71-year-old female with a history of psoriasis, 50 pack years smoking and recent Legionnaires disease who came to us complaining of a red to violaceous, blanching, edematous, mildly tender lesion covering the left lower lip and extending to the chin and anterior neck. After multiple biopsies, ILH was confirmed and the patient was initially started on tacrolimus 0.1% ointment b.i.d., but there was no response. Then, she was started on oral pentoxifylline and intermittent topical steroids, as well as continuing the topical tacrolimus. There was again no response, so now she is taking a TNF-ɑ inhibitor as it appears to be a granulomatous process. These ILH cases are very rare and there is limited literature that describes one treatment as a cure. Treatment of ILH is very difficult, but several different therapies have been reported with varying success. If the disease is secondary to an underlying inflammatory disease or malignancy, then treatment of the primary disorder can lead to resolution of the ILH.
Introduction
Intralymphatic histiocytosis (ILH) is a rare cutaneous condition initially described in 1994 by O'Grady et al. [1]. It often appears as a red to violaceous, livedoid patch or plaque usually on the extremities. The condition is most commonly seen in association with rheumatoid arthritis. Other associations have been identified such as orthopedic implants, chronic inflammation, and underlying malignancy [2, 3]. Interestingly, it has also been described as a histologic feature of granulomatous cheilitis and Melkersson-Rosenthal syndrome (MRS) [4]. We present the case of a 71-year-old female with cutaneous intralymphatic histiocytosis of the lower face with uncertain etiology.
Case Presentation
A 71-year-old female initially presented to another dermatologist complaining of a bright red, warm and tender plaque on the left lower lip. Her past medical history was significant for 50 pack years of smoking, psoriasis, and a hospitalization 1 year prior from Legionnaire's disease. She was initially treated for a presumed infection without improvement. She was also referred to ENT, who recommended CT of the face and sinuses, which was negative for any significant findings.
Six months after initial presentation to a dermatologist, the patient presented to our clinic with a 7-month history of a red to violaceous, blanching, edematous, mildly tender lesion covering the left lower lip and now extending to the chin and anterior neck (Fig. 1, 2). Intraoral exam was negative for any changes. On this visit, there was concern for possible malignancy, and a 3-mm punch biopsy of involved skin on the left lower cutaneous lip was performed. This was interpreted as having “features most consistent with glomeruloid hemangioma.” In light of this pathology report, a workup for POEMS syndrome was initiated, although clinically the lesion did not appear to be consistent with this diagnosis.
Three weeks later, a repeat biopsy was performed and sent to a different laboratory for evaluation. The initial 3-mm punch biopsy was also sent for a second opinion. These two biopsies were found to be most consistent with intravascular/intralymphatic histiocytosis with features of granulomatous vasculitis (Fig. 3, 4). The patient was also sent for a second opinion, and a third and confirmatory biopsy of the left chin again showed intralymphatic histiocytosis. Initial bloodwork showed hemoglobin of 16.6 and hematocrit of 49.7, CEA of 6.4 (ref: 0–4.7), with ANA and ANCA negative. Age-appropriate cancer screening was also recommended and is still pending at this time. The patient had an MRI done which showed asymmetric prominence of the subcutaneous fat over the left face with no abnormal soft tissue mass or lymphadenopathy.
As the diagnosis was not immediately evident, treatment was initiated with tacrolimus 0.1% ointment b.i.d. While this treatment did not shrink the lesion, it prevented the lesion from growing in size. Once the final diagnosis was made, it was decided to start oral pentoxyfylline and intermittent topical steroids, as well as continuing the topical tacrolimus. The patient was on this treatment regimen for 1 month with no improvement. As this appears to be a granulomatous process, our current plan is to pursue treatment with a TNF-ɑ inhibitor.
Discussion/Conclusion
Intralymphatic histiocytosis (ILH) is an extremely rare disease that most often affects elderly women [5]. This disease has an inconsistent presentation ranging from a single erythematous plaque to multiple papules or nodules [6]. The lesions can also be seen as poorly demarcated and irregularly shaped patches or plaques with a livedo-reticularis like pattern [7]. There is a strong association with rheumatoid arthritis with other less common associations such as Rosai-Dorfman disease and orthopedic metal implants. Of the 34 patients in the literature with ILH, 18 patients had rheumatoid arthritis and two additional patients had a positive rheumatoid factor [7]. There is some uncertainty about the pathogenesis of intralymphatic histiocytosis. It is widely accepted that chronic inflammation leads to obstruction and dilation of lymphatic vessels. Lymphostasis leads to poor antigen clearance, constant stimulation of the immune system, and proliferation of histiocytes. This proliferation perpetuates the obstruction as it leads to further adhesion of histiocytes [8].
In a review of 16 cases of ILH, the majority of the lesions were seen on the extremities and breast region [7, 8]. The most common morphology is a pink to violaceous plaque which is then followed by papules and nodules. One lesion on the upper eyelid in this review was associated with MRS [6]. Another case report described ILH in an 8-year-old boy with MRS of the upper lip [9]. In our case, the patient presented with a warm, tender, erythematous plaque of the lower lip which then spread to the chin and neck. The morphology was consistent with previously reported cases of ILH; however, the location of the lesion, and other histologic features not usually seen in orofacial granulomatosis, made it difficult to establish that specific diagnosis.
One review of 16 case reports of ILH identified some common characteristics of the disease. It was found that the epidermis and papillary dermis were unchanged, but the reticular dermis showed dilated vascular and lymphatic structures. Within these dilated vessels, some retained an empty lumen, while some contained histiocytes both singly and in aggregates [7]. The histiocytes within the lumen of the lymphatic system positively stain for CD31,34 and the vessel itself stains positive for D2–40 [8].
Treatment of ILH is very difficult, but several different therapies have been reported with varying success. If the disease is secondary to an underlying inflammatory disease or malignancy, then treatment of the primary disorder can lead to resolution of the ILH. One example is the treatment of rheumatoid arthritis with infliximab, which lead to resolution of ILH. Another example is the treatment of lung adenocarcinoma with pembrolizumab leading to improvement of ILH [10]. One case that was associated with tonsillitis showed response to antibiotic therapy and tonsillectomy [11]. Other reported treatment options include: electron beam therapy, cyclophosphamide, topical and systemic steroids, amoxicillin and acetylsalicylic acid, pentoxifylline, NSAIDs, excision, pressure bandages, topical tacrolimus, and methotrexate [11].
In summary, this is a very unique case that for now has been diagnosed based on its predominant pathologic feature: intralymphatic histiocytosis. This may represent a case of MRS with unusual pathologic features. However, two separate pathology labs confirmed the diagnosis of intralymphatic histiocytosis. Further discussion and research is needed to more fully understand the pathogenesis and treatment of this uncommon disease.
Statement of Ethics
The authors received written informed consent from this patient to publish this case (including images). The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Information revealing the subject's identity has been avoided and all patients were identified by aliases and not by their real names.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding sources were used for this project.
Author Contributions
Timothy J. Blackwell: manuscript contributor, author of discussion and case presentation. Zac Ingersoll: manuscript contributor, author of introduction and case presentation. Martin Blackwell: treating physician, consent of patient, manuscript contributor/author of introduction.
Fig. 1 Clinical presentation showing an ill-defined erythematous to violaceous plaque of the left lower face and chin.
Fig. 2 Clinical presentation showing an ill-defined erythematous to violaceous plaque of the left lower face and chin.
Fig. 3 Low power.
Fig. 4 Granulomatous and lymphoid aggregates. | Topical | DrugAdministrationRoute | CC BY-NC | 33613226 | 19,720,171 | 2021 |
What was the dosage of drug 'TACROLIMUS'? | Intralymphatic Histiocytosis: An Unusual Presentation.
Intralymphatic histiocytosis (ILH) is a rare cutaneous condition initially described in 1994 by O'Grady et al. It often appears as a red to violaceous, livedoid patch or plaque usually on the extremities. We present a 71-year-old female with a history of psoriasis, 50 pack years smoking and recent Legionnaires disease who came to us complaining of a red to violaceous, blanching, edematous, mildly tender lesion covering the left lower lip and extending to the chin and anterior neck. After multiple biopsies, ILH was confirmed and the patient was initially started on tacrolimus 0.1% ointment b.i.d., but there was no response. Then, she was started on oral pentoxifylline and intermittent topical steroids, as well as continuing the topical tacrolimus. There was again no response, so now she is taking a TNF-ɑ inhibitor as it appears to be a granulomatous process. These ILH cases are very rare and there is limited literature that describes one treatment as a cure. Treatment of ILH is very difficult, but several different therapies have been reported with varying success. If the disease is secondary to an underlying inflammatory disease or malignancy, then treatment of the primary disorder can lead to resolution of the ILH.
Introduction
Intralymphatic histiocytosis (ILH) is a rare cutaneous condition initially described in 1994 by O'Grady et al. [1]. It often appears as a red to violaceous, livedoid patch or plaque usually on the extremities. The condition is most commonly seen in association with rheumatoid arthritis. Other associations have been identified such as orthopedic implants, chronic inflammation, and underlying malignancy [2, 3]. Interestingly, it has also been described as a histologic feature of granulomatous cheilitis and Melkersson-Rosenthal syndrome (MRS) [4]. We present the case of a 71-year-old female with cutaneous intralymphatic histiocytosis of the lower face with uncertain etiology.
Case Presentation
A 71-year-old female initially presented to another dermatologist complaining of a bright red, warm and tender plaque on the left lower lip. Her past medical history was significant for 50 pack years of smoking, psoriasis, and a hospitalization 1 year prior from Legionnaire's disease. She was initially treated for a presumed infection without improvement. She was also referred to ENT, who recommended CT of the face and sinuses, which was negative for any significant findings.
Six months after initial presentation to a dermatologist, the patient presented to our clinic with a 7-month history of a red to violaceous, blanching, edematous, mildly tender lesion covering the left lower lip and now extending to the chin and anterior neck (Fig. 1, 2). Intraoral exam was negative for any changes. On this visit, there was concern for possible malignancy, and a 3-mm punch biopsy of involved skin on the left lower cutaneous lip was performed. This was interpreted as having “features most consistent with glomeruloid hemangioma.” In light of this pathology report, a workup for POEMS syndrome was initiated, although clinically the lesion did not appear to be consistent with this diagnosis.
Three weeks later, a repeat biopsy was performed and sent to a different laboratory for evaluation. The initial 3-mm punch biopsy was also sent for a second opinion. These two biopsies were found to be most consistent with intravascular/intralymphatic histiocytosis with features of granulomatous vasculitis (Fig. 3, 4). The patient was also sent for a second opinion, and a third and confirmatory biopsy of the left chin again showed intralymphatic histiocytosis. Initial bloodwork showed hemoglobin of 16.6 and hematocrit of 49.7, CEA of 6.4 (ref: 0–4.7), with ANA and ANCA negative. Age-appropriate cancer screening was also recommended and is still pending at this time. The patient had an MRI done which showed asymmetric prominence of the subcutaneous fat over the left face with no abnormal soft tissue mass or lymphadenopathy.
As the diagnosis was not immediately evident, treatment was initiated with tacrolimus 0.1% ointment b.i.d. While this treatment did not shrink the lesion, it prevented the lesion from growing in size. Once the final diagnosis was made, it was decided to start oral pentoxyfylline and intermittent topical steroids, as well as continuing the topical tacrolimus. The patient was on this treatment regimen for 1 month with no improvement. As this appears to be a granulomatous process, our current plan is to pursue treatment with a TNF-ɑ inhibitor.
Discussion/Conclusion
Intralymphatic histiocytosis (ILH) is an extremely rare disease that most often affects elderly women [5]. This disease has an inconsistent presentation ranging from a single erythematous plaque to multiple papules or nodules [6]. The lesions can also be seen as poorly demarcated and irregularly shaped patches or plaques with a livedo-reticularis like pattern [7]. There is a strong association with rheumatoid arthritis with other less common associations such as Rosai-Dorfman disease and orthopedic metal implants. Of the 34 patients in the literature with ILH, 18 patients had rheumatoid arthritis and two additional patients had a positive rheumatoid factor [7]. There is some uncertainty about the pathogenesis of intralymphatic histiocytosis. It is widely accepted that chronic inflammation leads to obstruction and dilation of lymphatic vessels. Lymphostasis leads to poor antigen clearance, constant stimulation of the immune system, and proliferation of histiocytes. This proliferation perpetuates the obstruction as it leads to further adhesion of histiocytes [8].
In a review of 16 cases of ILH, the majority of the lesions were seen on the extremities and breast region [7, 8]. The most common morphology is a pink to violaceous plaque which is then followed by papules and nodules. One lesion on the upper eyelid in this review was associated with MRS [6]. Another case report described ILH in an 8-year-old boy with MRS of the upper lip [9]. In our case, the patient presented with a warm, tender, erythematous plaque of the lower lip which then spread to the chin and neck. The morphology was consistent with previously reported cases of ILH; however, the location of the lesion, and other histologic features not usually seen in orofacial granulomatosis, made it difficult to establish that specific diagnosis.
One review of 16 case reports of ILH identified some common characteristics of the disease. It was found that the epidermis and papillary dermis were unchanged, but the reticular dermis showed dilated vascular and lymphatic structures. Within these dilated vessels, some retained an empty lumen, while some contained histiocytes both singly and in aggregates [7]. The histiocytes within the lumen of the lymphatic system positively stain for CD31,34 and the vessel itself stains positive for D2–40 [8].
Treatment of ILH is very difficult, but several different therapies have been reported with varying success. If the disease is secondary to an underlying inflammatory disease or malignancy, then treatment of the primary disorder can lead to resolution of the ILH. One example is the treatment of rheumatoid arthritis with infliximab, which lead to resolution of ILH. Another example is the treatment of lung adenocarcinoma with pembrolizumab leading to improvement of ILH [10]. One case that was associated with tonsillitis showed response to antibiotic therapy and tonsillectomy [11]. Other reported treatment options include: electron beam therapy, cyclophosphamide, topical and systemic steroids, amoxicillin and acetylsalicylic acid, pentoxifylline, NSAIDs, excision, pressure bandages, topical tacrolimus, and methotrexate [11].
In summary, this is a very unique case that for now has been diagnosed based on its predominant pathologic feature: intralymphatic histiocytosis. This may represent a case of MRS with unusual pathologic features. However, two separate pathology labs confirmed the diagnosis of intralymphatic histiocytosis. Further discussion and research is needed to more fully understand the pathogenesis and treatment of this uncommon disease.
Statement of Ethics
The authors received written informed consent from this patient to publish this case (including images). The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Information revealing the subject's identity has been avoided and all patients were identified by aliases and not by their real names.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No funding sources were used for this project.
Author Contributions
Timothy J. Blackwell: manuscript contributor, author of discussion and case presentation. Zac Ingersoll: manuscript contributor, author of introduction and case presentation. Martin Blackwell: treating physician, consent of patient, manuscript contributor/author of introduction.
Fig. 1 Clinical presentation showing an ill-defined erythematous to violaceous plaque of the left lower face and chin.
Fig. 2 Clinical presentation showing an ill-defined erythematous to violaceous plaque of the left lower face and chin.
Fig. 3 Low power.
Fig. 4 Granulomatous and lymphoid aggregates. | UNK UNK, BID | DrugDosageText | CC BY-NC | 33613226 | 19,720,171 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bladder tamponade'. | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | ASPARAGINASE, BUSULFAN, CYCLOPHOSPHAMIDE, DAUNORUBICIN, FLUDARABINE PHOSPHATE, MYCOPHENOLIC ACID, TACROLIMUS, VINCRISTINE | DrugsGivenReaction | CC BY-NC | 33613235 | 19,452,922 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematotoxicity'. | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | ASPARAGINASE, BUSULFAN, CYCLOPHOSPHAMIDE, DAUNORUBICIN, FLUDARABINE PHOSPHATE, MYCOPHENOLIC ACID, TACROLIMUS, VINCRISTINE | DrugsGivenReaction | CC BY-NC | 33613235 | 19,452,922 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematuria'. | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | ASPARAGINASE, BUSULFAN, CYCLOPHOSPHAMIDE, DAUNORUBICIN, FLUDARABINE PHOSPHATE, MYCOPHENOLIC ACID, TACROLIMUS, VINCRISTINE | DrugsGivenReaction | CC BY-NC | 33613235 | 19,452,922 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Platelet count decreased'. | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | ASPARAGINASE, BUSULFAN, CYCLOPHOSPHAMIDE, DAUNORUBICIN, FLUDARABINE PHOSPHATE, MYCOPHENOLIC ACID, TACROLIMUS, VINCRISTINE | DrugsGivenReaction | CC BY-NC | 33613235 | 19,452,922 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Viral haemorrhagic cystitis'. | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | ASPARAGINASE, BUSULFAN, CYCLOPHOSPHAMIDE, DAUNORUBICIN, FLUDARABINE PHOSPHATE, MYCOPHENOLIC ACID, TACROLIMUS, VINCRISTINE | DrugsGivenReaction | CC BY-NC | 33613235 | 19,452,922 | 2021 |
What was the dosage of drug 'CYCLOPHOSPHAMIDE'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | POSTTRANSPLANT CYCLOPHOSPHAMIDE | DrugDosageText | CC BY-NC | 33613235 | 19,452,922 | 2021 |
What was the dosage of drug 'MYCOPHENOLIC ACID'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | USED FOR HALF A YEAR BEFORE TRANSPLANTATION | DrugDosageText | CC BY-NC | 33613235 | 19,452,922 | 2021 |
What was the dosage of drug 'TACROLIMUS'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | USED FOR HALF A YEAR BEFORE TRANSPLANTATION | DrugDosageText | CC BY-NC | 33613235 | 19,452,922 | 2021 |
What was the outcome of reaction 'BK virus infection'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | Recovered | ReactionOutcome | CC BY-NC | 33613235 | 19,468,926 | 2021 |
What was the outcome of reaction 'Bladder tamponade'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | Recovered | ReactionOutcome | CC BY-NC | 33613235 | 19,452,922 | 2021 |
What was the outcome of reaction 'Haematotoxicity'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | Recovered | ReactionOutcome | CC BY-NC | 33613235 | 19,452,922 | 2021 |
What was the outcome of reaction 'Haematuria'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | Recovered | ReactionOutcome | CC BY-NC | 33613235 | 19,452,922 | 2021 |
What was the outcome of reaction 'Infection reactivation'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | Recovered | ReactionOutcome | CC BY-NC | 33613235 | 19,468,926 | 2021 |
What was the outcome of reaction 'Myelosuppression'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | Recovered | ReactionOutcome | CC BY-NC | 33613235 | 19,452,922 | 2021 |
What was the outcome of reaction 'Platelet count decreased'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | Recovered | ReactionOutcome | CC BY-NC | 33613235 | 19,452,922 | 2021 |
What was the outcome of reaction 'Transitional cell carcinoma'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | Recovered | ReactionOutcome | CC BY-NC | 33613235 | 19,468,926 | 2021 |
What was the outcome of reaction 'Viral haemorrhagic cystitis'? | BK Virus-Associated Urothelial Carcinoma in a Patient with Peripheral Blood Stem Cell Transplantation for Acute Lymphoblastic Leukemia: A Case Report.
Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.
Introduction
BK virus was initially isolated from a renal transplant patient in 1971 and is part of the polyomavirus family [1]. Several reports have suggested that BK virus may play a significant role in the pathogenesis of bladder cancer [2]. Furthermore, significant associations between urine cytological evidence of polyomavirus infection and bladder cancer have been demonstrated in immunocompetent patients [3]. On the other hand, BK viruria and hemorrhagic cystitis are reportedly more frequent in allogeneic hematopoietic stem cell transplant patients receiving full conditioning and unrelated-donor HLA-mismatched grafts [4]. Details of the pathogenesis, prognosis, and treatment of BK virus-associated urothelial carcinoma (BKVUC) are not well understood.
Case Report
A 54-year-old man presented to the Department of Hematology of our hospital with a diagnosis of acute lymphoblastic leukemia. Other than leukemia, his medical history was only surgery for cholesteatoma. He denied any history of tobacco use. He achieved remission after receiving chemotherapy (vincristine + daunorubicin + cyclophosphamide + L-asparaginase), but recurrence was identified 25 months later. He received HLA haploidentical stem cell transplantation with fludarabine and busulfan for conditioning, and tacrolimus, posttransplant cyclophosphamide, mycophenolate mofetil for graft versus host disease prophylaxis, and complete remission had been confirmed. However, 1 month after peripheral blood stem cell transplantation, he developed macrohematuria and his urinary viral examination was positive for BK virus. One month later, bladder tamponade developed multiple times and hemorrhagic cystitis due to BK virus was diagnosed in our Urological Department. Blood test showed severe bone marrow suppression attributed to the effects of chemotherapy. Despite daily transfusions, platelet counts remained at 30,000–40,000/µL. Cystoscopy revealed a massive blood clot and bleeding from the right wall. We performed transurethral electrocoagulation under a diagnosis of hemorrhagic cystitis. A small nodule was found on the right wall during surgery, and so it was resected. Histological examination of hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion with hemorrhagic cystitis (Fig. 1). Immunohistochemical staining of the urinary bladder performed for distinction between reactive proliferative changes and malignant epithelia revealed positive results for p53, p16, SV40, and CK7 and negative results for CK20. Finally, we concluded with the pathological diagnosis of pT1 stage BKVUC. Preoperative urinary cytology was negative for polyomavirus-infected cells. Contrast-enhanced computed tomography revealed no metastasis of bladder cancer.
One month later, we performed second transurethral electrocoagulation to control bleeding by electrocoagulation and adequately removed the lesion soon after relapse of bladder tamponade. Pathological findings again revealed pT1 stage BKVUC. Our patient has been recurrence free from BKVUC for 24 months after transurethral controlling of hemorrhage cystitis and single bladder instillation therapy with anticancer agents.
Discussion and Conclusion
BK virus reactivation can occur under an immunosuppressed status, notably in patients after kidney transplantation or blood stem cell transplantation. According to several studies, primary BK virus infection occurs in 90% of the population by 10 years old, but almost all people remain asymptomatic [5]. In our case, BK virus reactivation could have occurred immediately after transplantation, as hemorrhagic cystitis was found soon after peripheral blood stem cell transplantation. Cyclophosphamide had been administered for 3 years as an anticancer agent for leukemia and had probably contributed to reactivation of BK virus. BK virus is actually well known to be likely to provoke hemorrhagic cystitis in such immunocompromised individuals [6]. The possibility of a relationship between BK virus reactivation in immunosuppressed patients and oncogenesis in the urinary bladder was reported in 2013 [7]. In that report, BK virus showed potential for malignant transformation of activated cells, cell cycle shifts to proliferation and inhibition of apoptosis. BK virus could play significant roles in the pathogenesis of bladder cancer [8] and has been linked to urothelial carcinoma [9, 10].
BKVUC is likely to be found in an advanced stage and to show poor prognosis. It is supposed to coexist with BK virus-positive hemorrhagic cystitis. BKVUC in immune-suppressed patients with hemorrhagic cystitis is important to understand. We need to consider BKVUC hidden under hemorrhagic cystitis and achieve early diagnosis with histological examination to achieve good outcomes for patients.
Diagnosis of BKVUC requires confirming the expression of SV40 T antigen. Expression of SV40 has been recognized as an important mediator to disable tumor suppressor genes (e.g., p53) [11]. SV40 is a protein coded by simian virus 40, which converts infected cells to malignant formation by denaturing proteins crucial for tumor suppression, such as p53 and pRB. Then, large T antigen binds to p53 after accumulation by stabilizing in BKVUC. Furthermore, p16 was reported to be strongly expressed and diffusely positive in invasive BKVUC [7]. Therefore, expression of p53, p16, and SV40 on histological examination were essential to diagnose BKVUC.
Excessive immunosuppression with calcineurin inhibitors, mycophenolate derivatives, high-dose steroids plus monoclonal antibodies could reportedly increase the chance of BK virus reactivation [12]. In our case, calcineurin inhibitors and mycophenolate derivatives were used for half a year before transplantation, and BK virus reactivation was thought to have occurred about 1 month after transplantation. When hemorrhagic cystitis develops in immunosuppressed patients, we need to consider BK virus reactivation causing UC as soon as possible for early diagnosis.
BKVUC of the bladder in kidney transplant recipients with persistent BK viruria has already been reported [9, 10]. However, BKVUC in peripheral blood stem cell transplantation recipients is not well known. Innate immunity usually recovers during the several months after peripheral blood stem cell transplantation, and the reconstitution of adaptive immunity occurs over the first 1–2 years [13]. BKVUC might be rare in patients with peripheral blood stem cell transplants because of the short duration of their immunocompromised condition. In contrast, our case has received chemotherapy with lymphocytic toxicity for a few years before peripheral blood stem cell transplantation. Therefore, he could be more likely to contract BKVUC of the bladder than others who underwent peripheral blood stem cell transplantation. Our report could be the first report of BKVUC of the bladder found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is often found as an advanced cancer with muscle invasive tumor that needs to undergo total cystectomy. To date, a small number of reports have described a micropapillary variant with BKVUC. Hill et al. [14] reported that strong p53 positivity in micropapillary tumors suggested a molecular pathway of oncogenesis in a setting of BK virus infection. BK viruria may be a risk factor for this aggressive form of bladder cancer [9, 10]. However, the relationship between BK virus and development of the micropapillary variant was not elucidated in those reports.
Our case underwent transurethral resection of bladder tumor (TURBT) and immediate intravesical instillation of mitomycin C (MMC). Because his pathological stage was T1, further intravesical instillation therapy with bacille Calmette-Guérin (BCG) could be an option. Intravesical BCG is familiar to urologists as safe and effective for administration even in immunologically compromised patients with bladder cancer [15]. However, he did not undergo intravesical BCG therapy because he needed further therapy for leukemia and did not show any evidence of recurrence of urothelial carcinoma for 24 months of close urological follow-up with cystoscopy and urine cytology. Since the immunosuppressive state continues in our case, he has still been at risk of bladder cancer relapse due to BK virus reactivation. We need to continue close follow-up with cystoscopy, urine cytology, and TURBT, as needed.
In conclusion, this could be the first report of BKVUC found in a patient with peripheral blood stem cell transplantation. BKVUC of the bladder is supposed to coexist with BK virus-positive hemorrhagic cystitis and is likely to be an advanced cancer with poor prognosis. We need to identify patients with hemorrhagic cystitis at risk of BKVUC treated with immunosuppressive therapy. Our report highlights that adequate removal of bleeding lesions from the bladder mucosa during hemorrhagic cystitis could contribute to good outcomes of BKVUC of the balder.
Statement of Ethics
The patient has given his written informed consent to the publication of his case including images.
Conflict of Interest Statement
The authors declare no conflict of interest in association with this article.
Funding Sources
There were no funding sources.
Author Contributions
All individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version.
Fig. 1 a, b Hematoxylin-eosin-stained tissue sections demonstrated high-grade urothelial carcinoma with submucosal invasion (pT1) in a low-magnification picture (a) and a high-magnification picture (b). c, d, e Immunohistochemical staining of the urinary bladder tumor reveals positive results for p53 (c) and p16 (d) and weak positive results for SV40 (e). | Recovered | ReactionOutcome | CC BY-NC | 33613235 | 19,452,922 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebellar atrophy'. | Anti-N-Methyl-D-Aspartate Receptor Encephalitis with Decrease in Blood Flow in Cerebellum.
In anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, progressive cerebellar atrophy potentially leads to severe sequelae. We encountered a patient with anti-NMDAR antibody encephalitis who showed a decrease of blood flow in the cerebellum. A 15-year-old girl presented with consciousness disturbance. Influenza encephalopathy was suspected, and she was treated with glucocorticoid pulse therapy, high-dose intravenous immunoglobulins, and plasma exchange sequentially. She subsequently underwent left oophorectomy due to the presence of anti-NMDAR antibodies and a left ovarian teratoma. In spite of the surgery, her neuropsychiatric symptoms persisted, and she recovered slowly after the introduction of oral methotrexate (MTX). Sequential cerebral blood flow monitoring with single-photon emission computed tomography showed marked cerebellar hypoperfusion. Although mild impairments including working memory and verbal fluency persisted, she eventually returned to high school 3 years after onset. Profound cerebellar hypoperfusion including lobules VI and VII may be the reason for her working memory impairment and speaking problems. Oral MTX may be a promising alternative treatment for some refractory cases of anti-NMDAR encephalitis.
Introduction
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common antineuronal antibody encephalitis among the autoimmune types of encephalitis found at present. Progressive cerebellar atrophy potentially develops in patients with severe disabilities due to anti-NMDAR encephalitis [1, 2]. Here, we report a patient with anti-NMDAR antibody encephalitis who showed a persistent decrease of blood flow in the cerebellum with slight cerebellar atrophy. The patient did not respond to first- and second-line treatments, but slowly recovered after oral administration of oral methotrexate (MTX), resulting in a good outcome. The patient presented with mild working memory impairment and speaking problems as sequelae. We were able to detect the cerebellar involvement associated with these sequelae by sequential cerebral blood flow single-photon emission computed tomography (SPECT).
Case Report/Case Presentation
We described the clinical course of this case in Figure 1. A 15-year-old girl who was previously healthy had a headache with a high fever. She presented with consciousness disturbance 3 days later and was admitted, at which time she was found to be positive for influenza A virus infection based on nasal smear. Magnetic resonance imaging (MRI) did not reveal any abnormalities in the brain. Cerebrospinal fluid (CSF) study disclosed lymphocytic pleocytosis with 166 leukocytes/mm3 including 72% lymphocytes and increased total protein 1.1 g/L (normal <0.5 g/L). Influenza encephalopathy was suspected, and she was started on glucocorticoid pulse therapy, high-dose intravenous immunoglobulins (IVIG), and plasma exchange (PE) sequentially. Because of development of status epilepticus, she was mechanically ventilated with tracheostomy. Since the presence of anti-NMDAR antibodies in CSF and a left ovarian teratoma on MRI were subsequently found, she underwent left oophorectomy 90 days after onset. Additionally, she received cyclophosphamide pulse therapy. Although her status epilepticus subsided, she remained unconscious. She was transferred to our hospital 7 months after onset. On neurological examination, she opened her eyes occasionally, but she was unresponsive to external stimuli. All brainstem reflexes were preserved. She showed involuntary movements such as risus caninus and rotation of the right foot. Muscle tone in all four limbs was decreased. Babinski signs were negative on both feet. She showed marked salivation and sweating. Brain MRI showed atrophy of the hippocampus and dilation of the lateral and third ventricles (Fig. 2a), and slight cerebellar atrophy (Fig. 2b). SPECT using N-isopropyl-p-[123I] iodoamphetamine showed a blood flow decrease in the bilateral frontal lobes with slight hypoperfusion in the right anteromedial portion of the cerebellum (Fig. 3a). She was weaned off the ventilator 11 months after onset. However, her involuntary movements extended to the whole body and became ballistic. She remained mute without eye contact. In the follow-up CSF tests using a commercially available cell-based assay kit (EUROIMMUN, Lubeck, Germany), anti-NMDAR antibodies remained positive. She was started on MTX 6 mg per week via gastrectomy, following oral administration. She began to stare at people and watch television 15 months after onset but was often agitated and resisted medical care. Seventeen months after onset, she became able to communicate in writing and whispering, which was an echolalia at first and later conversation with short sentences. Additionally, she was able to walk without any assistance. She completed the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) 19 months after onset, showing full scale IQ 56 without a significant difference between each index scale. She was discharged and followed up in our hospital outpatient clinic. Twenty-four months after onset, she had difficulty memorizing what she heard, but she began to study elementary school subjects, and later she could study more advanced material. Her speech gradually became more natural, but stuttering and cluttering ultimately remained. On SPECT, hypoperfusion in the frontal lobe disappeared, while hypoperfusion of the cerebellum was more marked and extended bilaterally with right posterior side predominance (Fig. 3b). However, at that time, she did not show any motor complications based on cerebellar involvement. The CSF test was still positive for anti-NMDAR antibodies with a titer of 1: 20. However, MTX was stopped. On neuropsychological testing 34 months after onset, the Mini-Mental State Examination score and the Frontal Assessment Battery were 30/30 points and 17/18 points, respectively. On WAIS-IV, she showed improvement in full-scale IQ and all index scales, but the working memory index was still low. Thirty-six months after onset, anti-NMDAR antibodies in CSF remained positive with the titer decreasing to 1: 1, and SPECT still showed hypoperfusion of the cerebellum (Fig. 3c). On brain MRI, slight cerebellar atrophy was unchanged, while reversal of cerebral atrophy was found (Fig. 2c). She ultimately returned to high school.
Discussion/Conclusion
We found two important clinical implications, i.e. the patient showed a persistent decrease in blood flow in the cerebellum and her symptoms improved after oral administration of MTX.
It is reported that cerebellar atrophy on MRI is irreversible and associated with a poor outcome in anti-NMDAR encephalitis [1, 2]. Certainly, although slight cerebellar atrophy on MRI found during her course was irreversible, she did not present with any motor disabilities based on cerebellar involvement and subsequently had a good outcome. However, she presented with mild sequelae including working memory impairment and speaking problems such as stuttering and cluttering. Recently, increasing evidence has demonstrated that the cerebellum contributes to non-motor functions such as emotion, language, and working memory [3, 4, 5, 6, 7, 8]. The regions within the cerebellum responsible for these non-motor functions are identified by functional MRI and positron emission tomography studies.
Working memory uses attention to manipulate information that is immediately available to execute cognitive tasks, and activates bilateral cerebellar regions including lobules VI and VII (crus I) [3, 4, 5, 6, 7]. The damage to these areas causes working memory impairments including arithmetic, digit span, verbal comprehension, and story recall, which are strongly related to learning ability [3, 4, 5, 6, 7].
Non-motor and higher-level language function within the cerebellum is associated with word generation and verbal fluency. Language tasks activate predominantly right-hemisphere regions in lobules VI and VII [3, 4]. The damage to these lobules causes decreased word production and verbal disfluency [7, 8].
In our patient, SPECT performed 24 and 36 months after onset showed bilateral cerebellar hypoperfusion with a right-side predominance including lobules VI and VII. Taken together, we considered that the findings on SPECT reflect her working memory impairment and speaking problems.
The second clinical implication in this case is that her symptoms improved after oral administration of MTX. At the acute stage, she was treated with first-line (glucocorticoid, IVIG, and PE) and second-line treatments (cyclophosphamide) for anti-NMDAR encephalitis [9, 10, 11]. However, because she did not respond to these treatments and anti-NMDAR antibodies in CSF remained positive, we started oral administration of MTX. Although the effectiveness of MTX for anti-NMDAR encephalitis has been reported with intrathecal administration [12], we chose oral administration because of the difficulty of intrathecal administration due to her psychomotor agitation. Despite persistent anti-NMDAR antibodies in CSF, sufficient neurological improvement was achieved, so administration of MTX was discontinued 2 years after onset [11]. After that, she continued to recover slowly. Oral MTX should be considered as an additional option for anti-NMDAR encephalitis because of its ease of administration and safety.
In conclusion, our patient showed a decrease in blood flow in the cerebellum during long-term observation. We consider SPECT and neuropsychological tests to be important to detect mild cognitive sequelae in patients recovering from anti-NMDAR encephalitis. Her symptoms improved after oral administration of MTX. We suggest that oral MTX may be a promising alternative treatment for cases with anti-NMDAR encephalitis that do not respond to first-line and second-line treatments. Further data should be gathered regarding the effectiveness of oral administration of MTX for anti-NMDAR encephalitis.
Statement of Ethics
The parents of the patient provided both oral and written informed consent for the publishing of this report (including publication of images).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors did not receive any external funding.
Author Contributions
Koji Obara was the patient's primary neurologist and drafted the manuscript. Tomoko Ono performed the neuropsychological testing of the patient. Itaru Toyoshima revised the manuscript and edited the paper.
Fig. 1 The clinical course of this case. CPA, cyclophosphamide; CSF, cerebrospinal fluid; FSIQ, full-scale IQ; IVIG, intravenous immunoglobulin; M, month; MTX, methotrexate; NMDAR, N-methyl-D-aspartate receptor; PE, plasmapheresis; PRI, perceptual reasoning index; PSI, processing speed index; VCI, verbal comprehension index; WAIS-IV, Wechsler Adult Intelligence Scale-Fourth Edition; WMI, working memory index.
Fig. 2 Brain magnetic resonance imaging findings. a, b T2-weighted images taken at 7 months after onset. a Coronal image shows atrophy of the hippocampus (yellow arrow) and dilation of the lateral and third ventricles (red arrowheads). b Mid-sagittal image shows slight cerebellar atrophy (blue arrowhead). c, d T2-weighted images taken at 36 months after onset. c Coronal image shows reversal of the atrophy of the hippocampus (yellow arrow) and the dilation of the lateral and third ventricles (red arrowheads). d On mid-sagittal image, the cerebellar atrophy remains but has not progressed (blue arrowhead).
Fig. 3 Sequential findings of cerebral blood flow single-photon emission computed tomography using N-isopropyl-p-[123I] iodoamphetamine. Z-score images using normalized counts of the global brain. The Z-score is higher as the degree of decrease of cerebral blood flow is larger than that of an age-matched normal database. a The image at 7 months after onset shows a decrease in blood flow in the bilateral frontal lobes with slight hypoperfusion in the right anteromedial portion of the cerebellum. b The image at 24 months after onset shows marked cerebellar hypoperfusion extending bilaterally with right posterior-side predominance, whereas the hypoperfusion of the frontal lobes disappears. The axial images show hypoperfusion in the whole cerebellum including the cortex, white matter, and deep nucleus. c On the image at 36 months after onset, the cerebellar hypoperfusion remains. INF, inferior; L, left; LAT, lateral; R, right. | METHOTREXATE | DrugsGivenReaction | CC BY-NC | 33613239 | 19,793,498 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Anti-N-Methyl-D-Aspartate Receptor Encephalitis with Decrease in Blood Flow in Cerebellum.
In anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, progressive cerebellar atrophy potentially leads to severe sequelae. We encountered a patient with anti-NMDAR antibody encephalitis who showed a decrease of blood flow in the cerebellum. A 15-year-old girl presented with consciousness disturbance. Influenza encephalopathy was suspected, and she was treated with glucocorticoid pulse therapy, high-dose intravenous immunoglobulins, and plasma exchange sequentially. She subsequently underwent left oophorectomy due to the presence of anti-NMDAR antibodies and a left ovarian teratoma. In spite of the surgery, her neuropsychiatric symptoms persisted, and she recovered slowly after the introduction of oral methotrexate (MTX). Sequential cerebral blood flow monitoring with single-photon emission computed tomography showed marked cerebellar hypoperfusion. Although mild impairments including working memory and verbal fluency persisted, she eventually returned to high school 3 years after onset. Profound cerebellar hypoperfusion including lobules VI and VII may be the reason for her working memory impairment and speaking problems. Oral MTX may be a promising alternative treatment for some refractory cases of anti-NMDAR encephalitis.
Introduction
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common antineuronal antibody encephalitis among the autoimmune types of encephalitis found at present. Progressive cerebellar atrophy potentially develops in patients with severe disabilities due to anti-NMDAR encephalitis [1, 2]. Here, we report a patient with anti-NMDAR antibody encephalitis who showed a persistent decrease of blood flow in the cerebellum with slight cerebellar atrophy. The patient did not respond to first- and second-line treatments, but slowly recovered after oral administration of oral methotrexate (MTX), resulting in a good outcome. The patient presented with mild working memory impairment and speaking problems as sequelae. We were able to detect the cerebellar involvement associated with these sequelae by sequential cerebral blood flow single-photon emission computed tomography (SPECT).
Case Report/Case Presentation
We described the clinical course of this case in Figure 1. A 15-year-old girl who was previously healthy had a headache with a high fever. She presented with consciousness disturbance 3 days later and was admitted, at which time she was found to be positive for influenza A virus infection based on nasal smear. Magnetic resonance imaging (MRI) did not reveal any abnormalities in the brain. Cerebrospinal fluid (CSF) study disclosed lymphocytic pleocytosis with 166 leukocytes/mm3 including 72% lymphocytes and increased total protein 1.1 g/L (normal <0.5 g/L). Influenza encephalopathy was suspected, and she was started on glucocorticoid pulse therapy, high-dose intravenous immunoglobulins (IVIG), and plasma exchange (PE) sequentially. Because of development of status epilepticus, she was mechanically ventilated with tracheostomy. Since the presence of anti-NMDAR antibodies in CSF and a left ovarian teratoma on MRI were subsequently found, she underwent left oophorectomy 90 days after onset. Additionally, she received cyclophosphamide pulse therapy. Although her status epilepticus subsided, she remained unconscious. She was transferred to our hospital 7 months after onset. On neurological examination, she opened her eyes occasionally, but she was unresponsive to external stimuli. All brainstem reflexes were preserved. She showed involuntary movements such as risus caninus and rotation of the right foot. Muscle tone in all four limbs was decreased. Babinski signs were negative on both feet. She showed marked salivation and sweating. Brain MRI showed atrophy of the hippocampus and dilation of the lateral and third ventricles (Fig. 2a), and slight cerebellar atrophy (Fig. 2b). SPECT using N-isopropyl-p-[123I] iodoamphetamine showed a blood flow decrease in the bilateral frontal lobes with slight hypoperfusion in the right anteromedial portion of the cerebellum (Fig. 3a). She was weaned off the ventilator 11 months after onset. However, her involuntary movements extended to the whole body and became ballistic. She remained mute without eye contact. In the follow-up CSF tests using a commercially available cell-based assay kit (EUROIMMUN, Lubeck, Germany), anti-NMDAR antibodies remained positive. She was started on MTX 6 mg per week via gastrectomy, following oral administration. She began to stare at people and watch television 15 months after onset but was often agitated and resisted medical care. Seventeen months after onset, she became able to communicate in writing and whispering, which was an echolalia at first and later conversation with short sentences. Additionally, she was able to walk without any assistance. She completed the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) 19 months after onset, showing full scale IQ 56 without a significant difference between each index scale. She was discharged and followed up in our hospital outpatient clinic. Twenty-four months after onset, she had difficulty memorizing what she heard, but she began to study elementary school subjects, and later she could study more advanced material. Her speech gradually became more natural, but stuttering and cluttering ultimately remained. On SPECT, hypoperfusion in the frontal lobe disappeared, while hypoperfusion of the cerebellum was more marked and extended bilaterally with right posterior side predominance (Fig. 3b). However, at that time, she did not show any motor complications based on cerebellar involvement. The CSF test was still positive for anti-NMDAR antibodies with a titer of 1: 20. However, MTX was stopped. On neuropsychological testing 34 months after onset, the Mini-Mental State Examination score and the Frontal Assessment Battery were 30/30 points and 17/18 points, respectively. On WAIS-IV, she showed improvement in full-scale IQ and all index scales, but the working memory index was still low. Thirty-six months after onset, anti-NMDAR antibodies in CSF remained positive with the titer decreasing to 1: 1, and SPECT still showed hypoperfusion of the cerebellum (Fig. 3c). On brain MRI, slight cerebellar atrophy was unchanged, while reversal of cerebral atrophy was found (Fig. 2c). She ultimately returned to high school.
Discussion/Conclusion
We found two important clinical implications, i.e. the patient showed a persistent decrease in blood flow in the cerebellum and her symptoms improved after oral administration of MTX.
It is reported that cerebellar atrophy on MRI is irreversible and associated with a poor outcome in anti-NMDAR encephalitis [1, 2]. Certainly, although slight cerebellar atrophy on MRI found during her course was irreversible, she did not present with any motor disabilities based on cerebellar involvement and subsequently had a good outcome. However, she presented with mild sequelae including working memory impairment and speaking problems such as stuttering and cluttering. Recently, increasing evidence has demonstrated that the cerebellum contributes to non-motor functions such as emotion, language, and working memory [3, 4, 5, 6, 7, 8]. The regions within the cerebellum responsible for these non-motor functions are identified by functional MRI and positron emission tomography studies.
Working memory uses attention to manipulate information that is immediately available to execute cognitive tasks, and activates bilateral cerebellar regions including lobules VI and VII (crus I) [3, 4, 5, 6, 7]. The damage to these areas causes working memory impairments including arithmetic, digit span, verbal comprehension, and story recall, which are strongly related to learning ability [3, 4, 5, 6, 7].
Non-motor and higher-level language function within the cerebellum is associated with word generation and verbal fluency. Language tasks activate predominantly right-hemisphere regions in lobules VI and VII [3, 4]. The damage to these lobules causes decreased word production and verbal disfluency [7, 8].
In our patient, SPECT performed 24 and 36 months after onset showed bilateral cerebellar hypoperfusion with a right-side predominance including lobules VI and VII. Taken together, we considered that the findings on SPECT reflect her working memory impairment and speaking problems.
The second clinical implication in this case is that her symptoms improved after oral administration of MTX. At the acute stage, she was treated with first-line (glucocorticoid, IVIG, and PE) and second-line treatments (cyclophosphamide) for anti-NMDAR encephalitis [9, 10, 11]. However, because she did not respond to these treatments and anti-NMDAR antibodies in CSF remained positive, we started oral administration of MTX. Although the effectiveness of MTX for anti-NMDAR encephalitis has been reported with intrathecal administration [12], we chose oral administration because of the difficulty of intrathecal administration due to her psychomotor agitation. Despite persistent anti-NMDAR antibodies in CSF, sufficient neurological improvement was achieved, so administration of MTX was discontinued 2 years after onset [11]. After that, she continued to recover slowly. Oral MTX should be considered as an additional option for anti-NMDAR encephalitis because of its ease of administration and safety.
In conclusion, our patient showed a decrease in blood flow in the cerebellum during long-term observation. We consider SPECT and neuropsychological tests to be important to detect mild cognitive sequelae in patients recovering from anti-NMDAR encephalitis. Her symptoms improved after oral administration of MTX. We suggest that oral MTX may be a promising alternative treatment for cases with anti-NMDAR encephalitis that do not respond to first-line and second-line treatments. Further data should be gathered regarding the effectiveness of oral administration of MTX for anti-NMDAR encephalitis.
Statement of Ethics
The parents of the patient provided both oral and written informed consent for the publishing of this report (including publication of images).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors did not receive any external funding.
Author Contributions
Koji Obara was the patient's primary neurologist and drafted the manuscript. Tomoko Ono performed the neuropsychological testing of the patient. Itaru Toyoshima revised the manuscript and edited the paper.
Fig. 1 The clinical course of this case. CPA, cyclophosphamide; CSF, cerebrospinal fluid; FSIQ, full-scale IQ; IVIG, intravenous immunoglobulin; M, month; MTX, methotrexate; NMDAR, N-methyl-D-aspartate receptor; PE, plasmapheresis; PRI, perceptual reasoning index; PSI, processing speed index; VCI, verbal comprehension index; WAIS-IV, Wechsler Adult Intelligence Scale-Fourth Edition; WMI, working memory index.
Fig. 2 Brain magnetic resonance imaging findings. a, b T2-weighted images taken at 7 months after onset. a Coronal image shows atrophy of the hippocampus (yellow arrow) and dilation of the lateral and third ventricles (red arrowheads). b Mid-sagittal image shows slight cerebellar atrophy (blue arrowhead). c, d T2-weighted images taken at 36 months after onset. c Coronal image shows reversal of the atrophy of the hippocampus (yellow arrow) and the dilation of the lateral and third ventricles (red arrowheads). d On mid-sagittal image, the cerebellar atrophy remains but has not progressed (blue arrowhead).
Fig. 3 Sequential findings of cerebral blood flow single-photon emission computed tomography using N-isopropyl-p-[123I] iodoamphetamine. Z-score images using normalized counts of the global brain. The Z-score is higher as the degree of decrease of cerebral blood flow is larger than that of an age-matched normal database. a The image at 7 months after onset shows a decrease in blood flow in the bilateral frontal lobes with slight hypoperfusion in the right anteromedial portion of the cerebellum. b The image at 24 months after onset shows marked cerebellar hypoperfusion extending bilaterally with right posterior-side predominance, whereas the hypoperfusion of the frontal lobes disappears. The axial images show hypoperfusion in the whole cerebellum including the cortex, white matter, and deep nucleus. c On the image at 36 months after onset, the cerebellar hypoperfusion remains. INF, inferior; L, left; LAT, lateral; R, right. | METHOTREXATE | DrugsGivenReaction | CC BY-NC | 33613239 | 19,793,498 | 2021 |
What was the administration route of drug 'METHOTREXATE'? | Anti-N-Methyl-D-Aspartate Receptor Encephalitis with Decrease in Blood Flow in Cerebellum.
In anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, progressive cerebellar atrophy potentially leads to severe sequelae. We encountered a patient with anti-NMDAR antibody encephalitis who showed a decrease of blood flow in the cerebellum. A 15-year-old girl presented with consciousness disturbance. Influenza encephalopathy was suspected, and she was treated with glucocorticoid pulse therapy, high-dose intravenous immunoglobulins, and plasma exchange sequentially. She subsequently underwent left oophorectomy due to the presence of anti-NMDAR antibodies and a left ovarian teratoma. In spite of the surgery, her neuropsychiatric symptoms persisted, and she recovered slowly after the introduction of oral methotrexate (MTX). Sequential cerebral blood flow monitoring with single-photon emission computed tomography showed marked cerebellar hypoperfusion. Although mild impairments including working memory and verbal fluency persisted, she eventually returned to high school 3 years after onset. Profound cerebellar hypoperfusion including lobules VI and VII may be the reason for her working memory impairment and speaking problems. Oral MTX may be a promising alternative treatment for some refractory cases of anti-NMDAR encephalitis.
Introduction
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common antineuronal antibody encephalitis among the autoimmune types of encephalitis found at present. Progressive cerebellar atrophy potentially develops in patients with severe disabilities due to anti-NMDAR encephalitis [1, 2]. Here, we report a patient with anti-NMDAR antibody encephalitis who showed a persistent decrease of blood flow in the cerebellum with slight cerebellar atrophy. The patient did not respond to first- and second-line treatments, but slowly recovered after oral administration of oral methotrexate (MTX), resulting in a good outcome. The patient presented with mild working memory impairment and speaking problems as sequelae. We were able to detect the cerebellar involvement associated with these sequelae by sequential cerebral blood flow single-photon emission computed tomography (SPECT).
Case Report/Case Presentation
We described the clinical course of this case in Figure 1. A 15-year-old girl who was previously healthy had a headache with a high fever. She presented with consciousness disturbance 3 days later and was admitted, at which time she was found to be positive for influenza A virus infection based on nasal smear. Magnetic resonance imaging (MRI) did not reveal any abnormalities in the brain. Cerebrospinal fluid (CSF) study disclosed lymphocytic pleocytosis with 166 leukocytes/mm3 including 72% lymphocytes and increased total protein 1.1 g/L (normal <0.5 g/L). Influenza encephalopathy was suspected, and she was started on glucocorticoid pulse therapy, high-dose intravenous immunoglobulins (IVIG), and plasma exchange (PE) sequentially. Because of development of status epilepticus, she was mechanically ventilated with tracheostomy. Since the presence of anti-NMDAR antibodies in CSF and a left ovarian teratoma on MRI were subsequently found, she underwent left oophorectomy 90 days after onset. Additionally, she received cyclophosphamide pulse therapy. Although her status epilepticus subsided, she remained unconscious. She was transferred to our hospital 7 months after onset. On neurological examination, she opened her eyes occasionally, but she was unresponsive to external stimuli. All brainstem reflexes were preserved. She showed involuntary movements such as risus caninus and rotation of the right foot. Muscle tone in all four limbs was decreased. Babinski signs were negative on both feet. She showed marked salivation and sweating. Brain MRI showed atrophy of the hippocampus and dilation of the lateral and third ventricles (Fig. 2a), and slight cerebellar atrophy (Fig. 2b). SPECT using N-isopropyl-p-[123I] iodoamphetamine showed a blood flow decrease in the bilateral frontal lobes with slight hypoperfusion in the right anteromedial portion of the cerebellum (Fig. 3a). She was weaned off the ventilator 11 months after onset. However, her involuntary movements extended to the whole body and became ballistic. She remained mute without eye contact. In the follow-up CSF tests using a commercially available cell-based assay kit (EUROIMMUN, Lubeck, Germany), anti-NMDAR antibodies remained positive. She was started on MTX 6 mg per week via gastrectomy, following oral administration. She began to stare at people and watch television 15 months after onset but was often agitated and resisted medical care. Seventeen months after onset, she became able to communicate in writing and whispering, which was an echolalia at first and later conversation with short sentences. Additionally, she was able to walk without any assistance. She completed the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) 19 months after onset, showing full scale IQ 56 without a significant difference between each index scale. She was discharged and followed up in our hospital outpatient clinic. Twenty-four months after onset, she had difficulty memorizing what she heard, but she began to study elementary school subjects, and later she could study more advanced material. Her speech gradually became more natural, but stuttering and cluttering ultimately remained. On SPECT, hypoperfusion in the frontal lobe disappeared, while hypoperfusion of the cerebellum was more marked and extended bilaterally with right posterior side predominance (Fig. 3b). However, at that time, she did not show any motor complications based on cerebellar involvement. The CSF test was still positive for anti-NMDAR antibodies with a titer of 1: 20. However, MTX was stopped. On neuropsychological testing 34 months after onset, the Mini-Mental State Examination score and the Frontal Assessment Battery were 30/30 points and 17/18 points, respectively. On WAIS-IV, she showed improvement in full-scale IQ and all index scales, but the working memory index was still low. Thirty-six months after onset, anti-NMDAR antibodies in CSF remained positive with the titer decreasing to 1: 1, and SPECT still showed hypoperfusion of the cerebellum (Fig. 3c). On brain MRI, slight cerebellar atrophy was unchanged, while reversal of cerebral atrophy was found (Fig. 2c). She ultimately returned to high school.
Discussion/Conclusion
We found two important clinical implications, i.e. the patient showed a persistent decrease in blood flow in the cerebellum and her symptoms improved after oral administration of MTX.
It is reported that cerebellar atrophy on MRI is irreversible and associated with a poor outcome in anti-NMDAR encephalitis [1, 2]. Certainly, although slight cerebellar atrophy on MRI found during her course was irreversible, she did not present with any motor disabilities based on cerebellar involvement and subsequently had a good outcome. However, she presented with mild sequelae including working memory impairment and speaking problems such as stuttering and cluttering. Recently, increasing evidence has demonstrated that the cerebellum contributes to non-motor functions such as emotion, language, and working memory [3, 4, 5, 6, 7, 8]. The regions within the cerebellum responsible for these non-motor functions are identified by functional MRI and positron emission tomography studies.
Working memory uses attention to manipulate information that is immediately available to execute cognitive tasks, and activates bilateral cerebellar regions including lobules VI and VII (crus I) [3, 4, 5, 6, 7]. The damage to these areas causes working memory impairments including arithmetic, digit span, verbal comprehension, and story recall, which are strongly related to learning ability [3, 4, 5, 6, 7].
Non-motor and higher-level language function within the cerebellum is associated with word generation and verbal fluency. Language tasks activate predominantly right-hemisphere regions in lobules VI and VII [3, 4]. The damage to these lobules causes decreased word production and verbal disfluency [7, 8].
In our patient, SPECT performed 24 and 36 months after onset showed bilateral cerebellar hypoperfusion with a right-side predominance including lobules VI and VII. Taken together, we considered that the findings on SPECT reflect her working memory impairment and speaking problems.
The second clinical implication in this case is that her symptoms improved after oral administration of MTX. At the acute stage, she was treated with first-line (glucocorticoid, IVIG, and PE) and second-line treatments (cyclophosphamide) for anti-NMDAR encephalitis [9, 10, 11]. However, because she did not respond to these treatments and anti-NMDAR antibodies in CSF remained positive, we started oral administration of MTX. Although the effectiveness of MTX for anti-NMDAR encephalitis has been reported with intrathecal administration [12], we chose oral administration because of the difficulty of intrathecal administration due to her psychomotor agitation. Despite persistent anti-NMDAR antibodies in CSF, sufficient neurological improvement was achieved, so administration of MTX was discontinued 2 years after onset [11]. After that, she continued to recover slowly. Oral MTX should be considered as an additional option for anti-NMDAR encephalitis because of its ease of administration and safety.
In conclusion, our patient showed a decrease in blood flow in the cerebellum during long-term observation. We consider SPECT and neuropsychological tests to be important to detect mild cognitive sequelae in patients recovering from anti-NMDAR encephalitis. Her symptoms improved after oral administration of MTX. We suggest that oral MTX may be a promising alternative treatment for cases with anti-NMDAR encephalitis that do not respond to first-line and second-line treatments. Further data should be gathered regarding the effectiveness of oral administration of MTX for anti-NMDAR encephalitis.
Statement of Ethics
The parents of the patient provided both oral and written informed consent for the publishing of this report (including publication of images).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors did not receive any external funding.
Author Contributions
Koji Obara was the patient's primary neurologist and drafted the manuscript. Tomoko Ono performed the neuropsychological testing of the patient. Itaru Toyoshima revised the manuscript and edited the paper.
Fig. 1 The clinical course of this case. CPA, cyclophosphamide; CSF, cerebrospinal fluid; FSIQ, full-scale IQ; IVIG, intravenous immunoglobulin; M, month; MTX, methotrexate; NMDAR, N-methyl-D-aspartate receptor; PE, plasmapheresis; PRI, perceptual reasoning index; PSI, processing speed index; VCI, verbal comprehension index; WAIS-IV, Wechsler Adult Intelligence Scale-Fourth Edition; WMI, working memory index.
Fig. 2 Brain magnetic resonance imaging findings. a, b T2-weighted images taken at 7 months after onset. a Coronal image shows atrophy of the hippocampus (yellow arrow) and dilation of the lateral and third ventricles (red arrowheads). b Mid-sagittal image shows slight cerebellar atrophy (blue arrowhead). c, d T2-weighted images taken at 36 months after onset. c Coronal image shows reversal of the atrophy of the hippocampus (yellow arrow) and the dilation of the lateral and third ventricles (red arrowheads). d On mid-sagittal image, the cerebellar atrophy remains but has not progressed (blue arrowhead).
Fig. 3 Sequential findings of cerebral blood flow single-photon emission computed tomography using N-isopropyl-p-[123I] iodoamphetamine. Z-score images using normalized counts of the global brain. The Z-score is higher as the degree of decrease of cerebral blood flow is larger than that of an age-matched normal database. a The image at 7 months after onset shows a decrease in blood flow in the bilateral frontal lobes with slight hypoperfusion in the right anteromedial portion of the cerebellum. b The image at 24 months after onset shows marked cerebellar hypoperfusion extending bilaterally with right posterior-side predominance, whereas the hypoperfusion of the frontal lobes disappears. The axial images show hypoperfusion in the whole cerebellum including the cortex, white matter, and deep nucleus. c On the image at 36 months after onset, the cerebellar hypoperfusion remains. INF, inferior; L, left; LAT, lateral; R, right. | Oral | DrugAdministrationRoute | CC BY-NC | 33613239 | 19,793,498 | 2021 |
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