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What was the dosage of drug 'PRAVASTATIN SODIUM'? | Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency.
Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.
Introduction
The main goal of diabetes treatment is to ensure these patients have the same quality of life and longevity as healthy people by reducing the risk of micro- and macrovascular complications, such as diabetic nephropathy and cardiovascular disease (CVD). To achieve this goal, the comprehensive control of blood glucose without hypoglycemia as well as that of blood pressure, lipid, and body weight are crucial (1).
In Japan, as of June 2020, seven types of oral hypoglycemic agents (OHA) have been approved for the treatment of type 2 diabetes mellitus (T2DM). Repaglinide, as well as nateglinide and mitiglinide, belongs to the class of medications known as meglitinides, which act on sulfonylurea receptors on pancreatic β-cells to promote postprandial insulin secretion, thus mainly reducing postprandial glucose levels (2). Patients taking repaglinide are at risk of hypoglycemia, similar to that conferred by insulin and sulfonylureas. However, based on its rapid- and short-acting effects, repaglinide has a lower hypoglycemic risk than insulin or sulfonylureas (3). In addition, repaglinide is almost completely metabolized in the liver, and its metabolites are excreted primarily through the bile. Only a very small fraction (less than 8%) of the administered dose is excreted through the urine (4). Therefore, patients taking repaglinide are considered to have a low risk of hypoglycemia even when they have mild or moderate renal insufficiency (5).
Clopidogrel is a second-generation thienopyridine antiplatelet drug that is the mainstay of the treatment and secondary prevention of CVD in patients with T2DM. Recently, the concomitant use of repaglinide and clopidogrel has been shown to result in the elevation of blood concentration of repaglinide (6). In addition, few reports have shown that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). However, there are no reports on the clinical course of hypoglycemia due to the interaction of these drugs in patients with T2DM and severe renal insufficiency.
We herein report a patient with T2DM with severe renal insufficiency and describe the patient's clinical course, which included hypoglycemia owing to concomitant use of repaglinide and clopidogrel.
Case Report
Informed consent was obtained from the patient, and all procedures were approved by the appropriate institutional review board (the Ethics Committee of Osaka Police Hospital) and comply with the Declaration of Helsinki and its amendments.
We encountered an 81-year-old Japanese woman with T2DM and severe renal insufficiency who was receiving repaglinide and who developed hypoglycemia 3 days after starting clopidogrel. At 50 years old, she was diagnosed with T2DM and treated with OHAs. She subsequently had hypertension, dyslipidemia, atrial fibrillation, CVD, peripheral artery disease (PAD), and adrenal insufficiency owing to approximately five years of glucocorticoid treatment for autoimmune hepatitis, and her renal function gradually deteriorated. At 81 years old, she was admitted to our hospital for the treatment of acute coronary artery dissection. On admission, she was prescribed the following medications for T2DM, dyslipidemia, hyperuricemia, hypertension, CVD, PAD, atrial fibrillation, gastroesophageal reflux disease, and secondary adrenal insufficiency: teneligliptin 40 mg, repaglinide 1.5 mg, pravastatin 10 mg, febuxostat 20 mg, carvedilol 1.25 mg, azelnidipine 16 mg, verapamil 80 mg, cilostazol 200 mg, aspirin 100 mg, adoxaban 10 mg, propafenone 300 mg, vonoprazan 20 mg and hydrocortisone 10 mg per day, respectively.
She underwent emergent percutaneous coronary intervention for the dissection site of the left main coronary artery, and aspirin was changed to clopidogrel, while cilostazol was continued. At that time, her diabetes was treated with a 1,440-kcal diabetic diet and two OHAs (teneligliptin 20 mg×2/day, and repaglinide 0.5 mg×3/day). She did not develop hypoglycemia with these agents. However, her fasting plasma glucose level before breakfast gradually decreased, and hypoglycemia (63 mg/dL) developed 3 days after starting clopidogrel. Her cardiologist then reduced the 40 mg dose of teneligliptin to 20 mg, but her hypoglycemia (50-64 mg/dL) did not disappear. Nine days after starting clopidogrel, she was referred to our department for a detailed examination and treatment of her recurrent hypoglycemia (Figure).
Figure. Clinical course of the daily profile of blood glucose and medications. Blood glucose was measured with a glucometer. [ ] indicates the plasma glucose levels measured in the laboratory. PCI: percutaneous coronary intervention
On referral, the patient had no obvious hypoglycemic symptoms despite her pre-breakfast plasma glucose level of 50 mg/dL. Her body weight was 44.1 kg (body mass index: 16.0 kg/m2), blood pressure 101/60 mmHg, pulse rate 103 bpm, and body temperature 36.8°C. She had no abnormal physical signs. We suspected that her hypoglycemia was caused by the concomitant use of repaglinide and clopidogrel based on her clinical course and therefore discontinued repaglinide from before lunch on the referral day.
Her laboratory examination results the day after referral to our department are shown in Table 1. Her fasting plasma glucose level was 85 mg/dL, indicating no hypoglycemia, probably because repaglinide had been discontinued; her fasting C-peptide was 2.71 ng/mL, and her immunoreactive insulin level was 3.7 μU/mL. In addition, an insulin autoantibody test was negative. Her renal function was impaired, with a plasma urea nitrogen of 25.5 mg/dL, creatinine of 1.3 mg/dL, and estimated glomerular filtration ratio of 30.5 mL/min/1.73 m2. Endocrinological examinations revealed that the baseline levels of adrenocorticotropic hormone and cortisol were within the normal ranges, and the patient had a postmenopausal status.
Table 1. Laboratory Findings on Referral to Our Department.
Hematology ALP 128 U/L
WBC 8,400 /μL γ-GTP 20 U/L
RBC 284×10,000 /μL CRP 3.62 mg/dL
Hb 8.7 g/dL Glucose 85 mg/dL
Ht 25.3 % HbA1c 6.4 %
Plt 24.9×10,000 /μL IRI 3.7 μU/mL
C-peptide 2.71 ng/mL
Biochemistry Insulin antibody <0.4 %
TP 6.1 g/dL
Alb 2.8 g/dL Endocrine examination
BUN 25.5 mg/dL ACTH 15.7 pg/mL
Cr 1.3 mg/dL Cortisol 10.3 μg/dL
eGFR 30.5 mL/min/1.73 m2 TSH 2.43 μU/mL
Na 133 mEq/L Free T4 1.09 ng/mL
K 3.9 mEq/L GH 0.76 ng/mL
Cl 101 mEq/L IGF-1 76 ng/mL
Ca 9.1 mg/dL LH 16.61 mIU/mL
P 2.7 mg/dL FSH 48.7 mIU/mL
TB 0.5 mg/dL Estoradiol 22 pg/mL
AST 16 U/L Prolactin 16.52 ng/mL
ALT 10 U/L
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, HT: hematocrit, Plt: platelet, TP: total protein, Alb: albumin, BUN: urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration ratio, Na: sodium, K: potassium, Cl: chloride, Ca: calcium, P: phosphate, TB: total bilirubin, AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, ALP: alkaline phosphatase, γ-GTP: gamma glutamyl transpeptidase, CRP: C-reactive protein, HbA1c: glycated hemoglobin A1c, IRI: immunoreactive insulin, ACTH: adrenocorticotropic hormone, TSH: thyroid stimulating hormone, Free T4: free thyroxine, GH: growth hormone, IGF-1: insulin-like growth factor-1, LH: luteinizing hormone, FSH: follicle stimulating hormone
After discontinuing repaglinide, her fasting plasma glucose level increased. We evaluated fasting C-peptide levels using her preserved serum 2 days before stopping repaglinide, when hypoglycemia occurred repeatedly. We found that her fasting serum C-peptide level was high (4.73 ng/mL), glucose level was low (64 mg/dL), and C-peptide index (CPI; fasting plasma C-peptide ×100/fasting plasma glucose) was high at 7.4. However, her CPI decreased to 2.3 at 5 days after stopping repaglinide (15 days after admission) (Table 2). Based on these results and her clinical course, we diagnosed her with hypoglycemia due to the concomitant use of repaglinide and clopidogrel. Although we prescribed mitiglinide 10 mg×3/day 8 days after discontinuing repaglinide while continuing clopidogrel, her fasting plasma glucose levels were around 150 mg/dL without hypoglycemia at discharge. Thereafter, her diabetes was treated with teneligliptin 20 mg×2/day and mitiglinide 10 mg×3/day while continuing clopidogrel, and hypoglycemia was not detected 4 months after discharge.
Table 2. Changes in CPI with and without Repaglinide and Clopidogrel.
repaglinide clopidogrel FPG (mg/dL) CPR (ng/mL) CPI eGFR (mL/min/1.73 m2)
Day 8 + + 64 4.73 7.4 34.2
Day 10 - + 85 2.71 3.2 30.5
Day 15 - + 135 3.04 2.3 35.9
Day: Days after admission, FPG: fasting plasma glucose, CPI: C-peptide index (fasting plasma C-peptide×100/fasting plasma glucose), eGFR: estimated glomerular filtration ratio
Discussion
We encountered a patient with T2DM and severe renal insufficiency who received repaglinide and developed hypoglycemia three days after starting clopidogrel. To our knowledge, this is the first report to describe the clinical course leading to hypoglycemia due to the concomitant use of repaglinide and clopidogrel in a patient with T2DM and severe renal insufficiency.
Severe hypoglycemia has been shown to be associated with macro- and microvascular events, dementia, fracture, and mortality in patients with diabetes (9, 10). In addition, observational studies have suggested that hypoglycemia is associated with an increased risk of death in patients with diabetes hospitalized for acute coronary syndrome (11, 12). Furthermore, elderly patients with diabetes are more susceptible to hypoglycemic adverse events than younger ones owing to their unspecific and uncharacteristic hypoglycemic symptoms, probably caused by less effective counterregulatory mechanisms, reduced drug elimination caused by renal insufficiency, and motor and cognitive impairment (13). Fortunately, our patient did not experience any hypoglycemic adverse events. However, if she had not been under hospital observation, she might have experienced hypoglycemic adverse events because she did not present with typical hypoglycemic symptoms, and this may have delayed the detection of hypoglycemia. Therefore, various treatment guidelines for diabetes generally recommend not only avoiding hypoglycemia but also enacting less stringent glycemic control in elderly patients (14, 15). The Japan Diabetes Society recommends setting a lower limit for the target HbA1c value in elderly patients receiving insulin, sulfonylureas, or meglitinide, who are at risk of hypoglycemia (1). According to this recommendation, the target HbA1c value in our patient was 7.0-8.0%. Considering that the patient had mild anemia, probably because of severe renal insufficiency, and her actual HbA1c value was assumed to be slightly higher than the measured value (6.4%), we believe that our patient's condition was adequately controlled.
It has recently been reported that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). Wei et al. reported that the concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone in a population-based study using real-world data in Taiwan (adjusted odds ratio: 2.42; 95% confidence interval: 1.75, 3.35). In addition, no significant associations of hypoglycemia were found with the concomitant use of repaglinide with aspirin or with that of nateglinide and clopidogrel (7). Akagi et al. also reported a risk of hypoglycemia associated with the combined use of repaglinide and clopidogrel in a retrospective cohort study using hospitalized patients who started repaglinide and whose preprandial plasma glucose level was measured. In that study, hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, while it was observed only in 1 of 15 patients in the mitiglinide and clopidogrel group; no patients in the repaglinide alone group developed hypoglycemia. All patients who developed hypoglycemia had a plasma glucose level of ＜150 mg/dL measured 5 days before starting glinide (8). Based on this finding, our patient likely had hypoglycemia, since the preprandial plasma glucose level before starting clopidogrel was 112 mg/dL.
The mechanism underlying hypoglycemia development caused by the concomitant use of repaglinide and clopidogrel is assumed to be as follows: repaglinide is primarily metabolized by cytochrome P450 (CYP) 2C8 (16). However, clopidogrel is metabolized by multiple CYP enzymes, mainly CYP2C19, and its metabolite, clopidogrel acyl-β-D-glucuronide, has been shown to inhibit CYP2C8 potently in a time-dependent manner in vitro (6). A physiologically based pharmacokinetic model has also indicated that inactivation of CYP2C8 by clopidogrel acyl-β-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment (6). These results suggest that clopidogrel causes drug interactions with other medications metabolized by CYP2C8, such as repaglinide. In actuality, a placebo-controlled crossover study in 9 healthy volunteers who received clopidogrel for 3 days (300 mg on day 1 followed by 75 mg daily) and repaglinide (0.25 mg at 9 AM, 1 hour after clopidogrel intake on day 1 and 3) showed that the geometric mean area under the concentration-time curve (AUC0-∞) of repaglinide was increased by 5.1- and 3.9-fold on days 1 and 3 of clopidogrel treatment, respectively. In addition, that study showed that the maximum plasma concentration (Cmax) was increased 2.0- and 2.5-fold, the elimination half-life (t1/2) was prolonged by 42% and 22%, and the CYP2C8-dependent metabolite (M)4 to repaglinide AUC0-9h ratio was reduced to 19% and 27%, respectively. Furthermore, the lowest mean blood glucose for the study participants was 59.5 mg/dL despite an adequate food intake (6). These results strengthen the possibility that clopidogrel substantially increases the hypoglycemic risk in patients with T2DM who receive repaglinide. In fact, a retrospective survey in our hospital revealed that two of four patients who underwent concomitant use of repaglinide and clopidogrel, except for the patient in the present case, developed hypoglycemia (unpublished data). Based on these results and the fact that the concomitant use of repaglinide and clopidogrel has been contraindicated since 2015 in Canada (17) and cautioned against on the drug package insert since 2016 in Japan (18), the concomitant use of repaglinide and clopidogrel is now (as of 2020) contraindicated under the approval of our pharmaceutical affairs committee in our hospital. However, meglitinides other than repaglinide, such as nateglinide and mitiglinide, are presumed to not cause hypoglycemia when used concomitantly with clopidogrel, although this presumption needs to be confirmed. This is because nateglinide is metabolized by CYP2C9 (70%) and CYP3A4 (30%), on which clopidogrel has little inhibitory effect, and because mitiglinide is eliminated through gluconidation by uridine 5'-diphospho-glucuronosyltransferases 1A3 and 2B7 (19, 20). Therefore, if patients receiving clopidogrel need meglitinides, nateglinide or mitiglinide may be suitable for avoiding hypoglycemia.
Our patient had severe renal insufficiency due to diabetic kidney disease. Repaglinide is theoretically considered to confer a low risk of hypoglycemia even in patients with renal insufficiency, because repaglinide is metabolized mainly in the liver, and most of its metabolites are excreted through the bile. However, the AUC0-∞, Cmax and t1/2 of repaglinide in patients with severe renal insufficiency (creatinine clearance: 20-39 mL/min) as in our case, have been reported to be increased 1.7- and 1.3-fold and prolonged 130%, respectively, although these parameters in patients with mild-to-moderate renal insufficiency are comparable to those with a normal renal function (5). In addition, renal insufficiency impairs not only renal glucogenesis but also insulin clearance, leading to an increased risk of hypoglycemia (21). Therefore, based on these findings, severe renal insufficiency as in our case is assumed to enhance the risk of hypoglycemia owing to the concomitant use of repaglinide and clopidogrel.
Several limitations associated with the present study warrant mention. First, it is possible that hypoglycemia was caused by the direct effect of repaglinide, via the induction of glucose toxicity, rather than to the concomitant use of repaglinide and clopidogrel. Unfortunately, we were unable to evaluate the clinical course and CPI levels with repaglinide and without clopidogrel after hypoglycemia. However, considering the patient's HbA1c values with anemia 3 months before and after admission (6.7% and 6.4%, respectively) and the daily profile of blood glucose after hospitalization, we believe that the patient's diabetes was controlled without remarkable glucose toxicity. In addition, considering that the patient had no detected hypoglycemia during the treatment with repaglinide and without clopidogrel, before and after admission, and that hypoglycemia occurred after initiating clopidogrel, we considered the hypoglycemia to be due to the concomitant use of repaglinide and clopidogrel. Second, it is possible that adrenal insufficiency influenced the hypoglycemia. However, we speculate that adrenal insufficiency had little effect on the hypoglycemia in this patient, as the hypoglycemia did not occur before starting clopidogrel, and the discontinuation of repaglinide improved the hypoglycemia without changing the dose of hydrocortisone. In addition, insulin secretion was not suppressed during hypoglycemia. Third, the patient's blood concentration of repaglinide was not investigated. Fourth, CYP2C8 gene polymorphisms may have affected the blood concentration of repaglinide and were also not investigated (22). However, we believe that our report provides information on safe diabetes treatment that aims to prevent incidental hypoglycemia in patients with macrovascular complications requiring repaglinide and/or clopidogrel.
In conclusion, we encountered an elderly patient with T2DM and severe renal insufficiency who developed hypoglycemia due to the concomitant use of repaglinide and clopidogrel. The risk of developing hypoglycemia is considered to vary from patient to patient, but we should recognize that a patient's concomitant use of repaglinide and clopidogrel puts them at high risk of developing hypoglycemia, especially those with T2DM and severe renal insufficiency.
Author's disclosure of potential Conflicts of Interest (COI).
Tetsuyuki Yasuda: Honoraria, Takeda Pharmaceutical, Novartis Pharmaceuticals and Nippon Boehringer Ingelheim. | 10MG/DAY | DrugDosageText | CC BY-NC-ND | 33716254 | 19,137,817 | 2021 |
What was the outcome of reaction 'Drug interaction'? | Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency.
Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.
Introduction
The main goal of diabetes treatment is to ensure these patients have the same quality of life and longevity as healthy people by reducing the risk of micro- and macrovascular complications, such as diabetic nephropathy and cardiovascular disease (CVD). To achieve this goal, the comprehensive control of blood glucose without hypoglycemia as well as that of blood pressure, lipid, and body weight are crucial (1).
In Japan, as of June 2020, seven types of oral hypoglycemic agents (OHA) have been approved for the treatment of type 2 diabetes mellitus (T2DM). Repaglinide, as well as nateglinide and mitiglinide, belongs to the class of medications known as meglitinides, which act on sulfonylurea receptors on pancreatic β-cells to promote postprandial insulin secretion, thus mainly reducing postprandial glucose levels (2). Patients taking repaglinide are at risk of hypoglycemia, similar to that conferred by insulin and sulfonylureas. However, based on its rapid- and short-acting effects, repaglinide has a lower hypoglycemic risk than insulin or sulfonylureas (3). In addition, repaglinide is almost completely metabolized in the liver, and its metabolites are excreted primarily through the bile. Only a very small fraction (less than 8%) of the administered dose is excreted through the urine (4). Therefore, patients taking repaglinide are considered to have a low risk of hypoglycemia even when they have mild or moderate renal insufficiency (5).
Clopidogrel is a second-generation thienopyridine antiplatelet drug that is the mainstay of the treatment and secondary prevention of CVD in patients with T2DM. Recently, the concomitant use of repaglinide and clopidogrel has been shown to result in the elevation of blood concentration of repaglinide (6). In addition, few reports have shown that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). However, there are no reports on the clinical course of hypoglycemia due to the interaction of these drugs in patients with T2DM and severe renal insufficiency.
We herein report a patient with T2DM with severe renal insufficiency and describe the patient's clinical course, which included hypoglycemia owing to concomitant use of repaglinide and clopidogrel.
Case Report
Informed consent was obtained from the patient, and all procedures were approved by the appropriate institutional review board (the Ethics Committee of Osaka Police Hospital) and comply with the Declaration of Helsinki and its amendments.
We encountered an 81-year-old Japanese woman with T2DM and severe renal insufficiency who was receiving repaglinide and who developed hypoglycemia 3 days after starting clopidogrel. At 50 years old, she was diagnosed with T2DM and treated with OHAs. She subsequently had hypertension, dyslipidemia, atrial fibrillation, CVD, peripheral artery disease (PAD), and adrenal insufficiency owing to approximately five years of glucocorticoid treatment for autoimmune hepatitis, and her renal function gradually deteriorated. At 81 years old, she was admitted to our hospital for the treatment of acute coronary artery dissection. On admission, she was prescribed the following medications for T2DM, dyslipidemia, hyperuricemia, hypertension, CVD, PAD, atrial fibrillation, gastroesophageal reflux disease, and secondary adrenal insufficiency: teneligliptin 40 mg, repaglinide 1.5 mg, pravastatin 10 mg, febuxostat 20 mg, carvedilol 1.25 mg, azelnidipine 16 mg, verapamil 80 mg, cilostazol 200 mg, aspirin 100 mg, adoxaban 10 mg, propafenone 300 mg, vonoprazan 20 mg and hydrocortisone 10 mg per day, respectively.
She underwent emergent percutaneous coronary intervention for the dissection site of the left main coronary artery, and aspirin was changed to clopidogrel, while cilostazol was continued. At that time, her diabetes was treated with a 1,440-kcal diabetic diet and two OHAs (teneligliptin 20 mg×2/day, and repaglinide 0.5 mg×3/day). She did not develop hypoglycemia with these agents. However, her fasting plasma glucose level before breakfast gradually decreased, and hypoglycemia (63 mg/dL) developed 3 days after starting clopidogrel. Her cardiologist then reduced the 40 mg dose of teneligliptin to 20 mg, but her hypoglycemia (50-64 mg/dL) did not disappear. Nine days after starting clopidogrel, she was referred to our department for a detailed examination and treatment of her recurrent hypoglycemia (Figure).
Figure. Clinical course of the daily profile of blood glucose and medications. Blood glucose was measured with a glucometer. [ ] indicates the plasma glucose levels measured in the laboratory. PCI: percutaneous coronary intervention
On referral, the patient had no obvious hypoglycemic symptoms despite her pre-breakfast plasma glucose level of 50 mg/dL. Her body weight was 44.1 kg (body mass index: 16.0 kg/m2), blood pressure 101/60 mmHg, pulse rate 103 bpm, and body temperature 36.8°C. She had no abnormal physical signs. We suspected that her hypoglycemia was caused by the concomitant use of repaglinide and clopidogrel based on her clinical course and therefore discontinued repaglinide from before lunch on the referral day.
Her laboratory examination results the day after referral to our department are shown in Table 1. Her fasting plasma glucose level was 85 mg/dL, indicating no hypoglycemia, probably because repaglinide had been discontinued; her fasting C-peptide was 2.71 ng/mL, and her immunoreactive insulin level was 3.7 μU/mL. In addition, an insulin autoantibody test was negative. Her renal function was impaired, with a plasma urea nitrogen of 25.5 mg/dL, creatinine of 1.3 mg/dL, and estimated glomerular filtration ratio of 30.5 mL/min/1.73 m2. Endocrinological examinations revealed that the baseline levels of adrenocorticotropic hormone and cortisol were within the normal ranges, and the patient had a postmenopausal status.
Table 1. Laboratory Findings on Referral to Our Department.
Hematology ALP 128 U/L
WBC 8,400 /μL γ-GTP 20 U/L
RBC 284×10,000 /μL CRP 3.62 mg/dL
Hb 8.7 g/dL Glucose 85 mg/dL
Ht 25.3 % HbA1c 6.4 %
Plt 24.9×10,000 /μL IRI 3.7 μU/mL
C-peptide 2.71 ng/mL
Biochemistry Insulin antibody <0.4 %
TP 6.1 g/dL
Alb 2.8 g/dL Endocrine examination
BUN 25.5 mg/dL ACTH 15.7 pg/mL
Cr 1.3 mg/dL Cortisol 10.3 μg/dL
eGFR 30.5 mL/min/1.73 m2 TSH 2.43 μU/mL
Na 133 mEq/L Free T4 1.09 ng/mL
K 3.9 mEq/L GH 0.76 ng/mL
Cl 101 mEq/L IGF-1 76 ng/mL
Ca 9.1 mg/dL LH 16.61 mIU/mL
P 2.7 mg/dL FSH 48.7 mIU/mL
TB 0.5 mg/dL Estoradiol 22 pg/mL
AST 16 U/L Prolactin 16.52 ng/mL
ALT 10 U/L
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, HT: hematocrit, Plt: platelet, TP: total protein, Alb: albumin, BUN: urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration ratio, Na: sodium, K: potassium, Cl: chloride, Ca: calcium, P: phosphate, TB: total bilirubin, AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, ALP: alkaline phosphatase, γ-GTP: gamma glutamyl transpeptidase, CRP: C-reactive protein, HbA1c: glycated hemoglobin A1c, IRI: immunoreactive insulin, ACTH: adrenocorticotropic hormone, TSH: thyroid stimulating hormone, Free T4: free thyroxine, GH: growth hormone, IGF-1: insulin-like growth factor-1, LH: luteinizing hormone, FSH: follicle stimulating hormone
After discontinuing repaglinide, her fasting plasma glucose level increased. We evaluated fasting C-peptide levels using her preserved serum 2 days before stopping repaglinide, when hypoglycemia occurred repeatedly. We found that her fasting serum C-peptide level was high (4.73 ng/mL), glucose level was low (64 mg/dL), and C-peptide index (CPI; fasting plasma C-peptide ×100/fasting plasma glucose) was high at 7.4. However, her CPI decreased to 2.3 at 5 days after stopping repaglinide (15 days after admission) (Table 2). Based on these results and her clinical course, we diagnosed her with hypoglycemia due to the concomitant use of repaglinide and clopidogrel. Although we prescribed mitiglinide 10 mg×3/day 8 days after discontinuing repaglinide while continuing clopidogrel, her fasting plasma glucose levels were around 150 mg/dL without hypoglycemia at discharge. Thereafter, her diabetes was treated with teneligliptin 20 mg×2/day and mitiglinide 10 mg×3/day while continuing clopidogrel, and hypoglycemia was not detected 4 months after discharge.
Table 2. Changes in CPI with and without Repaglinide and Clopidogrel.
repaglinide clopidogrel FPG (mg/dL) CPR (ng/mL) CPI eGFR (mL/min/1.73 m2)
Day 8 + + 64 4.73 7.4 34.2
Day 10 - + 85 2.71 3.2 30.5
Day 15 - + 135 3.04 2.3 35.9
Day: Days after admission, FPG: fasting plasma glucose, CPI: C-peptide index (fasting plasma C-peptide×100/fasting plasma glucose), eGFR: estimated glomerular filtration ratio
Discussion
We encountered a patient with T2DM and severe renal insufficiency who received repaglinide and developed hypoglycemia three days after starting clopidogrel. To our knowledge, this is the first report to describe the clinical course leading to hypoglycemia due to the concomitant use of repaglinide and clopidogrel in a patient with T2DM and severe renal insufficiency.
Severe hypoglycemia has been shown to be associated with macro- and microvascular events, dementia, fracture, and mortality in patients with diabetes (9, 10). In addition, observational studies have suggested that hypoglycemia is associated with an increased risk of death in patients with diabetes hospitalized for acute coronary syndrome (11, 12). Furthermore, elderly patients with diabetes are more susceptible to hypoglycemic adverse events than younger ones owing to their unspecific and uncharacteristic hypoglycemic symptoms, probably caused by less effective counterregulatory mechanisms, reduced drug elimination caused by renal insufficiency, and motor and cognitive impairment (13). Fortunately, our patient did not experience any hypoglycemic adverse events. However, if she had not been under hospital observation, she might have experienced hypoglycemic adverse events because she did not present with typical hypoglycemic symptoms, and this may have delayed the detection of hypoglycemia. Therefore, various treatment guidelines for diabetes generally recommend not only avoiding hypoglycemia but also enacting less stringent glycemic control in elderly patients (14, 15). The Japan Diabetes Society recommends setting a lower limit for the target HbA1c value in elderly patients receiving insulin, sulfonylureas, or meglitinide, who are at risk of hypoglycemia (1). According to this recommendation, the target HbA1c value in our patient was 7.0-8.0%. Considering that the patient had mild anemia, probably because of severe renal insufficiency, and her actual HbA1c value was assumed to be slightly higher than the measured value (6.4%), we believe that our patient's condition was adequately controlled.
It has recently been reported that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). Wei et al. reported that the concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone in a population-based study using real-world data in Taiwan (adjusted odds ratio: 2.42; 95% confidence interval: 1.75, 3.35). In addition, no significant associations of hypoglycemia were found with the concomitant use of repaglinide with aspirin or with that of nateglinide and clopidogrel (7). Akagi et al. also reported a risk of hypoglycemia associated with the combined use of repaglinide and clopidogrel in a retrospective cohort study using hospitalized patients who started repaglinide and whose preprandial plasma glucose level was measured. In that study, hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, while it was observed only in 1 of 15 patients in the mitiglinide and clopidogrel group; no patients in the repaglinide alone group developed hypoglycemia. All patients who developed hypoglycemia had a plasma glucose level of ＜150 mg/dL measured 5 days before starting glinide (8). Based on this finding, our patient likely had hypoglycemia, since the preprandial plasma glucose level before starting clopidogrel was 112 mg/dL.
The mechanism underlying hypoglycemia development caused by the concomitant use of repaglinide and clopidogrel is assumed to be as follows: repaglinide is primarily metabolized by cytochrome P450 (CYP) 2C8 (16). However, clopidogrel is metabolized by multiple CYP enzymes, mainly CYP2C19, and its metabolite, clopidogrel acyl-β-D-glucuronide, has been shown to inhibit CYP2C8 potently in a time-dependent manner in vitro (6). A physiologically based pharmacokinetic model has also indicated that inactivation of CYP2C8 by clopidogrel acyl-β-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment (6). These results suggest that clopidogrel causes drug interactions with other medications metabolized by CYP2C8, such as repaglinide. In actuality, a placebo-controlled crossover study in 9 healthy volunteers who received clopidogrel for 3 days (300 mg on day 1 followed by 75 mg daily) and repaglinide (0.25 mg at 9 AM, 1 hour after clopidogrel intake on day 1 and 3) showed that the geometric mean area under the concentration-time curve (AUC0-∞) of repaglinide was increased by 5.1- and 3.9-fold on days 1 and 3 of clopidogrel treatment, respectively. In addition, that study showed that the maximum plasma concentration (Cmax) was increased 2.0- and 2.5-fold, the elimination half-life (t1/2) was prolonged by 42% and 22%, and the CYP2C8-dependent metabolite (M)4 to repaglinide AUC0-9h ratio was reduced to 19% and 27%, respectively. Furthermore, the lowest mean blood glucose for the study participants was 59.5 mg/dL despite an adequate food intake (6). These results strengthen the possibility that clopidogrel substantially increases the hypoglycemic risk in patients with T2DM who receive repaglinide. In fact, a retrospective survey in our hospital revealed that two of four patients who underwent concomitant use of repaglinide and clopidogrel, except for the patient in the present case, developed hypoglycemia (unpublished data). Based on these results and the fact that the concomitant use of repaglinide and clopidogrel has been contraindicated since 2015 in Canada (17) and cautioned against on the drug package insert since 2016 in Japan (18), the concomitant use of repaglinide and clopidogrel is now (as of 2020) contraindicated under the approval of our pharmaceutical affairs committee in our hospital. However, meglitinides other than repaglinide, such as nateglinide and mitiglinide, are presumed to not cause hypoglycemia when used concomitantly with clopidogrel, although this presumption needs to be confirmed. This is because nateglinide is metabolized by CYP2C9 (70%) and CYP3A4 (30%), on which clopidogrel has little inhibitory effect, and because mitiglinide is eliminated through gluconidation by uridine 5'-diphospho-glucuronosyltransferases 1A3 and 2B7 (19, 20). Therefore, if patients receiving clopidogrel need meglitinides, nateglinide or mitiglinide may be suitable for avoiding hypoglycemia.
Our patient had severe renal insufficiency due to diabetic kidney disease. Repaglinide is theoretically considered to confer a low risk of hypoglycemia even in patients with renal insufficiency, because repaglinide is metabolized mainly in the liver, and most of its metabolites are excreted through the bile. However, the AUC0-∞, Cmax and t1/2 of repaglinide in patients with severe renal insufficiency (creatinine clearance: 20-39 mL/min) as in our case, have been reported to be increased 1.7- and 1.3-fold and prolonged 130%, respectively, although these parameters in patients with mild-to-moderate renal insufficiency are comparable to those with a normal renal function (5). In addition, renal insufficiency impairs not only renal glucogenesis but also insulin clearance, leading to an increased risk of hypoglycemia (21). Therefore, based on these findings, severe renal insufficiency as in our case is assumed to enhance the risk of hypoglycemia owing to the concomitant use of repaglinide and clopidogrel.
Several limitations associated with the present study warrant mention. First, it is possible that hypoglycemia was caused by the direct effect of repaglinide, via the induction of glucose toxicity, rather than to the concomitant use of repaglinide and clopidogrel. Unfortunately, we were unable to evaluate the clinical course and CPI levels with repaglinide and without clopidogrel after hypoglycemia. However, considering the patient's HbA1c values with anemia 3 months before and after admission (6.7% and 6.4%, respectively) and the daily profile of blood glucose after hospitalization, we believe that the patient's diabetes was controlled without remarkable glucose toxicity. In addition, considering that the patient had no detected hypoglycemia during the treatment with repaglinide and without clopidogrel, before and after admission, and that hypoglycemia occurred after initiating clopidogrel, we considered the hypoglycemia to be due to the concomitant use of repaglinide and clopidogrel. Second, it is possible that adrenal insufficiency influenced the hypoglycemia. However, we speculate that adrenal insufficiency had little effect on the hypoglycemia in this patient, as the hypoglycemia did not occur before starting clopidogrel, and the discontinuation of repaglinide improved the hypoglycemia without changing the dose of hydrocortisone. In addition, insulin secretion was not suppressed during hypoglycemia. Third, the patient's blood concentration of repaglinide was not investigated. Fourth, CYP2C8 gene polymorphisms may have affected the blood concentration of repaglinide and were also not investigated (22). However, we believe that our report provides information on safe diabetes treatment that aims to prevent incidental hypoglycemia in patients with macrovascular complications requiring repaglinide and/or clopidogrel.
In conclusion, we encountered an elderly patient with T2DM and severe renal insufficiency who developed hypoglycemia due to the concomitant use of repaglinide and clopidogrel. The risk of developing hypoglycemia is considered to vary from patient to patient, but we should recognize that a patient's concomitant use of repaglinide and clopidogrel puts them at high risk of developing hypoglycemia, especially those with T2DM and severe renal insufficiency.
Author's disclosure of potential Conflicts of Interest (COI).
Tetsuyuki Yasuda: Honoraria, Takeda Pharmaceutical, Novartis Pharmaceuticals and Nippon Boehringer Ingelheim. | Recovered | ReactionOutcome | CC BY-NC-ND | 33716254 | 19,140,109 | 2021 |
What was the outcome of reaction 'Hypoglycaemia'? | Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency.
Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.
Introduction
The main goal of diabetes treatment is to ensure these patients have the same quality of life and longevity as healthy people by reducing the risk of micro- and macrovascular complications, such as diabetic nephropathy and cardiovascular disease (CVD). To achieve this goal, the comprehensive control of blood glucose without hypoglycemia as well as that of blood pressure, lipid, and body weight are crucial (1).
In Japan, as of June 2020, seven types of oral hypoglycemic agents (OHA) have been approved for the treatment of type 2 diabetes mellitus (T2DM). Repaglinide, as well as nateglinide and mitiglinide, belongs to the class of medications known as meglitinides, which act on sulfonylurea receptors on pancreatic β-cells to promote postprandial insulin secretion, thus mainly reducing postprandial glucose levels (2). Patients taking repaglinide are at risk of hypoglycemia, similar to that conferred by insulin and sulfonylureas. However, based on its rapid- and short-acting effects, repaglinide has a lower hypoglycemic risk than insulin or sulfonylureas (3). In addition, repaglinide is almost completely metabolized in the liver, and its metabolites are excreted primarily through the bile. Only a very small fraction (less than 8%) of the administered dose is excreted through the urine (4). Therefore, patients taking repaglinide are considered to have a low risk of hypoglycemia even when they have mild or moderate renal insufficiency (5).
Clopidogrel is a second-generation thienopyridine antiplatelet drug that is the mainstay of the treatment and secondary prevention of CVD in patients with T2DM. Recently, the concomitant use of repaglinide and clopidogrel has been shown to result in the elevation of blood concentration of repaglinide (6). In addition, few reports have shown that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). However, there are no reports on the clinical course of hypoglycemia due to the interaction of these drugs in patients with T2DM and severe renal insufficiency.
We herein report a patient with T2DM with severe renal insufficiency and describe the patient's clinical course, which included hypoglycemia owing to concomitant use of repaglinide and clopidogrel.
Case Report
Informed consent was obtained from the patient, and all procedures were approved by the appropriate institutional review board (the Ethics Committee of Osaka Police Hospital) and comply with the Declaration of Helsinki and its amendments.
We encountered an 81-year-old Japanese woman with T2DM and severe renal insufficiency who was receiving repaglinide and who developed hypoglycemia 3 days after starting clopidogrel. At 50 years old, she was diagnosed with T2DM and treated with OHAs. She subsequently had hypertension, dyslipidemia, atrial fibrillation, CVD, peripheral artery disease (PAD), and adrenal insufficiency owing to approximately five years of glucocorticoid treatment for autoimmune hepatitis, and her renal function gradually deteriorated. At 81 years old, she was admitted to our hospital for the treatment of acute coronary artery dissection. On admission, she was prescribed the following medications for T2DM, dyslipidemia, hyperuricemia, hypertension, CVD, PAD, atrial fibrillation, gastroesophageal reflux disease, and secondary adrenal insufficiency: teneligliptin 40 mg, repaglinide 1.5 mg, pravastatin 10 mg, febuxostat 20 mg, carvedilol 1.25 mg, azelnidipine 16 mg, verapamil 80 mg, cilostazol 200 mg, aspirin 100 mg, adoxaban 10 mg, propafenone 300 mg, vonoprazan 20 mg and hydrocortisone 10 mg per day, respectively.
She underwent emergent percutaneous coronary intervention for the dissection site of the left main coronary artery, and aspirin was changed to clopidogrel, while cilostazol was continued. At that time, her diabetes was treated with a 1,440-kcal diabetic diet and two OHAs (teneligliptin 20 mg×2/day, and repaglinide 0.5 mg×3/day). She did not develop hypoglycemia with these agents. However, her fasting plasma glucose level before breakfast gradually decreased, and hypoglycemia (63 mg/dL) developed 3 days after starting clopidogrel. Her cardiologist then reduced the 40 mg dose of teneligliptin to 20 mg, but her hypoglycemia (50-64 mg/dL) did not disappear. Nine days after starting clopidogrel, she was referred to our department for a detailed examination and treatment of her recurrent hypoglycemia (Figure).
Figure. Clinical course of the daily profile of blood glucose and medications. Blood glucose was measured with a glucometer. [ ] indicates the plasma glucose levels measured in the laboratory. PCI: percutaneous coronary intervention
On referral, the patient had no obvious hypoglycemic symptoms despite her pre-breakfast plasma glucose level of 50 mg/dL. Her body weight was 44.1 kg (body mass index: 16.0 kg/m2), blood pressure 101/60 mmHg, pulse rate 103 bpm, and body temperature 36.8°C. She had no abnormal physical signs. We suspected that her hypoglycemia was caused by the concomitant use of repaglinide and clopidogrel based on her clinical course and therefore discontinued repaglinide from before lunch on the referral day.
Her laboratory examination results the day after referral to our department are shown in Table 1. Her fasting plasma glucose level was 85 mg/dL, indicating no hypoglycemia, probably because repaglinide had been discontinued; her fasting C-peptide was 2.71 ng/mL, and her immunoreactive insulin level was 3.7 μU/mL. In addition, an insulin autoantibody test was negative. Her renal function was impaired, with a plasma urea nitrogen of 25.5 mg/dL, creatinine of 1.3 mg/dL, and estimated glomerular filtration ratio of 30.5 mL/min/1.73 m2. Endocrinological examinations revealed that the baseline levels of adrenocorticotropic hormone and cortisol were within the normal ranges, and the patient had a postmenopausal status.
Table 1. Laboratory Findings on Referral to Our Department.
Hematology ALP 128 U/L
WBC 8,400 /μL γ-GTP 20 U/L
RBC 284×10,000 /μL CRP 3.62 mg/dL
Hb 8.7 g/dL Glucose 85 mg/dL
Ht 25.3 % HbA1c 6.4 %
Plt 24.9×10,000 /μL IRI 3.7 μU/mL
C-peptide 2.71 ng/mL
Biochemistry Insulin antibody <0.4 %
TP 6.1 g/dL
Alb 2.8 g/dL Endocrine examination
BUN 25.5 mg/dL ACTH 15.7 pg/mL
Cr 1.3 mg/dL Cortisol 10.3 μg/dL
eGFR 30.5 mL/min/1.73 m2 TSH 2.43 μU/mL
Na 133 mEq/L Free T4 1.09 ng/mL
K 3.9 mEq/L GH 0.76 ng/mL
Cl 101 mEq/L IGF-1 76 ng/mL
Ca 9.1 mg/dL LH 16.61 mIU/mL
P 2.7 mg/dL FSH 48.7 mIU/mL
TB 0.5 mg/dL Estoradiol 22 pg/mL
AST 16 U/L Prolactin 16.52 ng/mL
ALT 10 U/L
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, HT: hematocrit, Plt: platelet, TP: total protein, Alb: albumin, BUN: urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration ratio, Na: sodium, K: potassium, Cl: chloride, Ca: calcium, P: phosphate, TB: total bilirubin, AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, ALP: alkaline phosphatase, γ-GTP: gamma glutamyl transpeptidase, CRP: C-reactive protein, HbA1c: glycated hemoglobin A1c, IRI: immunoreactive insulin, ACTH: adrenocorticotropic hormone, TSH: thyroid stimulating hormone, Free T4: free thyroxine, GH: growth hormone, IGF-1: insulin-like growth factor-1, LH: luteinizing hormone, FSH: follicle stimulating hormone
After discontinuing repaglinide, her fasting plasma glucose level increased. We evaluated fasting C-peptide levels using her preserved serum 2 days before stopping repaglinide, when hypoglycemia occurred repeatedly. We found that her fasting serum C-peptide level was high (4.73 ng/mL), glucose level was low (64 mg/dL), and C-peptide index (CPI; fasting plasma C-peptide ×100/fasting plasma glucose) was high at 7.4. However, her CPI decreased to 2.3 at 5 days after stopping repaglinide (15 days after admission) (Table 2). Based on these results and her clinical course, we diagnosed her with hypoglycemia due to the concomitant use of repaglinide and clopidogrel. Although we prescribed mitiglinide 10 mg×3/day 8 days after discontinuing repaglinide while continuing clopidogrel, her fasting plasma glucose levels were around 150 mg/dL without hypoglycemia at discharge. Thereafter, her diabetes was treated with teneligliptin 20 mg×2/day and mitiglinide 10 mg×3/day while continuing clopidogrel, and hypoglycemia was not detected 4 months after discharge.
Table 2. Changes in CPI with and without Repaglinide and Clopidogrel.
repaglinide clopidogrel FPG (mg/dL) CPR (ng/mL) CPI eGFR (mL/min/1.73 m2)
Day 8 + + 64 4.73 7.4 34.2
Day 10 - + 85 2.71 3.2 30.5
Day 15 - + 135 3.04 2.3 35.9
Day: Days after admission, FPG: fasting plasma glucose, CPI: C-peptide index (fasting plasma C-peptide×100/fasting plasma glucose), eGFR: estimated glomerular filtration ratio
Discussion
We encountered a patient with T2DM and severe renal insufficiency who received repaglinide and developed hypoglycemia three days after starting clopidogrel. To our knowledge, this is the first report to describe the clinical course leading to hypoglycemia due to the concomitant use of repaglinide and clopidogrel in a patient with T2DM and severe renal insufficiency.
Severe hypoglycemia has been shown to be associated with macro- and microvascular events, dementia, fracture, and mortality in patients with diabetes (9, 10). In addition, observational studies have suggested that hypoglycemia is associated with an increased risk of death in patients with diabetes hospitalized for acute coronary syndrome (11, 12). Furthermore, elderly patients with diabetes are more susceptible to hypoglycemic adverse events than younger ones owing to their unspecific and uncharacteristic hypoglycemic symptoms, probably caused by less effective counterregulatory mechanisms, reduced drug elimination caused by renal insufficiency, and motor and cognitive impairment (13). Fortunately, our patient did not experience any hypoglycemic adverse events. However, if she had not been under hospital observation, she might have experienced hypoglycemic adverse events because she did not present with typical hypoglycemic symptoms, and this may have delayed the detection of hypoglycemia. Therefore, various treatment guidelines for diabetes generally recommend not only avoiding hypoglycemia but also enacting less stringent glycemic control in elderly patients (14, 15). The Japan Diabetes Society recommends setting a lower limit for the target HbA1c value in elderly patients receiving insulin, sulfonylureas, or meglitinide, who are at risk of hypoglycemia (1). According to this recommendation, the target HbA1c value in our patient was 7.0-8.0%. Considering that the patient had mild anemia, probably because of severe renal insufficiency, and her actual HbA1c value was assumed to be slightly higher than the measured value (6.4%), we believe that our patient's condition was adequately controlled.
It has recently been reported that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). Wei et al. reported that the concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone in a population-based study using real-world data in Taiwan (adjusted odds ratio: 2.42; 95% confidence interval: 1.75, 3.35). In addition, no significant associations of hypoglycemia were found with the concomitant use of repaglinide with aspirin or with that of nateglinide and clopidogrel (7). Akagi et al. also reported a risk of hypoglycemia associated with the combined use of repaglinide and clopidogrel in a retrospective cohort study using hospitalized patients who started repaglinide and whose preprandial plasma glucose level was measured. In that study, hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, while it was observed only in 1 of 15 patients in the mitiglinide and clopidogrel group; no patients in the repaglinide alone group developed hypoglycemia. All patients who developed hypoglycemia had a plasma glucose level of ＜150 mg/dL measured 5 days before starting glinide (8). Based on this finding, our patient likely had hypoglycemia, since the preprandial plasma glucose level before starting clopidogrel was 112 mg/dL.
The mechanism underlying hypoglycemia development caused by the concomitant use of repaglinide and clopidogrel is assumed to be as follows: repaglinide is primarily metabolized by cytochrome P450 (CYP) 2C8 (16). However, clopidogrel is metabolized by multiple CYP enzymes, mainly CYP2C19, and its metabolite, clopidogrel acyl-β-D-glucuronide, has been shown to inhibit CYP2C8 potently in a time-dependent manner in vitro (6). A physiologically based pharmacokinetic model has also indicated that inactivation of CYP2C8 by clopidogrel acyl-β-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment (6). These results suggest that clopidogrel causes drug interactions with other medications metabolized by CYP2C8, such as repaglinide. In actuality, a placebo-controlled crossover study in 9 healthy volunteers who received clopidogrel for 3 days (300 mg on day 1 followed by 75 mg daily) and repaglinide (0.25 mg at 9 AM, 1 hour after clopidogrel intake on day 1 and 3) showed that the geometric mean area under the concentration-time curve (AUC0-∞) of repaglinide was increased by 5.1- and 3.9-fold on days 1 and 3 of clopidogrel treatment, respectively. In addition, that study showed that the maximum plasma concentration (Cmax) was increased 2.0- and 2.5-fold, the elimination half-life (t1/2) was prolonged by 42% and 22%, and the CYP2C8-dependent metabolite (M)4 to repaglinide AUC0-9h ratio was reduced to 19% and 27%, respectively. Furthermore, the lowest mean blood glucose for the study participants was 59.5 mg/dL despite an adequate food intake (6). These results strengthen the possibility that clopidogrel substantially increases the hypoglycemic risk in patients with T2DM who receive repaglinide. In fact, a retrospective survey in our hospital revealed that two of four patients who underwent concomitant use of repaglinide and clopidogrel, except for the patient in the present case, developed hypoglycemia (unpublished data). Based on these results and the fact that the concomitant use of repaglinide and clopidogrel has been contraindicated since 2015 in Canada (17) and cautioned against on the drug package insert since 2016 in Japan (18), the concomitant use of repaglinide and clopidogrel is now (as of 2020) contraindicated under the approval of our pharmaceutical affairs committee in our hospital. However, meglitinides other than repaglinide, such as nateglinide and mitiglinide, are presumed to not cause hypoglycemia when used concomitantly with clopidogrel, although this presumption needs to be confirmed. This is because nateglinide is metabolized by CYP2C9 (70%) and CYP3A4 (30%), on which clopidogrel has little inhibitory effect, and because mitiglinide is eliminated through gluconidation by uridine 5'-diphospho-glucuronosyltransferases 1A3 and 2B7 (19, 20). Therefore, if patients receiving clopidogrel need meglitinides, nateglinide or mitiglinide may be suitable for avoiding hypoglycemia.
Our patient had severe renal insufficiency due to diabetic kidney disease. Repaglinide is theoretically considered to confer a low risk of hypoglycemia even in patients with renal insufficiency, because repaglinide is metabolized mainly in the liver, and most of its metabolites are excreted through the bile. However, the AUC0-∞, Cmax and t1/2 of repaglinide in patients with severe renal insufficiency (creatinine clearance: 20-39 mL/min) as in our case, have been reported to be increased 1.7- and 1.3-fold and prolonged 130%, respectively, although these parameters in patients with mild-to-moderate renal insufficiency are comparable to those with a normal renal function (5). In addition, renal insufficiency impairs not only renal glucogenesis but also insulin clearance, leading to an increased risk of hypoglycemia (21). Therefore, based on these findings, severe renal insufficiency as in our case is assumed to enhance the risk of hypoglycemia owing to the concomitant use of repaglinide and clopidogrel.
Several limitations associated with the present study warrant mention. First, it is possible that hypoglycemia was caused by the direct effect of repaglinide, via the induction of glucose toxicity, rather than to the concomitant use of repaglinide and clopidogrel. Unfortunately, we were unable to evaluate the clinical course and CPI levels with repaglinide and without clopidogrel after hypoglycemia. However, considering the patient's HbA1c values with anemia 3 months before and after admission (6.7% and 6.4%, respectively) and the daily profile of blood glucose after hospitalization, we believe that the patient's diabetes was controlled without remarkable glucose toxicity. In addition, considering that the patient had no detected hypoglycemia during the treatment with repaglinide and without clopidogrel, before and after admission, and that hypoglycemia occurred after initiating clopidogrel, we considered the hypoglycemia to be due to the concomitant use of repaglinide and clopidogrel. Second, it is possible that adrenal insufficiency influenced the hypoglycemia. However, we speculate that adrenal insufficiency had little effect on the hypoglycemia in this patient, as the hypoglycemia did not occur before starting clopidogrel, and the discontinuation of repaglinide improved the hypoglycemia without changing the dose of hydrocortisone. In addition, insulin secretion was not suppressed during hypoglycemia. Third, the patient's blood concentration of repaglinide was not investigated. Fourth, CYP2C8 gene polymorphisms may have affected the blood concentration of repaglinide and were also not investigated (22). However, we believe that our report provides information on safe diabetes treatment that aims to prevent incidental hypoglycemia in patients with macrovascular complications requiring repaglinide and/or clopidogrel.
In conclusion, we encountered an elderly patient with T2DM and severe renal insufficiency who developed hypoglycemia due to the concomitant use of repaglinide and clopidogrel. The risk of developing hypoglycemia is considered to vary from patient to patient, but we should recognize that a patient's concomitant use of repaglinide and clopidogrel puts them at high risk of developing hypoglycemia, especially those with T2DM and severe renal insufficiency.
Author's disclosure of potential Conflicts of Interest (COI).
Tetsuyuki Yasuda: Honoraria, Takeda Pharmaceutical, Novartis Pharmaceuticals and Nippon Boehringer Ingelheim. | Recovered | ReactionOutcome | CC BY-NC-ND | 33716254 | 19,137,817 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'. | Pheochromocytoma Diagnosed during the Treatment of Diffuse Alveolar Hemorrhage, a Diagnostic Necessity before Using High-dose Glucocorticoids.
A 46-year-old woman with exacerbating hemoptysis and dyspnea was diagnosed with diffuse alveolar hemorrhage (DAH). High doses of glucocorticoids were initiated, but afterward, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain appeared. A 50-mm left adrenal tumor with an intense uptake by iodine-123 metaiodobenzylguanidine scintigraphy and catecholamine hypersecretion revealed complication with pheochromocytoma. Because high doses of glucocorticoids, sometimes required for DAH, can provoke life-threatening paroxysmal hypertension in pheochromocytoma and paraganglioma (PPGL), our case suggests that PPGL needs to be recognized as the cause of DAH and should be detected with whole-body imaging before starting glucocorticoids.
pmcIntroduction
Pheochromocytoma and paraganglioma (PPGL) are neoplastic diseases derived from chromaffin cells in adrenal medulla and extra-adrenal sympathetic paravertebral gangliasympathetic paravertebral ganglia, respectively (1). PPGL is usually characterized by hypersecretion of catecholamines, including adrenaline and noradrenaline (also known as epinephrine and norepinephrine, respectively) and dopamine (1), which cause various symptoms, such as headaches, palpitations, or anxiety (2). PPGL also causes paroxysmal or refractory hypertension and cardiovascular diseases (1). High-dose glucocorticoids can provoke paroxysmal hypertension in PPGL that can lead to a life-threatening condition called catecholamine crisis (3,4).
Diffuse alveolar hemorrhage (DAH) is a syndrome characterized by the leakage of red blood cells into the alveolar space (5). Clinical features of DAH vary in severity, but it can be life-threatening (5). The causes of DAH are multiple, including autoimmune and nonautoimmune diseases (5), and high-dose glucocorticoids are sometimes used as an immunosuppressive treatment, especially for DAH due to autoimmune diseases (5-7).
We herein report a case of pheochromocytoma that was diagnosed during the treatment of DAH, and paroxysmal hypertension was evoked after starting high-dose glucocorticoids for DAH. There have been reports of simultaneously diagnosed DAH and PPGL, and the hemodynamic effects of PPGL have been considered to be the cause of DAH. Therefore, our case suggests the importance of identifying PPGL as a cause of DAH with whole-body imaging before treatment with high-dose glucocorticoids to avoid the risk of catecholamine crisis.
Case Report
A 46-year-old woman was transported by ambulance with a chief complaint of dyspnea and hemoptysis. She had been treated for cough variant asthma and hypertension with medical histories of frequent hyperventilation attacks and conjunctival bleeding but had no history of surgery for pituitary, adrenal, or parathyroid diseases. Two days before her visit, she experienced sore throat and cough and was diagnosed with upper respiratory tract inflammation at a nearby clinic and treated with antibiotics and symptomatic drugs. On the day of hospitalization, dyspnea and hemoptysis appeared and worsened at midnight, at which point she was brought to our hospital.
The patient was 154.7 cm tall, weighed 62.8 kg, and had a blood pressure of 80/41 mmHg, a pulse rate of 96 beats/min, a body temperature of 36.6℃, a respiratory rate of 40 breaths/min, and pulse oximetry (SpO2) of 91% on room air. Because an electrocardiogram and transthoracic echocardiography revealed no remarkable abnormalities and the N-terminal pro-B-type natriuretic peptide levels were not increasing (67 pg/mL, reference range; <125 pg/mL), heart failure was excluded. Based on the results of chest X-ray and contrast-enhanced computed tomography (CT) (Fig. 1), DAH was diagnosed, and the patient was hospitalized.
Figure 1. Image showing diffuse alveolar hemorrhage (DAH). (A) Chest X-ray and (B) CT scan showing bilateral diffuse infiltrates.
She had been taking 20 mg/day of telmisartan and 15 mg/day of clotiazepam. The antibiotics and symptomatic drugs from a nearby clinic two days before were not the types of medications to induce catecholamine crisis. Considering the potential involvement of autoimmune diseases, immunosuppressive therapy with glucocorticoid (1,000 mg/day of methylprednisolone) and 500 mg/day of cyclophosphamide were initiated. Plasma exchange was also performed until the fifth day of hospitalization. At midnight, after the dosage of glucocorticoids had been reduced to 60 mg/day of prednisolone a day, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain occurred, but the administration of acetaminophen alone ameliorated both symptoms and blood pressure. Whole-body CT showed a left adrenal tumor over 50 mm in size with unenhanced attenuation at 20-60 Hounsfield units (Fig. 2A), suggesting pheochromocytoma. Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and single-photon emission CT (SPECT)-CT were performed, and a strong uptake at the left adrenal tumor was confirmed (Fig. 2B, C).
Figure 2. Image showing a left adrenal tumor. (A) Unenhanced CT scan showing a tumor of >50 mm (white arrowhead) in which the attenuation value was 20–60 Hounsfield units. (B) Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and (C) single-photon emission CT demonstrated an intense uptake in the adrenal tumor (white and black arrowheads).
Because no findings suggestive of immunological abnormalities (Table 1) in blood sampling tests were present and the patient's general condition improved, glucocorticoid treatment was gradually tapered and terminated until discharge due to concerns about catecholamine crisis caused by high-dose glucocorticoids. After DAH was cured, she was discharged on the 14th day of hospitalization and readmitted for a detailed diagnostic examination for pheochromocytoma 1 month later. Laboratory data from the blood and 24-hour urine collection samples showed higher levels of adrenaline, noradrenaline, metanephrine, and normetanephrine, demonstrating catecholamine hypersecretion (Table 2), whereas the plasma renin activity, plasma aldosterone concentration, adrenocorticotrophic hormone, cortisol, dehydroepiandrosterone sulfate, and estradiol were in the normal ranges (Table 2). The midnight cortisol level was 2.25 μg/dL, and the morning cortisol level after taking 1 mg of dexamethasone at midnight was 0.71 μg/dL. These data indicated that there was no complication with primary aldosteronism, Cushing's syndrome, or adrenocortical carcinoma.
Table 1. Immunology Tests.
Immunology tests
Antinuclear antibody Negative Anti-Sm antibody Negative
Anti-CCP antibody Negative Anti-Ro (SS-A) antibody Negative
MPO-ANCA Negative Anti-La (SS-B) antibody Negative
PR3-ANCA Negative Anti-Scl-70 antibody Negative
Anti-GBM antibody Negative Anti-ARS antibody Negative
Anti-RNP antibody Negative
ANA: antinuclear antibody, CCP: cyclic citrullinated peptide, MPO: myeroperoxidase, ANCA: anti-neutrophil cytoplasmic antibody, PR3: proteinase3, GBM: glomerular basement membrane, RNP: ribonucleoprotein, Sm: Smith, Scl-70: scleroderma-70, ARS: aminoacyl tRNA synthetase
Table 2. Endocrinology Tests.
Blood (Before surgery) Reference range
AD (pg/mL) 963 (<100)
NAD (pg/mL) 540 (100 - 450)
DA (pg/mL) 19 (<20)
PRA (ng/mL/hr) 1.1 (0.3 - 2.9)
PAC (pg/mL) 130 (29.9 - 158.8)
ACTH (pg/mL) 11.9 (7.2 - 63.3)
Cortisol (μg/dL) 8.49 (6.2 - 18.0)
DHEAS (µg/dL) 33 (19 - 231)
E2 (pg/mL) 5.8 (25 - 550)
Whole PTH (pg/mL) 34.3 (8.3 - 38.7)
24h-urine collection Before surgery (2 times) After surgery Reference range
AD (μg/day) 481.9 553.8 51.8 (3.4 - 26.9)
NAD (μg/day) 384.0 484.2 111.0 (48.6 - 168.4)
DA (μg/day) 2,126 3,046 746.8 (365.0 - 961.5)
VMA (mg/day) 25.7 27.3 3.5 (1.5 - 4.3)
HVA (mg/day) 6.0 6.3 3.6 (2.1 - 4.3)
MN (mg/day) 9.31 10.01 0.62 (0.0 - 0.2)
NMN (mg/day) 2.50 2.77 0.44 (0.1 - 0.3)
Free cortisol (µg/day) 31.4 33.9 (11.2 - 80.3)
ALD (µg/day) 15 14 (<10.0)
AD: adrenaline, NAD: noradrenaline, DA: dopamine, PRA: plasma renin activity, PAC: plasma aldosterone concentration, ACTH: adrenocorticotrophic hormone, DHEAS: dehydroepiandrosterone sulfate, E2: estradiol, PTH: parathyroid hormone, VMA: vanillylmandelic acid, HVA: homovanillic acid, MN: metanephrine, NMN: normetanephrine, ALD: aldosterone
A contrast-enhanced systemic scan showed no findings suggestive of thyroid, parathyroid, or pancreatic tumors, or other metastatic lesions. Based on these results, the patient was diagnosed with left adrenal pheochromocytoma. Although the patient's blood pressure was controlled with a small amount of doxazosin, sufficient α-blocking was considered important to prevent catecholamine hypersecretion due to intraoperative surgical procedures and postoperative vascular collapse. Therefore, we did not use other anti-hypertensive drugs, including calcium channel blocker, and administered increasing doses of doxazosin during hospitalization, exceeding the maximal dose.
After adjusting the drug dose, laparoscopic adrenalectomy was performed with 32 mg/day of doxazosin and 2.5 mg/day of bisoprolol. No serious adverse events occurred during or after the procedure. The histopathological tissue was a yellowish tumor with a diameter of 70 mm×55 mm. Histopathologically, cytoplasmic tumor cells proliferated in alveolar form via blood vessels, and immunohistologically, the tumor was positive for CD56, synaptophysin, and chromogranin A. The grading system for adrenal pheochromocytoma and paraganglioma (GAPP) score (8) was 2/10 points (positive for cellularity and Ki-67 labeling index), suggesting well-differentiated pheochromocytoma.
The clinical course after surgery is being monitored, and no recurrence or metastasis has been observed. She occasionally complained of sudden dyspnea even after the surgery, but the symptom was mild and resolved spontaneously each time.
Discussion
We herein report a case of pheochromocytoma that was diagnosed through the treatment of DAH. There have been reports describing PPGL diagnosed during DAH treatment (9-13). Table 3 shows an overview of each case, including our present case. The age at the diagnosis ranged from the teens to 60s, and PPGL has been observed in both men and women. At the time of the diagnosis, cases with a high blood pressure as well as a low blood pressure were observed, and many cases seemed to have a rapid heart rate, suggesting that there were large fluctuations in blood pressure. In addition, left adrenal tumors were observed in many cases, but extra-adrenal and bilateral adrenal tumors were also observed. It should be noted that the tumor sizes were ≥50 mm in all 4 cases for which the tumor size were measured, including our own case. Tumors of such sizes can be clearly identified by whole-body imaging.
Table 3. Case Series of PPGL with DAH or Hemoptysis.
Case Reference 9 Reference 10 Reference 11 Reference 12 Reference 13 Our case
Age (years old) 33 40 68 21 14 46
Gender M M M M F F
Blood pressure (mmHg) 150/100 85/59 >180/100 140/80 72/50 80/41
Heart rate (bpm) 160 116 120 90 126 96
Tumor localization Left adrenal Left adrenal Left adrenal Extraadrenal Bilateral adrenal Left adrenal
Tumor size (mm) 80×80×60 NA 46×60 NA Left 40×50×30 70×50
Right 60×40×30
Glucocorticoid use No No No No Yes* Yes
Paroxysmal hypertension Yes Yes Yes NA Yes Yes
Drugs for PPGL NA Phenoxybenzamine Phenoxybenzamine NA Phenoxybenzamine Doxazosin
Methyrosine Propranorol Bisoprorol
24h-urine AD (µg/day) 1,500 180 534 8.0 2.46** 553.8
24h-urine NAD (µg/day) 485 75 1,208.4 1,750 2,254** 484.2
24h-urine MN (mg/day) NA NA 12.3 NA NA 10.01
24h-urine NMN (mg/day) NA NA 5.7 NA NA 2.77
Other manifestations Nausea Nausa Nausea Chest pain Nausea, Vomiting Cough
Vomiting Vomiting Sweating Sweating, Pallor
Headache Headache Pallor Palpitation
Chest pain Chest pain, Cough
PPGL: pheochromocytoma and paraganglioma, DAH: diffuse alveolar hemorrhage, AD: adrenaline, NAD: noradrenaline, MN: metanephrine, NMN: normetanephrine, NA: Data not available. *In case from reference 13, the patient was treated with methylprednisolone under initial diagnosis of pneumonia, septic shock and multiple organ dysfunction syndrome. **In the original article, the unit of concentration of 24h-urine AD and NAD was described in ng/day, but the actual unit was considered to be µg/day from the contents of the manuscript. Therefore they are described in µg/day in Table 3. Reference range, 24h-urine AD; 3.4 - 26.9 µg/day, 24h-urine NAD; 48.6 - 168.4 µg/day, 24h-urine MN mg/day; 0.0 - 0.2, 24h-urine NMN; 0.1 - 0.3 mg/day
Glucocorticoids were used in only one case other than our present case (13), but it seemed to have been administered for a disease other than DAH. Conversely, paroxysmal hypertension was observed in most cases. Regarding hormone secretion, both the adrenaline-secreting type and noradrenaline-secreting type were observed. In addition, manifestations other than hemoptysis and dyspnea, such as nausea and vomiting and classic symptoms of pheochromocytoma, including headache, sweating, and pallor, were also observed. However, in emergency care, these were not considered specific symptoms based on which PPGL could be positively suspected.
Although a direct pathophysiological relationship between DAH and PPGL may be difficult to prove, the possible relationship between blood pressure fluctuation and the appearance of alveolar hemorrhage was discussed in these studies (9-13). The rapid increase in pulmonary vein pressure due to paroxysmal hypertension is considered to cause the rupture of capillaries, resulting in alveolar hemorrhage in patients with PPGL. In our case, we concluded that the DAH may not have been due to an autoimmune disease or drugs because of the patient's negative immunology tests and medication history. Considering her pathophysiology, blood pressure fluctuation may have occurred, as hypotension was present at the time of admission despite her having been treated for hypertension. Furthermore, the patient may have had a predisposition to mental stress because of her medical history of coexisting anxiety and frequent hyperventilation. Emotional stress has been reported to enhance catecholamine secretion (14), especially from PPGL (15). The frequent coughing observed until her transportation to our facility may have caused an increase in abdominal pressure, which would induce additional catecholamine secretion by the pheochromocytoma (16). Therefore, it is possible that these manifestations induced and worsened her blood pressure fluctuations, thereby resulting in increased pulmonary venous pressure and the provocation of alveolar hemorrhage.
In addition, in this case, immunosuppressive therapy including methylprednisolone was started because autoimmune diseases as causes of DAH could not be excluded at the initial hospitalization. High doses of glucocorticoids can provoke catecholamine crisis in PPGL (1,3). According to one literature review, in most cases of catecholamine crisis caused by glucocorticoids, the tumor diameters were reported to be ≥30 mm, while the glucocorticoid dosages were equivalent to ≥60 mg/day of hydrocortisone (3). Furthermore, catecholamine crisis does not develop at 1 mg/day of dexamethasone, which is equivalent to 24-30 mg/day of hydrocortisone (3). In our case, the tumor diameter was ≥50 mm, and the dose of prednisolone at the time of the paroxysmal hypertension was 60 mg/day, which was equivalent to hydrocortisone 300 mg/day. This situation may therefore have constituted a risk factor for catecholamine crisis.
Both DAH and PPGL-induced catecholamine crisis are life-threatening conditions, and urgent glucocorticoid treatment may be required during detection of the etiologies of DAH, as in our patient. Thus, PPGL should be considered a background disease of DAH, and detection efforts should be made whenever possible. Because paraganglioma develops from the extra-adrenal paraganglia from the neck to the pelvis (1), whole-body imaging is required, not merely imaging of the abdomen, to confirm the presence or absence of PPGL when DAH is suspected on chest X-ray. Although it should be noted that head and neck paraganglioma normally does not secrete catecholamine (1), when a tumor suspected of PPGL is found, therapeutic agents for catecholamine crisis, such as intravenous alpha- and beta-blockers (4), may be promptly prepared, even if high-dose glucocorticoids have to be used urgently.
In conclusion, we experienced a case of pheochromocytoma after the diagnosis and treatment of DAH. When the possibility of DAH due to autoimmune disease cannot be excluded, high-dose glucocorticoid treatment should be started. However, because high-dose glucocorticoids may induce catecholamine crisis and exacerbate the disease condition, PPGL should be considered as a cause of DAH, and the presence or absence of the tumor should be immediately confirmed by a systemic search with whole-body imaging, including CT.
The authors state that they have no Conflict of Interest (COI). | CLOTIAZEPAM, CYCLOPHOSPHAMIDE, METHYLPREDNISOLONE, PREDNISOLONE, TELMISARTAN | DrugsGivenReaction | CC BY-NC-ND | 33716288 | 19,913,035 | 2021-09-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Pheochromocytoma Diagnosed during the Treatment of Diffuse Alveolar Hemorrhage, a Diagnostic Necessity before Using High-dose Glucocorticoids.
A 46-year-old woman with exacerbating hemoptysis and dyspnea was diagnosed with diffuse alveolar hemorrhage (DAH). High doses of glucocorticoids were initiated, but afterward, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain appeared. A 50-mm left adrenal tumor with an intense uptake by iodine-123 metaiodobenzylguanidine scintigraphy and catecholamine hypersecretion revealed complication with pheochromocytoma. Because high doses of glucocorticoids, sometimes required for DAH, can provoke life-threatening paroxysmal hypertension in pheochromocytoma and paraganglioma (PPGL), our case suggests that PPGL needs to be recognized as the cause of DAH and should be detected with whole-body imaging before starting glucocorticoids.
pmcIntroduction
Pheochromocytoma and paraganglioma (PPGL) are neoplastic diseases derived from chromaffin cells in adrenal medulla and extra-adrenal sympathetic paravertebral gangliasympathetic paravertebral ganglia, respectively (1). PPGL is usually characterized by hypersecretion of catecholamines, including adrenaline and noradrenaline (also known as epinephrine and norepinephrine, respectively) and dopamine (1), which cause various symptoms, such as headaches, palpitations, or anxiety (2). PPGL also causes paroxysmal or refractory hypertension and cardiovascular diseases (1). High-dose glucocorticoids can provoke paroxysmal hypertension in PPGL that can lead to a life-threatening condition called catecholamine crisis (3,4).
Diffuse alveolar hemorrhage (DAH) is a syndrome characterized by the leakage of red blood cells into the alveolar space (5). Clinical features of DAH vary in severity, but it can be life-threatening (5). The causes of DAH are multiple, including autoimmune and nonautoimmune diseases (5), and high-dose glucocorticoids are sometimes used as an immunosuppressive treatment, especially for DAH due to autoimmune diseases (5-7).
We herein report a case of pheochromocytoma that was diagnosed during the treatment of DAH, and paroxysmal hypertension was evoked after starting high-dose glucocorticoids for DAH. There have been reports of simultaneously diagnosed DAH and PPGL, and the hemodynamic effects of PPGL have been considered to be the cause of DAH. Therefore, our case suggests the importance of identifying PPGL as a cause of DAH with whole-body imaging before treatment with high-dose glucocorticoids to avoid the risk of catecholamine crisis.
Case Report
A 46-year-old woman was transported by ambulance with a chief complaint of dyspnea and hemoptysis. She had been treated for cough variant asthma and hypertension with medical histories of frequent hyperventilation attacks and conjunctival bleeding but had no history of surgery for pituitary, adrenal, or parathyroid diseases. Two days before her visit, she experienced sore throat and cough and was diagnosed with upper respiratory tract inflammation at a nearby clinic and treated with antibiotics and symptomatic drugs. On the day of hospitalization, dyspnea and hemoptysis appeared and worsened at midnight, at which point she was brought to our hospital.
The patient was 154.7 cm tall, weighed 62.8 kg, and had a blood pressure of 80/41 mmHg, a pulse rate of 96 beats/min, a body temperature of 36.6℃, a respiratory rate of 40 breaths/min, and pulse oximetry (SpO2) of 91% on room air. Because an electrocardiogram and transthoracic echocardiography revealed no remarkable abnormalities and the N-terminal pro-B-type natriuretic peptide levels were not increasing (67 pg/mL, reference range; <125 pg/mL), heart failure was excluded. Based on the results of chest X-ray and contrast-enhanced computed tomography (CT) (Fig. 1), DAH was diagnosed, and the patient was hospitalized.
Figure 1. Image showing diffuse alveolar hemorrhage (DAH). (A) Chest X-ray and (B) CT scan showing bilateral diffuse infiltrates.
She had been taking 20 mg/day of telmisartan and 15 mg/day of clotiazepam. The antibiotics and symptomatic drugs from a nearby clinic two days before were not the types of medications to induce catecholamine crisis. Considering the potential involvement of autoimmune diseases, immunosuppressive therapy with glucocorticoid (1,000 mg/day of methylprednisolone) and 500 mg/day of cyclophosphamide were initiated. Plasma exchange was also performed until the fifth day of hospitalization. At midnight, after the dosage of glucocorticoids had been reduced to 60 mg/day of prednisolone a day, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain occurred, but the administration of acetaminophen alone ameliorated both symptoms and blood pressure. Whole-body CT showed a left adrenal tumor over 50 mm in size with unenhanced attenuation at 20-60 Hounsfield units (Fig. 2A), suggesting pheochromocytoma. Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and single-photon emission CT (SPECT)-CT were performed, and a strong uptake at the left adrenal tumor was confirmed (Fig. 2B, C).
Figure 2. Image showing a left adrenal tumor. (A) Unenhanced CT scan showing a tumor of >50 mm (white arrowhead) in which the attenuation value was 20–60 Hounsfield units. (B) Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and (C) single-photon emission CT demonstrated an intense uptake in the adrenal tumor (white and black arrowheads).
Because no findings suggestive of immunological abnormalities (Table 1) in blood sampling tests were present and the patient's general condition improved, glucocorticoid treatment was gradually tapered and terminated until discharge due to concerns about catecholamine crisis caused by high-dose glucocorticoids. After DAH was cured, she was discharged on the 14th day of hospitalization and readmitted for a detailed diagnostic examination for pheochromocytoma 1 month later. Laboratory data from the blood and 24-hour urine collection samples showed higher levels of adrenaline, noradrenaline, metanephrine, and normetanephrine, demonstrating catecholamine hypersecretion (Table 2), whereas the plasma renin activity, plasma aldosterone concentration, adrenocorticotrophic hormone, cortisol, dehydroepiandrosterone sulfate, and estradiol were in the normal ranges (Table 2). The midnight cortisol level was 2.25 μg/dL, and the morning cortisol level after taking 1 mg of dexamethasone at midnight was 0.71 μg/dL. These data indicated that there was no complication with primary aldosteronism, Cushing's syndrome, or adrenocortical carcinoma.
Table 1. Immunology Tests.
Immunology tests
Antinuclear antibody Negative Anti-Sm antibody Negative
Anti-CCP antibody Negative Anti-Ro (SS-A) antibody Negative
MPO-ANCA Negative Anti-La (SS-B) antibody Negative
PR3-ANCA Negative Anti-Scl-70 antibody Negative
Anti-GBM antibody Negative Anti-ARS antibody Negative
Anti-RNP antibody Negative
ANA: antinuclear antibody, CCP: cyclic citrullinated peptide, MPO: myeroperoxidase, ANCA: anti-neutrophil cytoplasmic antibody, PR3: proteinase3, GBM: glomerular basement membrane, RNP: ribonucleoprotein, Sm: Smith, Scl-70: scleroderma-70, ARS: aminoacyl tRNA synthetase
Table 2. Endocrinology Tests.
Blood (Before surgery) Reference range
AD (pg/mL) 963 (<100)
NAD (pg/mL) 540 (100 - 450)
DA (pg/mL) 19 (<20)
PRA (ng/mL/hr) 1.1 (0.3 - 2.9)
PAC (pg/mL) 130 (29.9 - 158.8)
ACTH (pg/mL) 11.9 (7.2 - 63.3)
Cortisol (μg/dL) 8.49 (6.2 - 18.0)
DHEAS (µg/dL) 33 (19 - 231)
E2 (pg/mL) 5.8 (25 - 550)
Whole PTH (pg/mL) 34.3 (8.3 - 38.7)
24h-urine collection Before surgery (2 times) After surgery Reference range
AD (μg/day) 481.9 553.8 51.8 (3.4 - 26.9)
NAD (μg/day) 384.0 484.2 111.0 (48.6 - 168.4)
DA (μg/day) 2,126 3,046 746.8 (365.0 - 961.5)
VMA (mg/day) 25.7 27.3 3.5 (1.5 - 4.3)
HVA (mg/day) 6.0 6.3 3.6 (2.1 - 4.3)
MN (mg/day) 9.31 10.01 0.62 (0.0 - 0.2)
NMN (mg/day) 2.50 2.77 0.44 (0.1 - 0.3)
Free cortisol (µg/day) 31.4 33.9 (11.2 - 80.3)
ALD (µg/day) 15 14 (<10.0)
AD: adrenaline, NAD: noradrenaline, DA: dopamine, PRA: plasma renin activity, PAC: plasma aldosterone concentration, ACTH: adrenocorticotrophic hormone, DHEAS: dehydroepiandrosterone sulfate, E2: estradiol, PTH: parathyroid hormone, VMA: vanillylmandelic acid, HVA: homovanillic acid, MN: metanephrine, NMN: normetanephrine, ALD: aldosterone
A contrast-enhanced systemic scan showed no findings suggestive of thyroid, parathyroid, or pancreatic tumors, or other metastatic lesions. Based on these results, the patient was diagnosed with left adrenal pheochromocytoma. Although the patient's blood pressure was controlled with a small amount of doxazosin, sufficient α-blocking was considered important to prevent catecholamine hypersecretion due to intraoperative surgical procedures and postoperative vascular collapse. Therefore, we did not use other anti-hypertensive drugs, including calcium channel blocker, and administered increasing doses of doxazosin during hospitalization, exceeding the maximal dose.
After adjusting the drug dose, laparoscopic adrenalectomy was performed with 32 mg/day of doxazosin and 2.5 mg/day of bisoprolol. No serious adverse events occurred during or after the procedure. The histopathological tissue was a yellowish tumor with a diameter of 70 mm×55 mm. Histopathologically, cytoplasmic tumor cells proliferated in alveolar form via blood vessels, and immunohistologically, the tumor was positive for CD56, synaptophysin, and chromogranin A. The grading system for adrenal pheochromocytoma and paraganglioma (GAPP) score (8) was 2/10 points (positive for cellularity and Ki-67 labeling index), suggesting well-differentiated pheochromocytoma.
The clinical course after surgery is being monitored, and no recurrence or metastasis has been observed. She occasionally complained of sudden dyspnea even after the surgery, but the symptom was mild and resolved spontaneously each time.
Discussion
We herein report a case of pheochromocytoma that was diagnosed through the treatment of DAH. There have been reports describing PPGL diagnosed during DAH treatment (9-13). Table 3 shows an overview of each case, including our present case. The age at the diagnosis ranged from the teens to 60s, and PPGL has been observed in both men and women. At the time of the diagnosis, cases with a high blood pressure as well as a low blood pressure were observed, and many cases seemed to have a rapid heart rate, suggesting that there were large fluctuations in blood pressure. In addition, left adrenal tumors were observed in many cases, but extra-adrenal and bilateral adrenal tumors were also observed. It should be noted that the tumor sizes were ≥50 mm in all 4 cases for which the tumor size were measured, including our own case. Tumors of such sizes can be clearly identified by whole-body imaging.
Table 3. Case Series of PPGL with DAH or Hemoptysis.
Case Reference 9 Reference 10 Reference 11 Reference 12 Reference 13 Our case
Age (years old) 33 40 68 21 14 46
Gender M M M M F F
Blood pressure (mmHg) 150/100 85/59 >180/100 140/80 72/50 80/41
Heart rate (bpm) 160 116 120 90 126 96
Tumor localization Left adrenal Left adrenal Left adrenal Extraadrenal Bilateral adrenal Left adrenal
Tumor size (mm) 80×80×60 NA 46×60 NA Left 40×50×30 70×50
Right 60×40×30
Glucocorticoid use No No No No Yes* Yes
Paroxysmal hypertension Yes Yes Yes NA Yes Yes
Drugs for PPGL NA Phenoxybenzamine Phenoxybenzamine NA Phenoxybenzamine Doxazosin
Methyrosine Propranorol Bisoprorol
24h-urine AD (µg/day) 1,500 180 534 8.0 2.46** 553.8
24h-urine NAD (µg/day) 485 75 1,208.4 1,750 2,254** 484.2
24h-urine MN (mg/day) NA NA 12.3 NA NA 10.01
24h-urine NMN (mg/day) NA NA 5.7 NA NA 2.77
Other manifestations Nausea Nausa Nausea Chest pain Nausea, Vomiting Cough
Vomiting Vomiting Sweating Sweating, Pallor
Headache Headache Pallor Palpitation
Chest pain Chest pain, Cough
PPGL: pheochromocytoma and paraganglioma, DAH: diffuse alveolar hemorrhage, AD: adrenaline, NAD: noradrenaline, MN: metanephrine, NMN: normetanephrine, NA: Data not available. *In case from reference 13, the patient was treated with methylprednisolone under initial diagnosis of pneumonia, septic shock and multiple organ dysfunction syndrome. **In the original article, the unit of concentration of 24h-urine AD and NAD was described in ng/day, but the actual unit was considered to be µg/day from the contents of the manuscript. Therefore they are described in µg/day in Table 3. Reference range, 24h-urine AD; 3.4 - 26.9 µg/day, 24h-urine NAD; 48.6 - 168.4 µg/day, 24h-urine MN mg/day; 0.0 - 0.2, 24h-urine NMN; 0.1 - 0.3 mg/day
Glucocorticoids were used in only one case other than our present case (13), but it seemed to have been administered for a disease other than DAH. Conversely, paroxysmal hypertension was observed in most cases. Regarding hormone secretion, both the adrenaline-secreting type and noradrenaline-secreting type were observed. In addition, manifestations other than hemoptysis and dyspnea, such as nausea and vomiting and classic symptoms of pheochromocytoma, including headache, sweating, and pallor, were also observed. However, in emergency care, these were not considered specific symptoms based on which PPGL could be positively suspected.
Although a direct pathophysiological relationship between DAH and PPGL may be difficult to prove, the possible relationship between blood pressure fluctuation and the appearance of alveolar hemorrhage was discussed in these studies (9-13). The rapid increase in pulmonary vein pressure due to paroxysmal hypertension is considered to cause the rupture of capillaries, resulting in alveolar hemorrhage in patients with PPGL. In our case, we concluded that the DAH may not have been due to an autoimmune disease or drugs because of the patient's negative immunology tests and medication history. Considering her pathophysiology, blood pressure fluctuation may have occurred, as hypotension was present at the time of admission despite her having been treated for hypertension. Furthermore, the patient may have had a predisposition to mental stress because of her medical history of coexisting anxiety and frequent hyperventilation. Emotional stress has been reported to enhance catecholamine secretion (14), especially from PPGL (15). The frequent coughing observed until her transportation to our facility may have caused an increase in abdominal pressure, which would induce additional catecholamine secretion by the pheochromocytoma (16). Therefore, it is possible that these manifestations induced and worsened her blood pressure fluctuations, thereby resulting in increased pulmonary venous pressure and the provocation of alveolar hemorrhage.
In addition, in this case, immunosuppressive therapy including methylprednisolone was started because autoimmune diseases as causes of DAH could not be excluded at the initial hospitalization. High doses of glucocorticoids can provoke catecholamine crisis in PPGL (1,3). According to one literature review, in most cases of catecholamine crisis caused by glucocorticoids, the tumor diameters were reported to be ≥30 mm, while the glucocorticoid dosages were equivalent to ≥60 mg/day of hydrocortisone (3). Furthermore, catecholamine crisis does not develop at 1 mg/day of dexamethasone, which is equivalent to 24-30 mg/day of hydrocortisone (3). In our case, the tumor diameter was ≥50 mm, and the dose of prednisolone at the time of the paroxysmal hypertension was 60 mg/day, which was equivalent to hydrocortisone 300 mg/day. This situation may therefore have constituted a risk factor for catecholamine crisis.
Both DAH and PPGL-induced catecholamine crisis are life-threatening conditions, and urgent glucocorticoid treatment may be required during detection of the etiologies of DAH, as in our patient. Thus, PPGL should be considered a background disease of DAH, and detection efforts should be made whenever possible. Because paraganglioma develops from the extra-adrenal paraganglia from the neck to the pelvis (1), whole-body imaging is required, not merely imaging of the abdomen, to confirm the presence or absence of PPGL when DAH is suspected on chest X-ray. Although it should be noted that head and neck paraganglioma normally does not secrete catecholamine (1), when a tumor suspected of PPGL is found, therapeutic agents for catecholamine crisis, such as intravenous alpha- and beta-blockers (4), may be promptly prepared, even if high-dose glucocorticoids have to be used urgently.
In conclusion, we experienced a case of pheochromocytoma after the diagnosis and treatment of DAH. When the possibility of DAH due to autoimmune disease cannot be excluded, high-dose glucocorticoid treatment should be started. However, because high-dose glucocorticoids may induce catecholamine crisis and exacerbate the disease condition, PPGL should be considered as a cause of DAH, and the presence or absence of the tumor should be immediately confirmed by a systemic search with whole-body imaging, including CT.
The authors state that they have no Conflict of Interest (COI). | CLOTIAZEPAM, CYCLOPHOSPHAMIDE, METHYLPREDNISOLONE SODIUM SUCCINATE, PREDNISOLONE, TELMISARTAN | DrugsGivenReaction | CC BY-NC-ND | 33716288 | 19,945,054 | 2021-09-01 |
What is the weight of the patient? | Pheochromocytoma Diagnosed during the Treatment of Diffuse Alveolar Hemorrhage, a Diagnostic Necessity before Using High-dose Glucocorticoids.
A 46-year-old woman with exacerbating hemoptysis and dyspnea was diagnosed with diffuse alveolar hemorrhage (DAH). High doses of glucocorticoids were initiated, but afterward, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain appeared. A 50-mm left adrenal tumor with an intense uptake by iodine-123 metaiodobenzylguanidine scintigraphy and catecholamine hypersecretion revealed complication with pheochromocytoma. Because high doses of glucocorticoids, sometimes required for DAH, can provoke life-threatening paroxysmal hypertension in pheochromocytoma and paraganglioma (PPGL), our case suggests that PPGL needs to be recognized as the cause of DAH and should be detected with whole-body imaging before starting glucocorticoids.
pmcIntroduction
Pheochromocytoma and paraganglioma (PPGL) are neoplastic diseases derived from chromaffin cells in adrenal medulla and extra-adrenal sympathetic paravertebral gangliasympathetic paravertebral ganglia, respectively (1). PPGL is usually characterized by hypersecretion of catecholamines, including adrenaline and noradrenaline (also known as epinephrine and norepinephrine, respectively) and dopamine (1), which cause various symptoms, such as headaches, palpitations, or anxiety (2). PPGL also causes paroxysmal or refractory hypertension and cardiovascular diseases (1). High-dose glucocorticoids can provoke paroxysmal hypertension in PPGL that can lead to a life-threatening condition called catecholamine crisis (3,4).
Diffuse alveolar hemorrhage (DAH) is a syndrome characterized by the leakage of red blood cells into the alveolar space (5). Clinical features of DAH vary in severity, but it can be life-threatening (5). The causes of DAH are multiple, including autoimmune and nonautoimmune diseases (5), and high-dose glucocorticoids are sometimes used as an immunosuppressive treatment, especially for DAH due to autoimmune diseases (5-7).
We herein report a case of pheochromocytoma that was diagnosed during the treatment of DAH, and paroxysmal hypertension was evoked after starting high-dose glucocorticoids for DAH. There have been reports of simultaneously diagnosed DAH and PPGL, and the hemodynamic effects of PPGL have been considered to be the cause of DAH. Therefore, our case suggests the importance of identifying PPGL as a cause of DAH with whole-body imaging before treatment with high-dose glucocorticoids to avoid the risk of catecholamine crisis.
Case Report
A 46-year-old woman was transported by ambulance with a chief complaint of dyspnea and hemoptysis. She had been treated for cough variant asthma and hypertension with medical histories of frequent hyperventilation attacks and conjunctival bleeding but had no history of surgery for pituitary, adrenal, or parathyroid diseases. Two days before her visit, she experienced sore throat and cough and was diagnosed with upper respiratory tract inflammation at a nearby clinic and treated with antibiotics and symptomatic drugs. On the day of hospitalization, dyspnea and hemoptysis appeared and worsened at midnight, at which point she was brought to our hospital.
The patient was 154.7 cm tall, weighed 62.8 kg, and had a blood pressure of 80/41 mmHg, a pulse rate of 96 beats/min, a body temperature of 36.6℃, a respiratory rate of 40 breaths/min, and pulse oximetry (SpO2) of 91% on room air. Because an electrocardiogram and transthoracic echocardiography revealed no remarkable abnormalities and the N-terminal pro-B-type natriuretic peptide levels were not increasing (67 pg/mL, reference range; <125 pg/mL), heart failure was excluded. Based on the results of chest X-ray and contrast-enhanced computed tomography (CT) (Fig. 1), DAH was diagnosed, and the patient was hospitalized.
Figure 1. Image showing diffuse alveolar hemorrhage (DAH). (A) Chest X-ray and (B) CT scan showing bilateral diffuse infiltrates.
She had been taking 20 mg/day of telmisartan and 15 mg/day of clotiazepam. The antibiotics and symptomatic drugs from a nearby clinic two days before were not the types of medications to induce catecholamine crisis. Considering the potential involvement of autoimmune diseases, immunosuppressive therapy with glucocorticoid (1,000 mg/day of methylprednisolone) and 500 mg/day of cyclophosphamide were initiated. Plasma exchange was also performed until the fifth day of hospitalization. At midnight, after the dosage of glucocorticoids had been reduced to 60 mg/day of prednisolone a day, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain occurred, but the administration of acetaminophen alone ameliorated both symptoms and blood pressure. Whole-body CT showed a left adrenal tumor over 50 mm in size with unenhanced attenuation at 20-60 Hounsfield units (Fig. 2A), suggesting pheochromocytoma. Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and single-photon emission CT (SPECT)-CT were performed, and a strong uptake at the left adrenal tumor was confirmed (Fig. 2B, C).
Figure 2. Image showing a left adrenal tumor. (A) Unenhanced CT scan showing a tumor of >50 mm (white arrowhead) in which the attenuation value was 20–60 Hounsfield units. (B) Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and (C) single-photon emission CT demonstrated an intense uptake in the adrenal tumor (white and black arrowheads).
Because no findings suggestive of immunological abnormalities (Table 1) in blood sampling tests were present and the patient's general condition improved, glucocorticoid treatment was gradually tapered and terminated until discharge due to concerns about catecholamine crisis caused by high-dose glucocorticoids. After DAH was cured, she was discharged on the 14th day of hospitalization and readmitted for a detailed diagnostic examination for pheochromocytoma 1 month later. Laboratory data from the blood and 24-hour urine collection samples showed higher levels of adrenaline, noradrenaline, metanephrine, and normetanephrine, demonstrating catecholamine hypersecretion (Table 2), whereas the plasma renin activity, plasma aldosterone concentration, adrenocorticotrophic hormone, cortisol, dehydroepiandrosterone sulfate, and estradiol were in the normal ranges (Table 2). The midnight cortisol level was 2.25 μg/dL, and the morning cortisol level after taking 1 mg of dexamethasone at midnight was 0.71 μg/dL. These data indicated that there was no complication with primary aldosteronism, Cushing's syndrome, or adrenocortical carcinoma.
Table 1. Immunology Tests.
Immunology tests
Antinuclear antibody Negative Anti-Sm antibody Negative
Anti-CCP antibody Negative Anti-Ro (SS-A) antibody Negative
MPO-ANCA Negative Anti-La (SS-B) antibody Negative
PR3-ANCA Negative Anti-Scl-70 antibody Negative
Anti-GBM antibody Negative Anti-ARS antibody Negative
Anti-RNP antibody Negative
ANA: antinuclear antibody, CCP: cyclic citrullinated peptide, MPO: myeroperoxidase, ANCA: anti-neutrophil cytoplasmic antibody, PR3: proteinase3, GBM: glomerular basement membrane, RNP: ribonucleoprotein, Sm: Smith, Scl-70: scleroderma-70, ARS: aminoacyl tRNA synthetase
Table 2. Endocrinology Tests.
Blood (Before surgery) Reference range
AD (pg/mL) 963 (<100)
NAD (pg/mL) 540 (100 - 450)
DA (pg/mL) 19 (<20)
PRA (ng/mL/hr) 1.1 (0.3 - 2.9)
PAC (pg/mL) 130 (29.9 - 158.8)
ACTH (pg/mL) 11.9 (7.2 - 63.3)
Cortisol (μg/dL) 8.49 (6.2 - 18.0)
DHEAS (µg/dL) 33 (19 - 231)
E2 (pg/mL) 5.8 (25 - 550)
Whole PTH (pg/mL) 34.3 (8.3 - 38.7)
24h-urine collection Before surgery (2 times) After surgery Reference range
AD (μg/day) 481.9 553.8 51.8 (3.4 - 26.9)
NAD (μg/day) 384.0 484.2 111.0 (48.6 - 168.4)
DA (μg/day) 2,126 3,046 746.8 (365.0 - 961.5)
VMA (mg/day) 25.7 27.3 3.5 (1.5 - 4.3)
HVA (mg/day) 6.0 6.3 3.6 (2.1 - 4.3)
MN (mg/day) 9.31 10.01 0.62 (0.0 - 0.2)
NMN (mg/day) 2.50 2.77 0.44 (0.1 - 0.3)
Free cortisol (µg/day) 31.4 33.9 (11.2 - 80.3)
ALD (µg/day) 15 14 (<10.0)
AD: adrenaline, NAD: noradrenaline, DA: dopamine, PRA: plasma renin activity, PAC: plasma aldosterone concentration, ACTH: adrenocorticotrophic hormone, DHEAS: dehydroepiandrosterone sulfate, E2: estradiol, PTH: parathyroid hormone, VMA: vanillylmandelic acid, HVA: homovanillic acid, MN: metanephrine, NMN: normetanephrine, ALD: aldosterone
A contrast-enhanced systemic scan showed no findings suggestive of thyroid, parathyroid, or pancreatic tumors, or other metastatic lesions. Based on these results, the patient was diagnosed with left adrenal pheochromocytoma. Although the patient's blood pressure was controlled with a small amount of doxazosin, sufficient α-blocking was considered important to prevent catecholamine hypersecretion due to intraoperative surgical procedures and postoperative vascular collapse. Therefore, we did not use other anti-hypertensive drugs, including calcium channel blocker, and administered increasing doses of doxazosin during hospitalization, exceeding the maximal dose.
After adjusting the drug dose, laparoscopic adrenalectomy was performed with 32 mg/day of doxazosin and 2.5 mg/day of bisoprolol. No serious adverse events occurred during or after the procedure. The histopathological tissue was a yellowish tumor with a diameter of 70 mm×55 mm. Histopathologically, cytoplasmic tumor cells proliferated in alveolar form via blood vessels, and immunohistologically, the tumor was positive for CD56, synaptophysin, and chromogranin A. The grading system for adrenal pheochromocytoma and paraganglioma (GAPP) score (8) was 2/10 points (positive for cellularity and Ki-67 labeling index), suggesting well-differentiated pheochromocytoma.
The clinical course after surgery is being monitored, and no recurrence or metastasis has been observed. She occasionally complained of sudden dyspnea even after the surgery, but the symptom was mild and resolved spontaneously each time.
Discussion
We herein report a case of pheochromocytoma that was diagnosed through the treatment of DAH. There have been reports describing PPGL diagnosed during DAH treatment (9-13). Table 3 shows an overview of each case, including our present case. The age at the diagnosis ranged from the teens to 60s, and PPGL has been observed in both men and women. At the time of the diagnosis, cases with a high blood pressure as well as a low blood pressure were observed, and many cases seemed to have a rapid heart rate, suggesting that there were large fluctuations in blood pressure. In addition, left adrenal tumors were observed in many cases, but extra-adrenal and bilateral adrenal tumors were also observed. It should be noted that the tumor sizes were ≥50 mm in all 4 cases for which the tumor size were measured, including our own case. Tumors of such sizes can be clearly identified by whole-body imaging.
Table 3. Case Series of PPGL with DAH or Hemoptysis.
Case Reference 9 Reference 10 Reference 11 Reference 12 Reference 13 Our case
Age (years old) 33 40 68 21 14 46
Gender M M M M F F
Blood pressure (mmHg) 150/100 85/59 >180/100 140/80 72/50 80/41
Heart rate (bpm) 160 116 120 90 126 96
Tumor localization Left adrenal Left adrenal Left adrenal Extraadrenal Bilateral adrenal Left adrenal
Tumor size (mm) 80×80×60 NA 46×60 NA Left 40×50×30 70×50
Right 60×40×30
Glucocorticoid use No No No No Yes* Yes
Paroxysmal hypertension Yes Yes Yes NA Yes Yes
Drugs for PPGL NA Phenoxybenzamine Phenoxybenzamine NA Phenoxybenzamine Doxazosin
Methyrosine Propranorol Bisoprorol
24h-urine AD (µg/day) 1,500 180 534 8.0 2.46** 553.8
24h-urine NAD (µg/day) 485 75 1,208.4 1,750 2,254** 484.2
24h-urine MN (mg/day) NA NA 12.3 NA NA 10.01
24h-urine NMN (mg/day) NA NA 5.7 NA NA 2.77
Other manifestations Nausea Nausa Nausea Chest pain Nausea, Vomiting Cough
Vomiting Vomiting Sweating Sweating, Pallor
Headache Headache Pallor Palpitation
Chest pain Chest pain, Cough
PPGL: pheochromocytoma and paraganglioma, DAH: diffuse alveolar hemorrhage, AD: adrenaline, NAD: noradrenaline, MN: metanephrine, NMN: normetanephrine, NA: Data not available. *In case from reference 13, the patient was treated with methylprednisolone under initial diagnosis of pneumonia, septic shock and multiple organ dysfunction syndrome. **In the original article, the unit of concentration of 24h-urine AD and NAD was described in ng/day, but the actual unit was considered to be µg/day from the contents of the manuscript. Therefore they are described in µg/day in Table 3. Reference range, 24h-urine AD; 3.4 - 26.9 µg/day, 24h-urine NAD; 48.6 - 168.4 µg/day, 24h-urine MN mg/day; 0.0 - 0.2, 24h-urine NMN; 0.1 - 0.3 mg/day
Glucocorticoids were used in only one case other than our present case (13), but it seemed to have been administered for a disease other than DAH. Conversely, paroxysmal hypertension was observed in most cases. Regarding hormone secretion, both the adrenaline-secreting type and noradrenaline-secreting type were observed. In addition, manifestations other than hemoptysis and dyspnea, such as nausea and vomiting and classic symptoms of pheochromocytoma, including headache, sweating, and pallor, were also observed. However, in emergency care, these were not considered specific symptoms based on which PPGL could be positively suspected.
Although a direct pathophysiological relationship between DAH and PPGL may be difficult to prove, the possible relationship between blood pressure fluctuation and the appearance of alveolar hemorrhage was discussed in these studies (9-13). The rapid increase in pulmonary vein pressure due to paroxysmal hypertension is considered to cause the rupture of capillaries, resulting in alveolar hemorrhage in patients with PPGL. In our case, we concluded that the DAH may not have been due to an autoimmune disease or drugs because of the patient's negative immunology tests and medication history. Considering her pathophysiology, blood pressure fluctuation may have occurred, as hypotension was present at the time of admission despite her having been treated for hypertension. Furthermore, the patient may have had a predisposition to mental stress because of her medical history of coexisting anxiety and frequent hyperventilation. Emotional stress has been reported to enhance catecholamine secretion (14), especially from PPGL (15). The frequent coughing observed until her transportation to our facility may have caused an increase in abdominal pressure, which would induce additional catecholamine secretion by the pheochromocytoma (16). Therefore, it is possible that these manifestations induced and worsened her blood pressure fluctuations, thereby resulting in increased pulmonary venous pressure and the provocation of alveolar hemorrhage.
In addition, in this case, immunosuppressive therapy including methylprednisolone was started because autoimmune diseases as causes of DAH could not be excluded at the initial hospitalization. High doses of glucocorticoids can provoke catecholamine crisis in PPGL (1,3). According to one literature review, in most cases of catecholamine crisis caused by glucocorticoids, the tumor diameters were reported to be ≥30 mm, while the glucocorticoid dosages were equivalent to ≥60 mg/day of hydrocortisone (3). Furthermore, catecholamine crisis does not develop at 1 mg/day of dexamethasone, which is equivalent to 24-30 mg/day of hydrocortisone (3). In our case, the tumor diameter was ≥50 mm, and the dose of prednisolone at the time of the paroxysmal hypertension was 60 mg/day, which was equivalent to hydrocortisone 300 mg/day. This situation may therefore have constituted a risk factor for catecholamine crisis.
Both DAH and PPGL-induced catecholamine crisis are life-threatening conditions, and urgent glucocorticoid treatment may be required during detection of the etiologies of DAH, as in our patient. Thus, PPGL should be considered a background disease of DAH, and detection efforts should be made whenever possible. Because paraganglioma develops from the extra-adrenal paraganglia from the neck to the pelvis (1), whole-body imaging is required, not merely imaging of the abdomen, to confirm the presence or absence of PPGL when DAH is suspected on chest X-ray. Although it should be noted that head and neck paraganglioma normally does not secrete catecholamine (1), when a tumor suspected of PPGL is found, therapeutic agents for catecholamine crisis, such as intravenous alpha- and beta-blockers (4), may be promptly prepared, even if high-dose glucocorticoids have to be used urgently.
In conclusion, we experienced a case of pheochromocytoma after the diagnosis and treatment of DAH. When the possibility of DAH due to autoimmune disease cannot be excluded, high-dose glucocorticoid treatment should be started. However, because high-dose glucocorticoids may induce catecholamine crisis and exacerbate the disease condition, PPGL should be considered as a cause of DAH, and the presence or absence of the tumor should be immediately confirmed by a systemic search with whole-body imaging, including CT.
The authors state that they have no Conflict of Interest (COI). | 62.8 kg. | Weight | CC BY-NC-ND | 33716288 | 19,945,054 | 2021-09-01 |
What was the outcome of reaction 'Catecholamine crisis'? | Pheochromocytoma Diagnosed during the Treatment of Diffuse Alveolar Hemorrhage, a Diagnostic Necessity before Using High-dose Glucocorticoids.
A 46-year-old woman with exacerbating hemoptysis and dyspnea was diagnosed with diffuse alveolar hemorrhage (DAH). High doses of glucocorticoids were initiated, but afterward, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain appeared. A 50-mm left adrenal tumor with an intense uptake by iodine-123 metaiodobenzylguanidine scintigraphy and catecholamine hypersecretion revealed complication with pheochromocytoma. Because high doses of glucocorticoids, sometimes required for DAH, can provoke life-threatening paroxysmal hypertension in pheochromocytoma and paraganglioma (PPGL), our case suggests that PPGL needs to be recognized as the cause of DAH and should be detected with whole-body imaging before starting glucocorticoids.
pmcIntroduction
Pheochromocytoma and paraganglioma (PPGL) are neoplastic diseases derived from chromaffin cells in adrenal medulla and extra-adrenal sympathetic paravertebral gangliasympathetic paravertebral ganglia, respectively (1). PPGL is usually characterized by hypersecretion of catecholamines, including adrenaline and noradrenaline (also known as epinephrine and norepinephrine, respectively) and dopamine (1), which cause various symptoms, such as headaches, palpitations, or anxiety (2). PPGL also causes paroxysmal or refractory hypertension and cardiovascular diseases (1). High-dose glucocorticoids can provoke paroxysmal hypertension in PPGL that can lead to a life-threatening condition called catecholamine crisis (3,4).
Diffuse alveolar hemorrhage (DAH) is a syndrome characterized by the leakage of red blood cells into the alveolar space (5). Clinical features of DAH vary in severity, but it can be life-threatening (5). The causes of DAH are multiple, including autoimmune and nonautoimmune diseases (5), and high-dose glucocorticoids are sometimes used as an immunosuppressive treatment, especially for DAH due to autoimmune diseases (5-7).
We herein report a case of pheochromocytoma that was diagnosed during the treatment of DAH, and paroxysmal hypertension was evoked after starting high-dose glucocorticoids for DAH. There have been reports of simultaneously diagnosed DAH and PPGL, and the hemodynamic effects of PPGL have been considered to be the cause of DAH. Therefore, our case suggests the importance of identifying PPGL as a cause of DAH with whole-body imaging before treatment with high-dose glucocorticoids to avoid the risk of catecholamine crisis.
Case Report
A 46-year-old woman was transported by ambulance with a chief complaint of dyspnea and hemoptysis. She had been treated for cough variant asthma and hypertension with medical histories of frequent hyperventilation attacks and conjunctival bleeding but had no history of surgery for pituitary, adrenal, or parathyroid diseases. Two days before her visit, she experienced sore throat and cough and was diagnosed with upper respiratory tract inflammation at a nearby clinic and treated with antibiotics and symptomatic drugs. On the day of hospitalization, dyspnea and hemoptysis appeared and worsened at midnight, at which point she was brought to our hospital.
The patient was 154.7 cm tall, weighed 62.8 kg, and had a blood pressure of 80/41 mmHg, a pulse rate of 96 beats/min, a body temperature of 36.6℃, a respiratory rate of 40 breaths/min, and pulse oximetry (SpO2) of 91% on room air. Because an electrocardiogram and transthoracic echocardiography revealed no remarkable abnormalities and the N-terminal pro-B-type natriuretic peptide levels were not increasing (67 pg/mL, reference range; <125 pg/mL), heart failure was excluded. Based on the results of chest X-ray and contrast-enhanced computed tomography (CT) (Fig. 1), DAH was diagnosed, and the patient was hospitalized.
Figure 1. Image showing diffuse alveolar hemorrhage (DAH). (A) Chest X-ray and (B) CT scan showing bilateral diffuse infiltrates.
She had been taking 20 mg/day of telmisartan and 15 mg/day of clotiazepam. The antibiotics and symptomatic drugs from a nearby clinic two days before were not the types of medications to induce catecholamine crisis. Considering the potential involvement of autoimmune diseases, immunosuppressive therapy with glucocorticoid (1,000 mg/day of methylprednisolone) and 500 mg/day of cyclophosphamide were initiated. Plasma exchange was also performed until the fifth day of hospitalization. At midnight, after the dosage of glucocorticoids had been reduced to 60 mg/day of prednisolone a day, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain occurred, but the administration of acetaminophen alone ameliorated both symptoms and blood pressure. Whole-body CT showed a left adrenal tumor over 50 mm in size with unenhanced attenuation at 20-60 Hounsfield units (Fig. 2A), suggesting pheochromocytoma. Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and single-photon emission CT (SPECT)-CT were performed, and a strong uptake at the left adrenal tumor was confirmed (Fig. 2B, C).
Figure 2. Image showing a left adrenal tumor. (A) Unenhanced CT scan showing a tumor of >50 mm (white arrowhead) in which the attenuation value was 20–60 Hounsfield units. (B) Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and (C) single-photon emission CT demonstrated an intense uptake in the adrenal tumor (white and black arrowheads).
Because no findings suggestive of immunological abnormalities (Table 1) in blood sampling tests were present and the patient's general condition improved, glucocorticoid treatment was gradually tapered and terminated until discharge due to concerns about catecholamine crisis caused by high-dose glucocorticoids. After DAH was cured, she was discharged on the 14th day of hospitalization and readmitted for a detailed diagnostic examination for pheochromocytoma 1 month later. Laboratory data from the blood and 24-hour urine collection samples showed higher levels of adrenaline, noradrenaline, metanephrine, and normetanephrine, demonstrating catecholamine hypersecretion (Table 2), whereas the plasma renin activity, plasma aldosterone concentration, adrenocorticotrophic hormone, cortisol, dehydroepiandrosterone sulfate, and estradiol were in the normal ranges (Table 2). The midnight cortisol level was 2.25 μg/dL, and the morning cortisol level after taking 1 mg of dexamethasone at midnight was 0.71 μg/dL. These data indicated that there was no complication with primary aldosteronism, Cushing's syndrome, or adrenocortical carcinoma.
Table 1. Immunology Tests.
Immunology tests
Antinuclear antibody Negative Anti-Sm antibody Negative
Anti-CCP antibody Negative Anti-Ro (SS-A) antibody Negative
MPO-ANCA Negative Anti-La (SS-B) antibody Negative
PR3-ANCA Negative Anti-Scl-70 antibody Negative
Anti-GBM antibody Negative Anti-ARS antibody Negative
Anti-RNP antibody Negative
ANA: antinuclear antibody, CCP: cyclic citrullinated peptide, MPO: myeroperoxidase, ANCA: anti-neutrophil cytoplasmic antibody, PR3: proteinase3, GBM: glomerular basement membrane, RNP: ribonucleoprotein, Sm: Smith, Scl-70: scleroderma-70, ARS: aminoacyl tRNA synthetase
Table 2. Endocrinology Tests.
Blood (Before surgery) Reference range
AD (pg/mL) 963 (<100)
NAD (pg/mL) 540 (100 - 450)
DA (pg/mL) 19 (<20)
PRA (ng/mL/hr) 1.1 (0.3 - 2.9)
PAC (pg/mL) 130 (29.9 - 158.8)
ACTH (pg/mL) 11.9 (7.2 - 63.3)
Cortisol (μg/dL) 8.49 (6.2 - 18.0)
DHEAS (µg/dL) 33 (19 - 231)
E2 (pg/mL) 5.8 (25 - 550)
Whole PTH (pg/mL) 34.3 (8.3 - 38.7)
24h-urine collection Before surgery (2 times) After surgery Reference range
AD (μg/day) 481.9 553.8 51.8 (3.4 - 26.9)
NAD (μg/day) 384.0 484.2 111.0 (48.6 - 168.4)
DA (μg/day) 2,126 3,046 746.8 (365.0 - 961.5)
VMA (mg/day) 25.7 27.3 3.5 (1.5 - 4.3)
HVA (mg/day) 6.0 6.3 3.6 (2.1 - 4.3)
MN (mg/day) 9.31 10.01 0.62 (0.0 - 0.2)
NMN (mg/day) 2.50 2.77 0.44 (0.1 - 0.3)
Free cortisol (µg/day) 31.4 33.9 (11.2 - 80.3)
ALD (µg/day) 15 14 (<10.0)
AD: adrenaline, NAD: noradrenaline, DA: dopamine, PRA: plasma renin activity, PAC: plasma aldosterone concentration, ACTH: adrenocorticotrophic hormone, DHEAS: dehydroepiandrosterone sulfate, E2: estradiol, PTH: parathyroid hormone, VMA: vanillylmandelic acid, HVA: homovanillic acid, MN: metanephrine, NMN: normetanephrine, ALD: aldosterone
A contrast-enhanced systemic scan showed no findings suggestive of thyroid, parathyroid, or pancreatic tumors, or other metastatic lesions. Based on these results, the patient was diagnosed with left adrenal pheochromocytoma. Although the patient's blood pressure was controlled with a small amount of doxazosin, sufficient α-blocking was considered important to prevent catecholamine hypersecretion due to intraoperative surgical procedures and postoperative vascular collapse. Therefore, we did not use other anti-hypertensive drugs, including calcium channel blocker, and administered increasing doses of doxazosin during hospitalization, exceeding the maximal dose.
After adjusting the drug dose, laparoscopic adrenalectomy was performed with 32 mg/day of doxazosin and 2.5 mg/day of bisoprolol. No serious adverse events occurred during or after the procedure. The histopathological tissue was a yellowish tumor with a diameter of 70 mm×55 mm. Histopathologically, cytoplasmic tumor cells proliferated in alveolar form via blood vessels, and immunohistologically, the tumor was positive for CD56, synaptophysin, and chromogranin A. The grading system for adrenal pheochromocytoma and paraganglioma (GAPP) score (8) was 2/10 points (positive for cellularity and Ki-67 labeling index), suggesting well-differentiated pheochromocytoma.
The clinical course after surgery is being monitored, and no recurrence or metastasis has been observed. She occasionally complained of sudden dyspnea even after the surgery, but the symptom was mild and resolved spontaneously each time.
Discussion
We herein report a case of pheochromocytoma that was diagnosed through the treatment of DAH. There have been reports describing PPGL diagnosed during DAH treatment (9-13). Table 3 shows an overview of each case, including our present case. The age at the diagnosis ranged from the teens to 60s, and PPGL has been observed in both men and women. At the time of the diagnosis, cases with a high blood pressure as well as a low blood pressure were observed, and many cases seemed to have a rapid heart rate, suggesting that there were large fluctuations in blood pressure. In addition, left adrenal tumors were observed in many cases, but extra-adrenal and bilateral adrenal tumors were also observed. It should be noted that the tumor sizes were ≥50 mm in all 4 cases for which the tumor size were measured, including our own case. Tumors of such sizes can be clearly identified by whole-body imaging.
Table 3. Case Series of PPGL with DAH or Hemoptysis.
Case Reference 9 Reference 10 Reference 11 Reference 12 Reference 13 Our case
Age (years old) 33 40 68 21 14 46
Gender M M M M F F
Blood pressure (mmHg) 150/100 85/59 >180/100 140/80 72/50 80/41
Heart rate (bpm) 160 116 120 90 126 96
Tumor localization Left adrenal Left adrenal Left adrenal Extraadrenal Bilateral adrenal Left adrenal
Tumor size (mm) 80×80×60 NA 46×60 NA Left 40×50×30 70×50
Right 60×40×30
Glucocorticoid use No No No No Yes* Yes
Paroxysmal hypertension Yes Yes Yes NA Yes Yes
Drugs for PPGL NA Phenoxybenzamine Phenoxybenzamine NA Phenoxybenzamine Doxazosin
Methyrosine Propranorol Bisoprorol
24h-urine AD (µg/day) 1,500 180 534 8.0 2.46** 553.8
24h-urine NAD (µg/day) 485 75 1,208.4 1,750 2,254** 484.2
24h-urine MN (mg/day) NA NA 12.3 NA NA 10.01
24h-urine NMN (mg/day) NA NA 5.7 NA NA 2.77
Other manifestations Nausea Nausa Nausea Chest pain Nausea, Vomiting Cough
Vomiting Vomiting Sweating Sweating, Pallor
Headache Headache Pallor Palpitation
Chest pain Chest pain, Cough
PPGL: pheochromocytoma and paraganglioma, DAH: diffuse alveolar hemorrhage, AD: adrenaline, NAD: noradrenaline, MN: metanephrine, NMN: normetanephrine, NA: Data not available. *In case from reference 13, the patient was treated with methylprednisolone under initial diagnosis of pneumonia, septic shock and multiple organ dysfunction syndrome. **In the original article, the unit of concentration of 24h-urine AD and NAD was described in ng/day, but the actual unit was considered to be µg/day from the contents of the manuscript. Therefore they are described in µg/day in Table 3. Reference range, 24h-urine AD; 3.4 - 26.9 µg/day, 24h-urine NAD; 48.6 - 168.4 µg/day, 24h-urine MN mg/day; 0.0 - 0.2, 24h-urine NMN; 0.1 - 0.3 mg/day
Glucocorticoids were used in only one case other than our present case (13), but it seemed to have been administered for a disease other than DAH. Conversely, paroxysmal hypertension was observed in most cases. Regarding hormone secretion, both the adrenaline-secreting type and noradrenaline-secreting type were observed. In addition, manifestations other than hemoptysis and dyspnea, such as nausea and vomiting and classic symptoms of pheochromocytoma, including headache, sweating, and pallor, were also observed. However, in emergency care, these were not considered specific symptoms based on which PPGL could be positively suspected.
Although a direct pathophysiological relationship between DAH and PPGL may be difficult to prove, the possible relationship between blood pressure fluctuation and the appearance of alveolar hemorrhage was discussed in these studies (9-13). The rapid increase in pulmonary vein pressure due to paroxysmal hypertension is considered to cause the rupture of capillaries, resulting in alveolar hemorrhage in patients with PPGL. In our case, we concluded that the DAH may not have been due to an autoimmune disease or drugs because of the patient's negative immunology tests and medication history. Considering her pathophysiology, blood pressure fluctuation may have occurred, as hypotension was present at the time of admission despite her having been treated for hypertension. Furthermore, the patient may have had a predisposition to mental stress because of her medical history of coexisting anxiety and frequent hyperventilation. Emotional stress has been reported to enhance catecholamine secretion (14), especially from PPGL (15). The frequent coughing observed until her transportation to our facility may have caused an increase in abdominal pressure, which would induce additional catecholamine secretion by the pheochromocytoma (16). Therefore, it is possible that these manifestations induced and worsened her blood pressure fluctuations, thereby resulting in increased pulmonary venous pressure and the provocation of alveolar hemorrhage.
In addition, in this case, immunosuppressive therapy including methylprednisolone was started because autoimmune diseases as causes of DAH could not be excluded at the initial hospitalization. High doses of glucocorticoids can provoke catecholamine crisis in PPGL (1,3). According to one literature review, in most cases of catecholamine crisis caused by glucocorticoids, the tumor diameters were reported to be ≥30 mm, while the glucocorticoid dosages were equivalent to ≥60 mg/day of hydrocortisone (3). Furthermore, catecholamine crisis does not develop at 1 mg/day of dexamethasone, which is equivalent to 24-30 mg/day of hydrocortisone (3). In our case, the tumor diameter was ≥50 mm, and the dose of prednisolone at the time of the paroxysmal hypertension was 60 mg/day, which was equivalent to hydrocortisone 300 mg/day. This situation may therefore have constituted a risk factor for catecholamine crisis.
Both DAH and PPGL-induced catecholamine crisis are life-threatening conditions, and urgent glucocorticoid treatment may be required during detection of the etiologies of DAH, as in our patient. Thus, PPGL should be considered a background disease of DAH, and detection efforts should be made whenever possible. Because paraganglioma develops from the extra-adrenal paraganglia from the neck to the pelvis (1), whole-body imaging is required, not merely imaging of the abdomen, to confirm the presence or absence of PPGL when DAH is suspected on chest X-ray. Although it should be noted that head and neck paraganglioma normally does not secrete catecholamine (1), when a tumor suspected of PPGL is found, therapeutic agents for catecholamine crisis, such as intravenous alpha- and beta-blockers (4), may be promptly prepared, even if high-dose glucocorticoids have to be used urgently.
In conclusion, we experienced a case of pheochromocytoma after the diagnosis and treatment of DAH. When the possibility of DAH due to autoimmune disease cannot be excluded, high-dose glucocorticoid treatment should be started. However, because high-dose glucocorticoids may induce catecholamine crisis and exacerbate the disease condition, PPGL should be considered as a cause of DAH, and the presence or absence of the tumor should be immediately confirmed by a systemic search with whole-body imaging, including CT.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33716288 | 19,945,054 | 2021-09-01 |
What was the outcome of reaction 'Hypertension'? | Pheochromocytoma Diagnosed during the Treatment of Diffuse Alveolar Hemorrhage, a Diagnostic Necessity before Using High-dose Glucocorticoids.
A 46-year-old woman with exacerbating hemoptysis and dyspnea was diagnosed with diffuse alveolar hemorrhage (DAH). High doses of glucocorticoids were initiated, but afterward, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain appeared. A 50-mm left adrenal tumor with an intense uptake by iodine-123 metaiodobenzylguanidine scintigraphy and catecholamine hypersecretion revealed complication with pheochromocytoma. Because high doses of glucocorticoids, sometimes required for DAH, can provoke life-threatening paroxysmal hypertension in pheochromocytoma and paraganglioma (PPGL), our case suggests that PPGL needs to be recognized as the cause of DAH and should be detected with whole-body imaging before starting glucocorticoids.
pmcIntroduction
Pheochromocytoma and paraganglioma (PPGL) are neoplastic diseases derived from chromaffin cells in adrenal medulla and extra-adrenal sympathetic paravertebral gangliasympathetic paravertebral ganglia, respectively (1). PPGL is usually characterized by hypersecretion of catecholamines, including adrenaline and noradrenaline (also known as epinephrine and norepinephrine, respectively) and dopamine (1), which cause various symptoms, such as headaches, palpitations, or anxiety (2). PPGL also causes paroxysmal or refractory hypertension and cardiovascular diseases (1). High-dose glucocorticoids can provoke paroxysmal hypertension in PPGL that can lead to a life-threatening condition called catecholamine crisis (3,4).
Diffuse alveolar hemorrhage (DAH) is a syndrome characterized by the leakage of red blood cells into the alveolar space (5). Clinical features of DAH vary in severity, but it can be life-threatening (5). The causes of DAH are multiple, including autoimmune and nonautoimmune diseases (5), and high-dose glucocorticoids are sometimes used as an immunosuppressive treatment, especially for DAH due to autoimmune diseases (5-7).
We herein report a case of pheochromocytoma that was diagnosed during the treatment of DAH, and paroxysmal hypertension was evoked after starting high-dose glucocorticoids for DAH. There have been reports of simultaneously diagnosed DAH and PPGL, and the hemodynamic effects of PPGL have been considered to be the cause of DAH. Therefore, our case suggests the importance of identifying PPGL as a cause of DAH with whole-body imaging before treatment with high-dose glucocorticoids to avoid the risk of catecholamine crisis.
Case Report
A 46-year-old woman was transported by ambulance with a chief complaint of dyspnea and hemoptysis. She had been treated for cough variant asthma and hypertension with medical histories of frequent hyperventilation attacks and conjunctival bleeding but had no history of surgery for pituitary, adrenal, or parathyroid diseases. Two days before her visit, she experienced sore throat and cough and was diagnosed with upper respiratory tract inflammation at a nearby clinic and treated with antibiotics and symptomatic drugs. On the day of hospitalization, dyspnea and hemoptysis appeared and worsened at midnight, at which point she was brought to our hospital.
The patient was 154.7 cm tall, weighed 62.8 kg, and had a blood pressure of 80/41 mmHg, a pulse rate of 96 beats/min, a body temperature of 36.6℃, a respiratory rate of 40 breaths/min, and pulse oximetry (SpO2) of 91% on room air. Because an electrocardiogram and transthoracic echocardiography revealed no remarkable abnormalities and the N-terminal pro-B-type natriuretic peptide levels were not increasing (67 pg/mL, reference range; <125 pg/mL), heart failure was excluded. Based on the results of chest X-ray and contrast-enhanced computed tomography (CT) (Fig. 1), DAH was diagnosed, and the patient was hospitalized.
Figure 1. Image showing diffuse alveolar hemorrhage (DAH). (A) Chest X-ray and (B) CT scan showing bilateral diffuse infiltrates.
She had been taking 20 mg/day of telmisartan and 15 mg/day of clotiazepam. The antibiotics and symptomatic drugs from a nearby clinic two days before were not the types of medications to induce catecholamine crisis. Considering the potential involvement of autoimmune diseases, immunosuppressive therapy with glucocorticoid (1,000 mg/day of methylprednisolone) and 500 mg/day of cyclophosphamide were initiated. Plasma exchange was also performed until the fifth day of hospitalization. At midnight, after the dosage of glucocorticoids had been reduced to 60 mg/day of prednisolone a day, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain occurred, but the administration of acetaminophen alone ameliorated both symptoms and blood pressure. Whole-body CT showed a left adrenal tumor over 50 mm in size with unenhanced attenuation at 20-60 Hounsfield units (Fig. 2A), suggesting pheochromocytoma. Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and single-photon emission CT (SPECT)-CT were performed, and a strong uptake at the left adrenal tumor was confirmed (Fig. 2B, C).
Figure 2. Image showing a left adrenal tumor. (A) Unenhanced CT scan showing a tumor of >50 mm (white arrowhead) in which the attenuation value was 20–60 Hounsfield units. (B) Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and (C) single-photon emission CT demonstrated an intense uptake in the adrenal tumor (white and black arrowheads).
Because no findings suggestive of immunological abnormalities (Table 1) in blood sampling tests were present and the patient's general condition improved, glucocorticoid treatment was gradually tapered and terminated until discharge due to concerns about catecholamine crisis caused by high-dose glucocorticoids. After DAH was cured, she was discharged on the 14th day of hospitalization and readmitted for a detailed diagnostic examination for pheochromocytoma 1 month later. Laboratory data from the blood and 24-hour urine collection samples showed higher levels of adrenaline, noradrenaline, metanephrine, and normetanephrine, demonstrating catecholamine hypersecretion (Table 2), whereas the plasma renin activity, plasma aldosterone concentration, adrenocorticotrophic hormone, cortisol, dehydroepiandrosterone sulfate, and estradiol were in the normal ranges (Table 2). The midnight cortisol level was 2.25 μg/dL, and the morning cortisol level after taking 1 mg of dexamethasone at midnight was 0.71 μg/dL. These data indicated that there was no complication with primary aldosteronism, Cushing's syndrome, or adrenocortical carcinoma.
Table 1. Immunology Tests.
Immunology tests
Antinuclear antibody Negative Anti-Sm antibody Negative
Anti-CCP antibody Negative Anti-Ro (SS-A) antibody Negative
MPO-ANCA Negative Anti-La (SS-B) antibody Negative
PR3-ANCA Negative Anti-Scl-70 antibody Negative
Anti-GBM antibody Negative Anti-ARS antibody Negative
Anti-RNP antibody Negative
ANA: antinuclear antibody, CCP: cyclic citrullinated peptide, MPO: myeroperoxidase, ANCA: anti-neutrophil cytoplasmic antibody, PR3: proteinase3, GBM: glomerular basement membrane, RNP: ribonucleoprotein, Sm: Smith, Scl-70: scleroderma-70, ARS: aminoacyl tRNA synthetase
Table 2. Endocrinology Tests.
Blood (Before surgery) Reference range
AD (pg/mL) 963 (<100)
NAD (pg/mL) 540 (100 - 450)
DA (pg/mL) 19 (<20)
PRA (ng/mL/hr) 1.1 (0.3 - 2.9)
PAC (pg/mL) 130 (29.9 - 158.8)
ACTH (pg/mL) 11.9 (7.2 - 63.3)
Cortisol (μg/dL) 8.49 (6.2 - 18.0)
DHEAS (µg/dL) 33 (19 - 231)
E2 (pg/mL) 5.8 (25 - 550)
Whole PTH (pg/mL) 34.3 (8.3 - 38.7)
24h-urine collection Before surgery (2 times) After surgery Reference range
AD (μg/day) 481.9 553.8 51.8 (3.4 - 26.9)
NAD (μg/day) 384.0 484.2 111.0 (48.6 - 168.4)
DA (μg/day) 2,126 3,046 746.8 (365.0 - 961.5)
VMA (mg/day) 25.7 27.3 3.5 (1.5 - 4.3)
HVA (mg/day) 6.0 6.3 3.6 (2.1 - 4.3)
MN (mg/day) 9.31 10.01 0.62 (0.0 - 0.2)
NMN (mg/day) 2.50 2.77 0.44 (0.1 - 0.3)
Free cortisol (µg/day) 31.4 33.9 (11.2 - 80.3)
ALD (µg/day) 15 14 (<10.0)
AD: adrenaline, NAD: noradrenaline, DA: dopamine, PRA: plasma renin activity, PAC: plasma aldosterone concentration, ACTH: adrenocorticotrophic hormone, DHEAS: dehydroepiandrosterone sulfate, E2: estradiol, PTH: parathyroid hormone, VMA: vanillylmandelic acid, HVA: homovanillic acid, MN: metanephrine, NMN: normetanephrine, ALD: aldosterone
A contrast-enhanced systemic scan showed no findings suggestive of thyroid, parathyroid, or pancreatic tumors, or other metastatic lesions. Based on these results, the patient was diagnosed with left adrenal pheochromocytoma. Although the patient's blood pressure was controlled with a small amount of doxazosin, sufficient α-blocking was considered important to prevent catecholamine hypersecretion due to intraoperative surgical procedures and postoperative vascular collapse. Therefore, we did not use other anti-hypertensive drugs, including calcium channel blocker, and administered increasing doses of doxazosin during hospitalization, exceeding the maximal dose.
After adjusting the drug dose, laparoscopic adrenalectomy was performed with 32 mg/day of doxazosin and 2.5 mg/day of bisoprolol. No serious adverse events occurred during or after the procedure. The histopathological tissue was a yellowish tumor with a diameter of 70 mm×55 mm. Histopathologically, cytoplasmic tumor cells proliferated in alveolar form via blood vessels, and immunohistologically, the tumor was positive for CD56, synaptophysin, and chromogranin A. The grading system for adrenal pheochromocytoma and paraganglioma (GAPP) score (8) was 2/10 points (positive for cellularity and Ki-67 labeling index), suggesting well-differentiated pheochromocytoma.
The clinical course after surgery is being monitored, and no recurrence or metastasis has been observed. She occasionally complained of sudden dyspnea even after the surgery, but the symptom was mild and resolved spontaneously each time.
Discussion
We herein report a case of pheochromocytoma that was diagnosed through the treatment of DAH. There have been reports describing PPGL diagnosed during DAH treatment (9-13). Table 3 shows an overview of each case, including our present case. The age at the diagnosis ranged from the teens to 60s, and PPGL has been observed in both men and women. At the time of the diagnosis, cases with a high blood pressure as well as a low blood pressure were observed, and many cases seemed to have a rapid heart rate, suggesting that there were large fluctuations in blood pressure. In addition, left adrenal tumors were observed in many cases, but extra-adrenal and bilateral adrenal tumors were also observed. It should be noted that the tumor sizes were ≥50 mm in all 4 cases for which the tumor size were measured, including our own case. Tumors of such sizes can be clearly identified by whole-body imaging.
Table 3. Case Series of PPGL with DAH or Hemoptysis.
Case Reference 9 Reference 10 Reference 11 Reference 12 Reference 13 Our case
Age (years old) 33 40 68 21 14 46
Gender M M M M F F
Blood pressure (mmHg) 150/100 85/59 >180/100 140/80 72/50 80/41
Heart rate (bpm) 160 116 120 90 126 96
Tumor localization Left adrenal Left adrenal Left adrenal Extraadrenal Bilateral adrenal Left adrenal
Tumor size (mm) 80×80×60 NA 46×60 NA Left 40×50×30 70×50
Right 60×40×30
Glucocorticoid use No No No No Yes* Yes
Paroxysmal hypertension Yes Yes Yes NA Yes Yes
Drugs for PPGL NA Phenoxybenzamine Phenoxybenzamine NA Phenoxybenzamine Doxazosin
Methyrosine Propranorol Bisoprorol
24h-urine AD (µg/day) 1,500 180 534 8.0 2.46** 553.8
24h-urine NAD (µg/day) 485 75 1,208.4 1,750 2,254** 484.2
24h-urine MN (mg/day) NA NA 12.3 NA NA 10.01
24h-urine NMN (mg/day) NA NA 5.7 NA NA 2.77
Other manifestations Nausea Nausa Nausea Chest pain Nausea, Vomiting Cough
Vomiting Vomiting Sweating Sweating, Pallor
Headache Headache Pallor Palpitation
Chest pain Chest pain, Cough
PPGL: pheochromocytoma and paraganglioma, DAH: diffuse alveolar hemorrhage, AD: adrenaline, NAD: noradrenaline, MN: metanephrine, NMN: normetanephrine, NA: Data not available. *In case from reference 13, the patient was treated with methylprednisolone under initial diagnosis of pneumonia, septic shock and multiple organ dysfunction syndrome. **In the original article, the unit of concentration of 24h-urine AD and NAD was described in ng/day, but the actual unit was considered to be µg/day from the contents of the manuscript. Therefore they are described in µg/day in Table 3. Reference range, 24h-urine AD; 3.4 - 26.9 µg/day, 24h-urine NAD; 48.6 - 168.4 µg/day, 24h-urine MN mg/day; 0.0 - 0.2, 24h-urine NMN; 0.1 - 0.3 mg/day
Glucocorticoids were used in only one case other than our present case (13), but it seemed to have been administered for a disease other than DAH. Conversely, paroxysmal hypertension was observed in most cases. Regarding hormone secretion, both the adrenaline-secreting type and noradrenaline-secreting type were observed. In addition, manifestations other than hemoptysis and dyspnea, such as nausea and vomiting and classic symptoms of pheochromocytoma, including headache, sweating, and pallor, were also observed. However, in emergency care, these were not considered specific symptoms based on which PPGL could be positively suspected.
Although a direct pathophysiological relationship between DAH and PPGL may be difficult to prove, the possible relationship between blood pressure fluctuation and the appearance of alveolar hemorrhage was discussed in these studies (9-13). The rapid increase in pulmonary vein pressure due to paroxysmal hypertension is considered to cause the rupture of capillaries, resulting in alveolar hemorrhage in patients with PPGL. In our case, we concluded that the DAH may not have been due to an autoimmune disease or drugs because of the patient's negative immunology tests and medication history. Considering her pathophysiology, blood pressure fluctuation may have occurred, as hypotension was present at the time of admission despite her having been treated for hypertension. Furthermore, the patient may have had a predisposition to mental stress because of her medical history of coexisting anxiety and frequent hyperventilation. Emotional stress has been reported to enhance catecholamine secretion (14), especially from PPGL (15). The frequent coughing observed until her transportation to our facility may have caused an increase in abdominal pressure, which would induce additional catecholamine secretion by the pheochromocytoma (16). Therefore, it is possible that these manifestations induced and worsened her blood pressure fluctuations, thereby resulting in increased pulmonary venous pressure and the provocation of alveolar hemorrhage.
In addition, in this case, immunosuppressive therapy including methylprednisolone was started because autoimmune diseases as causes of DAH could not be excluded at the initial hospitalization. High doses of glucocorticoids can provoke catecholamine crisis in PPGL (1,3). According to one literature review, in most cases of catecholamine crisis caused by glucocorticoids, the tumor diameters were reported to be ≥30 mm, while the glucocorticoid dosages were equivalent to ≥60 mg/day of hydrocortisone (3). Furthermore, catecholamine crisis does not develop at 1 mg/day of dexamethasone, which is equivalent to 24-30 mg/day of hydrocortisone (3). In our case, the tumor diameter was ≥50 mm, and the dose of prednisolone at the time of the paroxysmal hypertension was 60 mg/day, which was equivalent to hydrocortisone 300 mg/day. This situation may therefore have constituted a risk factor for catecholamine crisis.
Both DAH and PPGL-induced catecholamine crisis are life-threatening conditions, and urgent glucocorticoid treatment may be required during detection of the etiologies of DAH, as in our patient. Thus, PPGL should be considered a background disease of DAH, and detection efforts should be made whenever possible. Because paraganglioma develops from the extra-adrenal paraganglia from the neck to the pelvis (1), whole-body imaging is required, not merely imaging of the abdomen, to confirm the presence or absence of PPGL when DAH is suspected on chest X-ray. Although it should be noted that head and neck paraganglioma normally does not secrete catecholamine (1), when a tumor suspected of PPGL is found, therapeutic agents for catecholamine crisis, such as intravenous alpha- and beta-blockers (4), may be promptly prepared, even if high-dose glucocorticoids have to be used urgently.
In conclusion, we experienced a case of pheochromocytoma after the diagnosis and treatment of DAH. When the possibility of DAH due to autoimmune disease cannot be excluded, high-dose glucocorticoid treatment should be started. However, because high-dose glucocorticoids may induce catecholamine crisis and exacerbate the disease condition, PPGL should be considered as a cause of DAH, and the presence or absence of the tumor should be immediately confirmed by a systemic search with whole-body imaging, including CT.
The authors state that they have no Conflict of Interest (COI). | Recovering | ReactionOutcome | CC BY-NC-ND | 33716288 | 19,913,035 | 2021-09-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Florid Interstitial Hemorrhages: A Novel Feature of Amoxicillin-Clavulanate-Induced Acute Tubulointerstitial Nephritis.
BACKGROUND Acute tubulointerstitial nephritis is most often induced by drug therapy and is characterized by the presence of edema, inflammatory infiltrates, and sometimes granulomas within the interstitium. We report this case to describe florid interstitial hemorrhages as a novel feature of Amoxicillin-Clavulanate-induced acute tubulointerstitial nephritis. CASE REPORT A young man presented with intermittent visible hematuria and acute kidney injury after a course of Amoxicillin-Clavulanate for upper respiratory tract illness. Renal biopsy demonstrated acute tubulointerstitial nephritis with multifocal intense interstitial hemorrhages, intratubular red blood cells, and red blood cell casts. At the same time, he was diagnosed with acute lymphoblastic leukemia. Leukemic cellular infiltration and other potential causes of tubulointerstitial nephritis were ruled out. CONCLUSIONS Drug-induced tubulointerstitial nephritis can be associated with florid interstitial hemorrhages. This can lead to an atypical clinicopathological presentation of tubulointerstitial nephritis, masquerading as glomerulonephritis, vasculitis, or infectious interstitial nephritis.
Background
Over two-thirds of tubulointerstitial nephritis (TIN) cases are drug-induced, most commonly due to non-steroidal anti-inflammatory agents and antibiotics. Beta-lactam antibiotics are among the worst precipitating agents, causing tubulointerstitial nephritis in days to weeks following exposure via cell-mediated immunity [1].
The histopathological hallmark of drug-induced TIN is inter-stitial edema associated with inflammatory cells, within the renal interstitium, whereas the glomeruli and blood vessels are spared [2]. Interstitial infiltrates are mostly composed of lymphocytes, macrophages, eosinophils and plasma cells. Sometimes, interstitial granulomas may be observed. The usual renal presentation is with acute/subacute kidney injury associated with pyuria, white blood cell casts, microscopic hematuria, and low-grade proteinuria [3].
We report this case to describe florid interstitial hemorrhages as a novel feature of Amoxicillin-Clavulanate-induced TIN. This was associated with visible hematuria and red blood cell casts, which are features uncharacteristic of TIN.
Case Report
A 33-year-old Arab male patient was admitted via the emergency department with intermittent painless visible hematuria of 3 weeks’ duration. Three weeks before the onset of hematuria, he had a throat infection for which he took a 2-week course of Amoxicillin-Clavulanate. He denied any previous episodes of hematuria, family history of renal disease, intake of non-steroidal anti-inflammatory agents or any medication other than Amoxicillin-Clavulanate. One week before admission, he had consulted a physician for bilateral flank pain. At that time, laboratory tests revealed a serum creatinine of 106 μmol/L, microscopic hematuria, and pyuria. The coagulation profile was normal. A non-contrast computed tomography scan ruled out nephrolithiasis, pyelonephritis, and urinary tract obstruction.
At the time of admission, the patient was apyrexial. Blood pressure was 127/79 mmHg. There was no evidence of skin rash, arthritis, or facial/peripheral edema. Posterior cervical, supraclavicular, and axillary lymphadenopathy was noted. Lymph nodes were 2-3 cm in size, non-tender, and mobile. The rest of the physical examination was unremarkable. Basic laboratory studies (summarized in Table 1) disclosed severe renal dys-function, with serum creatinine of 466 μmol/L. This was associated with hematuria, pyuria, and low-grade proteinuria, but no bacteriuria or crystaluria. A Doppler ultrasound scan of the kidneys was normal. Renal biopsy was organized to exclude rapidly progressive glomerulonephritis and tubulointerstitial nephritis. A peripheral blood smear demonstrated eosinophilia, monocytosis, and circulating blast cells, prompting urgent bone marrow examination. An immunology workup was negative for antinuclear, anti-glomerular basement membrane, and anti-neutrophil cytoplasmic antibodies. Serum C3 and C4 levels were normal. Serology was negative for HBV, HCV, and HIV, and serum protein electrophoresis did not show any monoclonal bands.
A renal biopsy was performed on day 2 of admission. All salient histopathological findings were limited to the interstitial compartment and tubules. The cortical and medullary interstitium was edematous and infiltrated with a mixture of lymphocytes, plasma cells, and eosinophils (Figure 1). However, the most striking feature was florid multifocal interstitial hemorrhages (Figure 2). Abundant red blood cells in several tubules and red blood cell casts in some tubules were also seen. The glomeruli appeared normal, with patent capillary lumina and normal thickness of the capillary walls. No red blood cells were noted in the Bowman’s spaces. Direct immunofluorescence studies did not show any significant deposition of immunoglobulins (IgG, IgA, and IgM), complement components (C3, C1q), fibrinogen, or kappa/lambda light chains. Small arteries and arterioles were within normal limits. Mild (5-10%) focal tubular atrophy and interstitial fibrosis was seen. Hence, a diagnosis of drug-induced acute TIN was made. Bone marrow aspiration and trephine biopsy was done on day 3 of admission; flow cytometry confirmed the diagnosis of T cell acute lymphoblastic leukemia. The diagnosis of acute lymphoblastic leukemia broadened the differential diagnosis of renal dysfunction, as kidney injury from leukemia or its complications is well recognized. Immunohistochemical staining was carried out by an experienced hematopathologist to detect possible leukemic infiltration; staining was negative for TdT, CD10, CD7, CD99, and CD56. SV40 antibody staining for BK virus was also negative.
The patient was transferred to the Hematology/Oncology Center. Treatment of T cell acute lymphoblastic leukemia was initiated according to the UKALL 14 protocol on day 6 of admission. At that time, serum creatinine was 822 μmol/L, although the patient remained non-oliguric with no significant electrolyte or acid-base disturbances. Dexamethasone was given at a dose of 16 mg/day for 7 days (Steroid-Pre-phase) followed by 3 pulses of Dexamethasone (20 mg/day for 4 days each) combined with Vincristine, Daunorubicin, Pegylated Asparaginase, and Methotrexate as phase 1 of induction chemotherapy. It was felt that the glucocorticoid component of this therapeutic regimen will constitute an effective therapy for TIN as well. Serum creatinine levels started to decrease 3 days after initiation of Dexamethasone, decreasing to 80 μmol/L 8 weeks later (Figure 3). Eosinophilia, hematuria, and proteinuria resolved by 2 weeks, 4 weeks, and 6 weeks, respectively, after initiation of steroid therapy. The patient traveled abroad for stem cell transplantation after receiving the second phase of induction therapy.
Discussion
Initial evaluation of this patient was focused on determining the etiology of the visible hematuria and acute kidney injury. Urinary tract infection, coagulopathies, structural lesions of the urinary tract, and nephrolithiasis had already been excluded by initial laboratory tests and radiological imaging of the urinary tract 1 week earlier.
Glomerular diseases such as IgA nephropathy, crescentic glomerulonephritis, and post-streptococcal glomerulonephritis were considered as a cause of macroscopic hematuria and acute kidney injury. Heavy glomerular hematuria in IgA nephropathy can also induce acute kidney injury through oxidative stress and tubulotoxicity. This possibility was also contemplated. On the other hand, absence of edema, normal blood pressure, eosinophilia, pyuria, and low-grade proteinuria after recent intake of antibiotics also raised the suspicion of drug-induced TIN. Red blood cell casts, once considered a hallmark of glomerular pathology, have also been described in acute TIN, caused by red blood cell entry into tubular lumens where they admix with Tamm-Horsfall glycoprotein [4]. Conversely, macroscopic hematuria is uncommon with the use of modern antibiotics (in contrast to Methicillin-induced TIN, which has long been considered prototypical of drug-induced TIN) [3,5,6]. Renal histopathology not only confirmed TIN but also disclosed a remarkable finding of florid interstitial hemorrhages. Interstitial hemorrhage is usually seen in rather different clinical settings, such as renal infarction, infectious nephritides (eg, Herpes simplex virus, Adenovirus, Hantavirus, Rickettsia), ANCA-related vasculitis, trauma, coagulopathies, and in kidney transplant patients, acute cellular/antibody-mediated rejection. It appears that the interstitial inflammation was severe enough to lead to a significant breach in the integrity of the walls of the interstitial blood vessels and tubular basement membranes. This resulted in generous extravasation of red blood cells from the peri-tubular capillaries into the interstitium, causing widespread interstitial hemorrhages. The hemorrhages then extended into the renal tubules, producing visible hematuria and red blood cell casts [7]. Raised interstitial pressure secondary to the inflammatory process may have facilitated the entry of red blood cells into the tubules through disrupted tubular basement membranes. Interestingly, Ferrari et al described a case of acute interstitial nephritis after Amoxicillin, featuring intratubular red blood cells and red blood cell casts on renal biopsy [8]. By contrast, frank interstitial hemorrhages were not seen. Interstitial hemorrhages have been reported in patients with IgA nephropathy who were concurrently taking oral anticoagulants [9,10]. Direct immunofluorescence studies ruled out IgA nephropathy in our patient. Slightly raised anti-streptolysin O antibodies’ titer probably indicated previous streptococcal infection. However, there was no serological or histo-logical evidence of post-infectious glomerulonephritis: serum complement levels were normal, the glomeruli did not show any proliferative/crescentic change, and immunofluorescence studies precluded immune complex mediated glomerulopathies. Ultrastructural examination of glomeruli was desirable to rule out the possibility of co-existing thin basement membrane disease or Alport syndrome, but electron microscopy is not available at our institution. Nevertheless, the presence of many red blood cells in renal tubules, but not in the Bowman’s spaces, was suggestive of a ‘tubular’ rather than ‘glomerular’ origin of hematuria.
An important consideration in our patient, excluded by immunohistochemical workup, was renal interstitial infiltration by leukemic cells. This has been documented in 83% of autopsy cases of acute lymphoblastic leukemia, although interstitial hemorrhages have not been described [11]. Renal interstitial infiltration by leukemic cells can cause acute kidney injury, either by causing vascular stasis without any structural injury to the nephrons, or by inducing TIN [12–15]. However, in both these situations, immunohistochemical staining is positive for leukemic cells. BK virus infection has been reported to induce hemorrhagic tubulointerstitial nephritis in patients with acute leukemia. This possibility was also excluded by negative SV40 staining.
In summary, antecedent exposure to Amoxicillin-Clavulanate, systemic eosinophilia, abundance of eosinophils and plasma cells in the interstitial infiltrate, and exclusion of other renal pathologies in our patient suggested Amoxicillin-Clavulanate-induced hemorrhagic tubulointerstitial nephritis. The hematuria started within 3 weeks of exposure to Amoxicillin-Clavulanate, which is consistent with the time course of drug-induced TIN. An analysis of more than 150 cases of drug-induced TIN by Rosert et al revealed that renal manifestations developed within 3 weeks of starting the inciting drug in about 80% of patients [6]. The etiology is a delayed hypersensitivity immune reaction driven by antigen-reactive T cells; therefore, the reaction is idiosyncratic, not related to the dose of Amoxicillin-Clavulanate or duration of therapy [3,16,17]. We believe that glucocorticoids given during the steroid-pre-phase and as a part of induction therapy promoted the resolution of interstitial inflammation and recovery of renal function, thereby avoiding the need for dialysis. Glucocorticoids are often employed to treat severe interstitial nephritis that persists despite discontinuation of the inciting agent.
Conclusions
This patient with T cell acute lymphoblastic leukemia had Amoxicillin-Clavulanate-induced TIN featuring extensive interstitial hemorrhages in conjunction with visible hematuria and red blood cell casts. Antibiotic-related TIN should be considered in patients presenting with these features, simulating glomerulonephritis, vasculitis, or infectious interstitial nephritis. The key is to follow an open-minded diagnostic approach, moving from a broader to a narrower differential diagnosis list.
We thank Kinza Asim for her assistance with computer graphics.
Figure 1. Photomicrograph depicting renal biopsy with marked interstitial edema and renal tubules full of red blood cells (stars). Inflammatory cells including lymphocytes and eosinophils (arrows) are seen within the interstitium. Hematoxylin and Eosin stain; original magnification ×400.
Figure 2. Renal tissue with marked interstitial (arrowheads) and intratubular hemorrhages (star). Hematoxylin and Eosin stain; original magnification ×400.
Figure 3. Evolution of serum creatinine during treatment and follow-up (please see text for details).
Table 1. Laboratory investigations at the time of admission.
Test Result Reference
Hemoglobin (gm/dL) 14.2 13–17
White blood cells (×103/μL) 9.6 4–10
Neutrophils (%) 41.5 55–70
Lymphocytes (%) 22.7 20–40
Monocytes (%) 18.2 2–8
Eosinophils (%) 17.2 1–4
Basophil (%) 0.4 0.5–1
Platelets (×103/μL) 253 150–400
Prothrombin time (sec) 11.2 9.7–11.8
Partial thromboplastin time (sec) 27.4 24.6–31.2
INR 1.0 0.9–1.1
BUN (mmol/L) 12.3 3–8
Creatinine (μmol/L) 466 62–106
Sodium (mmol/L) 139 136–145
Potassium (mmol/L) 4.5 3.5–5.1
Bicarbonate (mmol/L) 28 22–29
Chloride (mmol/L) 102 98–107
Calcium (mmol/L) 2.27 2.20–2.55
Phosphate (mmol/L) 1.23 0.81–1.45
Uric acid (μmol/L) 493 202–416
24-hour urine protein (g) 1.1 <0.15
Urine red blood cells (/μL) 1,824 1–9
Urine white blood cells (/μL) 197 1–9
Urine casts RBC, WBC, Granular –
Urine culture Negative
ASO titer (IU/ml) 208 <200
Conflict of Interests
None. | AMOXICILLIN\CLAVULANIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33716294 | 19,154,527 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tubulointerstitial nephritis'. | Florid Interstitial Hemorrhages: A Novel Feature of Amoxicillin-Clavulanate-Induced Acute Tubulointerstitial Nephritis.
BACKGROUND Acute tubulointerstitial nephritis is most often induced by drug therapy and is characterized by the presence of edema, inflammatory infiltrates, and sometimes granulomas within the interstitium. We report this case to describe florid interstitial hemorrhages as a novel feature of Amoxicillin-Clavulanate-induced acute tubulointerstitial nephritis. CASE REPORT A young man presented with intermittent visible hematuria and acute kidney injury after a course of Amoxicillin-Clavulanate for upper respiratory tract illness. Renal biopsy demonstrated acute tubulointerstitial nephritis with multifocal intense interstitial hemorrhages, intratubular red blood cells, and red blood cell casts. At the same time, he was diagnosed with acute lymphoblastic leukemia. Leukemic cellular infiltration and other potential causes of tubulointerstitial nephritis were ruled out. CONCLUSIONS Drug-induced tubulointerstitial nephritis can be associated with florid interstitial hemorrhages. This can lead to an atypical clinicopathological presentation of tubulointerstitial nephritis, masquerading as glomerulonephritis, vasculitis, or infectious interstitial nephritis.
Background
Over two-thirds of tubulointerstitial nephritis (TIN) cases are drug-induced, most commonly due to non-steroidal anti-inflammatory agents and antibiotics. Beta-lactam antibiotics are among the worst precipitating agents, causing tubulointerstitial nephritis in days to weeks following exposure via cell-mediated immunity [1].
The histopathological hallmark of drug-induced TIN is inter-stitial edema associated with inflammatory cells, within the renal interstitium, whereas the glomeruli and blood vessels are spared [2]. Interstitial infiltrates are mostly composed of lymphocytes, macrophages, eosinophils and plasma cells. Sometimes, interstitial granulomas may be observed. The usual renal presentation is with acute/subacute kidney injury associated with pyuria, white blood cell casts, microscopic hematuria, and low-grade proteinuria [3].
We report this case to describe florid interstitial hemorrhages as a novel feature of Amoxicillin-Clavulanate-induced TIN. This was associated with visible hematuria and red blood cell casts, which are features uncharacteristic of TIN.
Case Report
A 33-year-old Arab male patient was admitted via the emergency department with intermittent painless visible hematuria of 3 weeks’ duration. Three weeks before the onset of hematuria, he had a throat infection for which he took a 2-week course of Amoxicillin-Clavulanate. He denied any previous episodes of hematuria, family history of renal disease, intake of non-steroidal anti-inflammatory agents or any medication other than Amoxicillin-Clavulanate. One week before admission, he had consulted a physician for bilateral flank pain. At that time, laboratory tests revealed a serum creatinine of 106 μmol/L, microscopic hematuria, and pyuria. The coagulation profile was normal. A non-contrast computed tomography scan ruled out nephrolithiasis, pyelonephritis, and urinary tract obstruction.
At the time of admission, the patient was apyrexial. Blood pressure was 127/79 mmHg. There was no evidence of skin rash, arthritis, or facial/peripheral edema. Posterior cervical, supraclavicular, and axillary lymphadenopathy was noted. Lymph nodes were 2-3 cm in size, non-tender, and mobile. The rest of the physical examination was unremarkable. Basic laboratory studies (summarized in Table 1) disclosed severe renal dys-function, with serum creatinine of 466 μmol/L. This was associated with hematuria, pyuria, and low-grade proteinuria, but no bacteriuria or crystaluria. A Doppler ultrasound scan of the kidneys was normal. Renal biopsy was organized to exclude rapidly progressive glomerulonephritis and tubulointerstitial nephritis. A peripheral blood smear demonstrated eosinophilia, monocytosis, and circulating blast cells, prompting urgent bone marrow examination. An immunology workup was negative for antinuclear, anti-glomerular basement membrane, and anti-neutrophil cytoplasmic antibodies. Serum C3 and C4 levels were normal. Serology was negative for HBV, HCV, and HIV, and serum protein electrophoresis did not show any monoclonal bands.
A renal biopsy was performed on day 2 of admission. All salient histopathological findings were limited to the interstitial compartment and tubules. The cortical and medullary interstitium was edematous and infiltrated with a mixture of lymphocytes, plasma cells, and eosinophils (Figure 1). However, the most striking feature was florid multifocal interstitial hemorrhages (Figure 2). Abundant red blood cells in several tubules and red blood cell casts in some tubules were also seen. The glomeruli appeared normal, with patent capillary lumina and normal thickness of the capillary walls. No red blood cells were noted in the Bowman’s spaces. Direct immunofluorescence studies did not show any significant deposition of immunoglobulins (IgG, IgA, and IgM), complement components (C3, C1q), fibrinogen, or kappa/lambda light chains. Small arteries and arterioles were within normal limits. Mild (5-10%) focal tubular atrophy and interstitial fibrosis was seen. Hence, a diagnosis of drug-induced acute TIN was made. Bone marrow aspiration and trephine biopsy was done on day 3 of admission; flow cytometry confirmed the diagnosis of T cell acute lymphoblastic leukemia. The diagnosis of acute lymphoblastic leukemia broadened the differential diagnosis of renal dysfunction, as kidney injury from leukemia or its complications is well recognized. Immunohistochemical staining was carried out by an experienced hematopathologist to detect possible leukemic infiltration; staining was negative for TdT, CD10, CD7, CD99, and CD56. SV40 antibody staining for BK virus was also negative.
The patient was transferred to the Hematology/Oncology Center. Treatment of T cell acute lymphoblastic leukemia was initiated according to the UKALL 14 protocol on day 6 of admission. At that time, serum creatinine was 822 μmol/L, although the patient remained non-oliguric with no significant electrolyte or acid-base disturbances. Dexamethasone was given at a dose of 16 mg/day for 7 days (Steroid-Pre-phase) followed by 3 pulses of Dexamethasone (20 mg/day for 4 days each) combined with Vincristine, Daunorubicin, Pegylated Asparaginase, and Methotrexate as phase 1 of induction chemotherapy. It was felt that the glucocorticoid component of this therapeutic regimen will constitute an effective therapy for TIN as well. Serum creatinine levels started to decrease 3 days after initiation of Dexamethasone, decreasing to 80 μmol/L 8 weeks later (Figure 3). Eosinophilia, hematuria, and proteinuria resolved by 2 weeks, 4 weeks, and 6 weeks, respectively, after initiation of steroid therapy. The patient traveled abroad for stem cell transplantation after receiving the second phase of induction therapy.
Discussion
Initial evaluation of this patient was focused on determining the etiology of the visible hematuria and acute kidney injury. Urinary tract infection, coagulopathies, structural lesions of the urinary tract, and nephrolithiasis had already been excluded by initial laboratory tests and radiological imaging of the urinary tract 1 week earlier.
Glomerular diseases such as IgA nephropathy, crescentic glomerulonephritis, and post-streptococcal glomerulonephritis were considered as a cause of macroscopic hematuria and acute kidney injury. Heavy glomerular hematuria in IgA nephropathy can also induce acute kidney injury through oxidative stress and tubulotoxicity. This possibility was also contemplated. On the other hand, absence of edema, normal blood pressure, eosinophilia, pyuria, and low-grade proteinuria after recent intake of antibiotics also raised the suspicion of drug-induced TIN. Red blood cell casts, once considered a hallmark of glomerular pathology, have also been described in acute TIN, caused by red blood cell entry into tubular lumens where they admix with Tamm-Horsfall glycoprotein [4]. Conversely, macroscopic hematuria is uncommon with the use of modern antibiotics (in contrast to Methicillin-induced TIN, which has long been considered prototypical of drug-induced TIN) [3,5,6]. Renal histopathology not only confirmed TIN but also disclosed a remarkable finding of florid interstitial hemorrhages. Interstitial hemorrhage is usually seen in rather different clinical settings, such as renal infarction, infectious nephritides (eg, Herpes simplex virus, Adenovirus, Hantavirus, Rickettsia), ANCA-related vasculitis, trauma, coagulopathies, and in kidney transplant patients, acute cellular/antibody-mediated rejection. It appears that the interstitial inflammation was severe enough to lead to a significant breach in the integrity of the walls of the interstitial blood vessels and tubular basement membranes. This resulted in generous extravasation of red blood cells from the peri-tubular capillaries into the interstitium, causing widespread interstitial hemorrhages. The hemorrhages then extended into the renal tubules, producing visible hematuria and red blood cell casts [7]. Raised interstitial pressure secondary to the inflammatory process may have facilitated the entry of red blood cells into the tubules through disrupted tubular basement membranes. Interestingly, Ferrari et al described a case of acute interstitial nephritis after Amoxicillin, featuring intratubular red blood cells and red blood cell casts on renal biopsy [8]. By contrast, frank interstitial hemorrhages were not seen. Interstitial hemorrhages have been reported in patients with IgA nephropathy who were concurrently taking oral anticoagulants [9,10]. Direct immunofluorescence studies ruled out IgA nephropathy in our patient. Slightly raised anti-streptolysin O antibodies’ titer probably indicated previous streptococcal infection. However, there was no serological or histo-logical evidence of post-infectious glomerulonephritis: serum complement levels were normal, the glomeruli did not show any proliferative/crescentic change, and immunofluorescence studies precluded immune complex mediated glomerulopathies. Ultrastructural examination of glomeruli was desirable to rule out the possibility of co-existing thin basement membrane disease or Alport syndrome, but electron microscopy is not available at our institution. Nevertheless, the presence of many red blood cells in renal tubules, but not in the Bowman’s spaces, was suggestive of a ‘tubular’ rather than ‘glomerular’ origin of hematuria.
An important consideration in our patient, excluded by immunohistochemical workup, was renal interstitial infiltration by leukemic cells. This has been documented in 83% of autopsy cases of acute lymphoblastic leukemia, although interstitial hemorrhages have not been described [11]. Renal interstitial infiltration by leukemic cells can cause acute kidney injury, either by causing vascular stasis without any structural injury to the nephrons, or by inducing TIN [12–15]. However, in both these situations, immunohistochemical staining is positive for leukemic cells. BK virus infection has been reported to induce hemorrhagic tubulointerstitial nephritis in patients with acute leukemia. This possibility was also excluded by negative SV40 staining.
In summary, antecedent exposure to Amoxicillin-Clavulanate, systemic eosinophilia, abundance of eosinophils and plasma cells in the interstitial infiltrate, and exclusion of other renal pathologies in our patient suggested Amoxicillin-Clavulanate-induced hemorrhagic tubulointerstitial nephritis. The hematuria started within 3 weeks of exposure to Amoxicillin-Clavulanate, which is consistent with the time course of drug-induced TIN. An analysis of more than 150 cases of drug-induced TIN by Rosert et al revealed that renal manifestations developed within 3 weeks of starting the inciting drug in about 80% of patients [6]. The etiology is a delayed hypersensitivity immune reaction driven by antigen-reactive T cells; therefore, the reaction is idiosyncratic, not related to the dose of Amoxicillin-Clavulanate or duration of therapy [3,16,17]. We believe that glucocorticoids given during the steroid-pre-phase and as a part of induction therapy promoted the resolution of interstitial inflammation and recovery of renal function, thereby avoiding the need for dialysis. Glucocorticoids are often employed to treat severe interstitial nephritis that persists despite discontinuation of the inciting agent.
Conclusions
This patient with T cell acute lymphoblastic leukemia had Amoxicillin-Clavulanate-induced TIN featuring extensive interstitial hemorrhages in conjunction with visible hematuria and red blood cell casts. Antibiotic-related TIN should be considered in patients presenting with these features, simulating glomerulonephritis, vasculitis, or infectious interstitial nephritis. The key is to follow an open-minded diagnostic approach, moving from a broader to a narrower differential diagnosis list.
We thank Kinza Asim for her assistance with computer graphics.
Figure 1. Photomicrograph depicting renal biopsy with marked interstitial edema and renal tubules full of red blood cells (stars). Inflammatory cells including lymphocytes and eosinophils (arrows) are seen within the interstitium. Hematoxylin and Eosin stain; original magnification ×400.
Figure 2. Renal tissue with marked interstitial (arrowheads) and intratubular hemorrhages (star). Hematoxylin and Eosin stain; original magnification ×400.
Figure 3. Evolution of serum creatinine during treatment and follow-up (please see text for details).
Table 1. Laboratory investigations at the time of admission.
Test Result Reference
Hemoglobin (gm/dL) 14.2 13–17
White blood cells (×103/μL) 9.6 4–10
Neutrophils (%) 41.5 55–70
Lymphocytes (%) 22.7 20–40
Monocytes (%) 18.2 2–8
Eosinophils (%) 17.2 1–4
Basophil (%) 0.4 0.5–1
Platelets (×103/μL) 253 150–400
Prothrombin time (sec) 11.2 9.7–11.8
Partial thromboplastin time (sec) 27.4 24.6–31.2
INR 1.0 0.9–1.1
BUN (mmol/L) 12.3 3–8
Creatinine (μmol/L) 466 62–106
Sodium (mmol/L) 139 136–145
Potassium (mmol/L) 4.5 3.5–5.1
Bicarbonate (mmol/L) 28 22–29
Chloride (mmol/L) 102 98–107
Calcium (mmol/L) 2.27 2.20–2.55
Phosphate (mmol/L) 1.23 0.81–1.45
Uric acid (μmol/L) 493 202–416
24-hour urine protein (g) 1.1 <0.15
Urine red blood cells (/μL) 1,824 1–9
Urine white blood cells (/μL) 197 1–9
Urine casts RBC, WBC, Granular –
Urine culture Negative
ASO titer (IU/ml) 208 <200
Conflict of Interests
None. | AMOXICILLIN\CLAVULANIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33716294 | 19,154,527 | 2021-03-15 |
What was the outcome of reaction 'Tubulointerstitial nephritis'? | Florid Interstitial Hemorrhages: A Novel Feature of Amoxicillin-Clavulanate-Induced Acute Tubulointerstitial Nephritis.
BACKGROUND Acute tubulointerstitial nephritis is most often induced by drug therapy and is characterized by the presence of edema, inflammatory infiltrates, and sometimes granulomas within the interstitium. We report this case to describe florid interstitial hemorrhages as a novel feature of Amoxicillin-Clavulanate-induced acute tubulointerstitial nephritis. CASE REPORT A young man presented with intermittent visible hematuria and acute kidney injury after a course of Amoxicillin-Clavulanate for upper respiratory tract illness. Renal biopsy demonstrated acute tubulointerstitial nephritis with multifocal intense interstitial hemorrhages, intratubular red blood cells, and red blood cell casts. At the same time, he was diagnosed with acute lymphoblastic leukemia. Leukemic cellular infiltration and other potential causes of tubulointerstitial nephritis were ruled out. CONCLUSIONS Drug-induced tubulointerstitial nephritis can be associated with florid interstitial hemorrhages. This can lead to an atypical clinicopathological presentation of tubulointerstitial nephritis, masquerading as glomerulonephritis, vasculitis, or infectious interstitial nephritis.
Background
Over two-thirds of tubulointerstitial nephritis (TIN) cases are drug-induced, most commonly due to non-steroidal anti-inflammatory agents and antibiotics. Beta-lactam antibiotics are among the worst precipitating agents, causing tubulointerstitial nephritis in days to weeks following exposure via cell-mediated immunity [1].
The histopathological hallmark of drug-induced TIN is inter-stitial edema associated with inflammatory cells, within the renal interstitium, whereas the glomeruli and blood vessels are spared [2]. Interstitial infiltrates are mostly composed of lymphocytes, macrophages, eosinophils and plasma cells. Sometimes, interstitial granulomas may be observed. The usual renal presentation is with acute/subacute kidney injury associated with pyuria, white blood cell casts, microscopic hematuria, and low-grade proteinuria [3].
We report this case to describe florid interstitial hemorrhages as a novel feature of Amoxicillin-Clavulanate-induced TIN. This was associated with visible hematuria and red blood cell casts, which are features uncharacteristic of TIN.
Case Report
A 33-year-old Arab male patient was admitted via the emergency department with intermittent painless visible hematuria of 3 weeks’ duration. Three weeks before the onset of hematuria, he had a throat infection for which he took a 2-week course of Amoxicillin-Clavulanate. He denied any previous episodes of hematuria, family history of renal disease, intake of non-steroidal anti-inflammatory agents or any medication other than Amoxicillin-Clavulanate. One week before admission, he had consulted a physician for bilateral flank pain. At that time, laboratory tests revealed a serum creatinine of 106 μmol/L, microscopic hematuria, and pyuria. The coagulation profile was normal. A non-contrast computed tomography scan ruled out nephrolithiasis, pyelonephritis, and urinary tract obstruction.
At the time of admission, the patient was apyrexial. Blood pressure was 127/79 mmHg. There was no evidence of skin rash, arthritis, or facial/peripheral edema. Posterior cervical, supraclavicular, and axillary lymphadenopathy was noted. Lymph nodes were 2-3 cm in size, non-tender, and mobile. The rest of the physical examination was unremarkable. Basic laboratory studies (summarized in Table 1) disclosed severe renal dys-function, with serum creatinine of 466 μmol/L. This was associated with hematuria, pyuria, and low-grade proteinuria, but no bacteriuria or crystaluria. A Doppler ultrasound scan of the kidneys was normal. Renal biopsy was organized to exclude rapidly progressive glomerulonephritis and tubulointerstitial nephritis. A peripheral blood smear demonstrated eosinophilia, monocytosis, and circulating blast cells, prompting urgent bone marrow examination. An immunology workup was negative for antinuclear, anti-glomerular basement membrane, and anti-neutrophil cytoplasmic antibodies. Serum C3 and C4 levels were normal. Serology was negative for HBV, HCV, and HIV, and serum protein electrophoresis did not show any monoclonal bands.
A renal biopsy was performed on day 2 of admission. All salient histopathological findings were limited to the interstitial compartment and tubules. The cortical and medullary interstitium was edematous and infiltrated with a mixture of lymphocytes, plasma cells, and eosinophils (Figure 1). However, the most striking feature was florid multifocal interstitial hemorrhages (Figure 2). Abundant red blood cells in several tubules and red blood cell casts in some tubules were also seen. The glomeruli appeared normal, with patent capillary lumina and normal thickness of the capillary walls. No red blood cells were noted in the Bowman’s spaces. Direct immunofluorescence studies did not show any significant deposition of immunoglobulins (IgG, IgA, and IgM), complement components (C3, C1q), fibrinogen, or kappa/lambda light chains. Small arteries and arterioles were within normal limits. Mild (5-10%) focal tubular atrophy and interstitial fibrosis was seen. Hence, a diagnosis of drug-induced acute TIN was made. Bone marrow aspiration and trephine biopsy was done on day 3 of admission; flow cytometry confirmed the diagnosis of T cell acute lymphoblastic leukemia. The diagnosis of acute lymphoblastic leukemia broadened the differential diagnosis of renal dysfunction, as kidney injury from leukemia or its complications is well recognized. Immunohistochemical staining was carried out by an experienced hematopathologist to detect possible leukemic infiltration; staining was negative for TdT, CD10, CD7, CD99, and CD56. SV40 antibody staining for BK virus was also negative.
The patient was transferred to the Hematology/Oncology Center. Treatment of T cell acute lymphoblastic leukemia was initiated according to the UKALL 14 protocol on day 6 of admission. At that time, serum creatinine was 822 μmol/L, although the patient remained non-oliguric with no significant electrolyte or acid-base disturbances. Dexamethasone was given at a dose of 16 mg/day for 7 days (Steroid-Pre-phase) followed by 3 pulses of Dexamethasone (20 mg/day for 4 days each) combined with Vincristine, Daunorubicin, Pegylated Asparaginase, and Methotrexate as phase 1 of induction chemotherapy. It was felt that the glucocorticoid component of this therapeutic regimen will constitute an effective therapy for TIN as well. Serum creatinine levels started to decrease 3 days after initiation of Dexamethasone, decreasing to 80 μmol/L 8 weeks later (Figure 3). Eosinophilia, hematuria, and proteinuria resolved by 2 weeks, 4 weeks, and 6 weeks, respectively, after initiation of steroid therapy. The patient traveled abroad for stem cell transplantation after receiving the second phase of induction therapy.
Discussion
Initial evaluation of this patient was focused on determining the etiology of the visible hematuria and acute kidney injury. Urinary tract infection, coagulopathies, structural lesions of the urinary tract, and nephrolithiasis had already been excluded by initial laboratory tests and radiological imaging of the urinary tract 1 week earlier.
Glomerular diseases such as IgA nephropathy, crescentic glomerulonephritis, and post-streptococcal glomerulonephritis were considered as a cause of macroscopic hematuria and acute kidney injury. Heavy glomerular hematuria in IgA nephropathy can also induce acute kidney injury through oxidative stress and tubulotoxicity. This possibility was also contemplated. On the other hand, absence of edema, normal blood pressure, eosinophilia, pyuria, and low-grade proteinuria after recent intake of antibiotics also raised the suspicion of drug-induced TIN. Red blood cell casts, once considered a hallmark of glomerular pathology, have also been described in acute TIN, caused by red blood cell entry into tubular lumens where they admix with Tamm-Horsfall glycoprotein [4]. Conversely, macroscopic hematuria is uncommon with the use of modern antibiotics (in contrast to Methicillin-induced TIN, which has long been considered prototypical of drug-induced TIN) [3,5,6]. Renal histopathology not only confirmed TIN but also disclosed a remarkable finding of florid interstitial hemorrhages. Interstitial hemorrhage is usually seen in rather different clinical settings, such as renal infarction, infectious nephritides (eg, Herpes simplex virus, Adenovirus, Hantavirus, Rickettsia), ANCA-related vasculitis, trauma, coagulopathies, and in kidney transplant patients, acute cellular/antibody-mediated rejection. It appears that the interstitial inflammation was severe enough to lead to a significant breach in the integrity of the walls of the interstitial blood vessels and tubular basement membranes. This resulted in generous extravasation of red blood cells from the peri-tubular capillaries into the interstitium, causing widespread interstitial hemorrhages. The hemorrhages then extended into the renal tubules, producing visible hematuria and red blood cell casts [7]. Raised interstitial pressure secondary to the inflammatory process may have facilitated the entry of red blood cells into the tubules through disrupted tubular basement membranes. Interestingly, Ferrari et al described a case of acute interstitial nephritis after Amoxicillin, featuring intratubular red blood cells and red blood cell casts on renal biopsy [8]. By contrast, frank interstitial hemorrhages were not seen. Interstitial hemorrhages have been reported in patients with IgA nephropathy who were concurrently taking oral anticoagulants [9,10]. Direct immunofluorescence studies ruled out IgA nephropathy in our patient. Slightly raised anti-streptolysin O antibodies’ titer probably indicated previous streptococcal infection. However, there was no serological or histo-logical evidence of post-infectious glomerulonephritis: serum complement levels were normal, the glomeruli did not show any proliferative/crescentic change, and immunofluorescence studies precluded immune complex mediated glomerulopathies. Ultrastructural examination of glomeruli was desirable to rule out the possibility of co-existing thin basement membrane disease or Alport syndrome, but electron microscopy is not available at our institution. Nevertheless, the presence of many red blood cells in renal tubules, but not in the Bowman’s spaces, was suggestive of a ‘tubular’ rather than ‘glomerular’ origin of hematuria.
An important consideration in our patient, excluded by immunohistochemical workup, was renal interstitial infiltration by leukemic cells. This has been documented in 83% of autopsy cases of acute lymphoblastic leukemia, although interstitial hemorrhages have not been described [11]. Renal interstitial infiltration by leukemic cells can cause acute kidney injury, either by causing vascular stasis without any structural injury to the nephrons, or by inducing TIN [12–15]. However, in both these situations, immunohistochemical staining is positive for leukemic cells. BK virus infection has been reported to induce hemorrhagic tubulointerstitial nephritis in patients with acute leukemia. This possibility was also excluded by negative SV40 staining.
In summary, antecedent exposure to Amoxicillin-Clavulanate, systemic eosinophilia, abundance of eosinophils and plasma cells in the interstitial infiltrate, and exclusion of other renal pathologies in our patient suggested Amoxicillin-Clavulanate-induced hemorrhagic tubulointerstitial nephritis. The hematuria started within 3 weeks of exposure to Amoxicillin-Clavulanate, which is consistent with the time course of drug-induced TIN. An analysis of more than 150 cases of drug-induced TIN by Rosert et al revealed that renal manifestations developed within 3 weeks of starting the inciting drug in about 80% of patients [6]. The etiology is a delayed hypersensitivity immune reaction driven by antigen-reactive T cells; therefore, the reaction is idiosyncratic, not related to the dose of Amoxicillin-Clavulanate or duration of therapy [3,16,17]. We believe that glucocorticoids given during the steroid-pre-phase and as a part of induction therapy promoted the resolution of interstitial inflammation and recovery of renal function, thereby avoiding the need for dialysis. Glucocorticoids are often employed to treat severe interstitial nephritis that persists despite discontinuation of the inciting agent.
Conclusions
This patient with T cell acute lymphoblastic leukemia had Amoxicillin-Clavulanate-induced TIN featuring extensive interstitial hemorrhages in conjunction with visible hematuria and red blood cell casts. Antibiotic-related TIN should be considered in patients presenting with these features, simulating glomerulonephritis, vasculitis, or infectious interstitial nephritis. The key is to follow an open-minded diagnostic approach, moving from a broader to a narrower differential diagnosis list.
We thank Kinza Asim for her assistance with computer graphics.
Figure 1. Photomicrograph depicting renal biopsy with marked interstitial edema and renal tubules full of red blood cells (stars). Inflammatory cells including lymphocytes and eosinophils (arrows) are seen within the interstitium. Hematoxylin and Eosin stain; original magnification ×400.
Figure 2. Renal tissue with marked interstitial (arrowheads) and intratubular hemorrhages (star). Hematoxylin and Eosin stain; original magnification ×400.
Figure 3. Evolution of serum creatinine during treatment and follow-up (please see text for details).
Table 1. Laboratory investigations at the time of admission.
Test Result Reference
Hemoglobin (gm/dL) 14.2 13–17
White blood cells (×103/μL) 9.6 4–10
Neutrophils (%) 41.5 55–70
Lymphocytes (%) 22.7 20–40
Monocytes (%) 18.2 2–8
Eosinophils (%) 17.2 1–4
Basophil (%) 0.4 0.5–1
Platelets (×103/μL) 253 150–400
Prothrombin time (sec) 11.2 9.7–11.8
Partial thromboplastin time (sec) 27.4 24.6–31.2
INR 1.0 0.9–1.1
BUN (mmol/L) 12.3 3–8
Creatinine (μmol/L) 466 62–106
Sodium (mmol/L) 139 136–145
Potassium (mmol/L) 4.5 3.5–5.1
Bicarbonate (mmol/L) 28 22–29
Chloride (mmol/L) 102 98–107
Calcium (mmol/L) 2.27 2.20–2.55
Phosphate (mmol/L) 1.23 0.81–1.45
Uric acid (μmol/L) 493 202–416
24-hour urine protein (g) 1.1 <0.15
Urine red blood cells (/μL) 1,824 1–9
Urine white blood cells (/μL) 197 1–9
Urine casts RBC, WBC, Granular –
Urine culture Negative
ASO titer (IU/ml) 208 <200
Conflict of Interests
None. | Recovering | ReactionOutcome | CC BY-NC-ND | 33716294 | 19,154,527 | 2021-03-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Management of Primary Plasma Cell Leukemia Remains Challenging Even in the Era of Novel Agents.
Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.
Introduction
Primary plasma cell leukemia (PCL) is a rare and aggressive form of multiple myeloma (MM). The PCL accounts for 0.5% to 2% of MM cases with annual incidence ranging between 0.4 and 1.2 cases per million individuals per year.1,2 Although the definition of PCL is still evolving, a circulating plasma cell count that exceeds 20% of peripheral blood leukocytes, or an absolute plasma cell count >2000/mm3, has been the arbitrary but traditional definition of PCL.3 Multiple myeloma (MM) patients exhibiting circulating plasma cell levels as low as 2%, counted morphologically at the time of diagnosis, demonstrated poor survival, similar to that seen in PCL patients.4 Granell et al5 in another analysis of 482 newly diagnosed MM patients, demonstrated that the presence of ⩾5% circulating plasma cells counted in the peripheral blood has a similar adverse prognostic impact as that of PCL. As also reported, extremely low levels (~0.26%) of circulating clonal plasma cells (CPC) in MM patients, as detected by immunophenotyping (flow cytometry) at the time of diagnosis and treated with novel agents, was also associated with inferior overall survival (OS).6 For example, the 3-year OS for the MM patients with presence of CPC was 67% compared with 87% for those with no CPC.6 Currently, the optimal diagnostic threshold of CPC levels necessary to define PCL is being debated by multiple myeloma experts worldwide.
Primary PCL is rare and arises de novo, but secondary PCL occurs via clonal evolution from a pre-existing MM. This is typically observed following several lines of therapy and often as a terminal event as part of aggressive relapsed of multiple myeloma. Therefore, for the purpose of this report, “PCL” will refer to primary PCL only.
A brief comparison of the clinical features of PCL and MM is presented in Table 1. Compared to MM, PCL is more aggressive at presentation, patients more often than not present with bone marrow insufficiency (in the form of anemia, or thrombocytopenia,) and end organ damage (in the form of hypercalcemia or renal dysfunction) and multi-organ dysfunction. The clinical course is much more aggressive and outcome is associated with poorer prognosis despite treatment in PCL when compared to MM.5 Additionally, higher LDH and B2-microglobulin levels are often observed in PCL, indicating significantly higher disease burden and proliferation rate at the time of presentation. The higher propensity for extra-medullary involvement at diagnosis, in addition to a larger incidence of high-risk cytogenetics (eg, 17p deletion/TP53 mutation and t[14;16]) also reflects the biologically much more aggressive nature of PCL compared to MM.7,8
Table 1. Clinical features of primary plasma cell leukemia (PCL) compared to multiple myeloma.
Clinical features Multiple myeloma Plasma cell leukemia
Incidence 52 to 75 cases per million individuals per year1,2 0.4 to 1.2 cases per million individuals per year or 0.5% to 2% of all MM cases1,2
Age of onset (years) Older (median age, 65-74)23 Relatively younger (median age 55)1-3
Most common subtype IgG (46%) followed by IgA IgG (58%) followed by light chain only
Bone marrow failure (anemia, thrombocytopenia) Less common More common
Hypercalcemia Less common More common
B2-microglobulin + +++
LDH + +++
Renal dysfunction + +++
Tumor lysis syndrome Less common More common
Extra-medullary involvement (liver, spleen, other organs) at diagnosis Less common More common
Deletion 17p/TP53 mutation Less common (~10%) More common (~50%)12
t (11;14) Less common (10%-31%)24 More common 30%12 to 50%14
Prognosis (median overall survival) Better (median OS = 5.2 years with median follow up 5.9 years)25 Worse [median OS 28% at 4 years (range 22%-35%)]10
Abbreviations: LDH, lactate dehydrogenase; MM, multiple myeloma; OS, overall survival; PFS, progression free survival.
In this review, we present a patient with primary PCL who exhibited complete response to induction therapy with lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE), but relapsed quickly after autologous peripheral blood hematopoietic stem cell transplantation (HSCT). A second remission was not inducible with salvage therapy containing carfilzomib, pomalidomide, and dexamethasone, and the patient subsequently died from progression of PCL.
Case Presentation
A 62-year-old male with a history of bladder cancer status post transurethral resection of the bladder tumor 5 years prior, was seen in the emergency room for progressively worsening low back pain for 6 weeks prior to his presentation. His past medical history was complicated and included: anxiety/depression, Type II diabetes, hypertension, coronary artery disease, hypercholesterolemia, morbid obesity, obstructive sleep apnea, and cigaratte smoking(active smoker with 20-pack year history). In the emergency room, patient’s vital signs were normal and laboratory studies showed WBC 10 500/mm3, hemoglobin 13.7 gm/dL, platelets 66 000/mm3, absolute neutrophil count 4400/mm3, absolute lymphocyte count, 4200/mm3, and 13% blasts. The patient’s creatinine, uric acid, bilirubin, calcium, total protein, and serum albumin levels were normal. The LDH was elevated to 958 IU/L (normal range 135-225). A peripheral blood smear showed frequent (53%) atypical plasmacytoid cells (Figure 1A) and the flow cytometry of peripheral blood confirmed 50% monotypic lambda restricted clonal plasma cells consistent with PCL. The Serum protein electrophoresis with immunofixation revealed IgG lambda monoclonal gammopathy, with M spike 0.52 gm/dL, serum free kappa light chain level 4.3 mg/L (range 3.3-19.4), serum free lambda light chain level was 2695 mg/L (range 5.7-26.3), with lambda to kappa ratio of ~627. The Beta-2-microglobulin level was 4.5 mg/L (range 0.3-1.9), and levels of IgG, IgA, and IgM levels were 775, 31, and 13 mg/dL respectively. A lumbar spine magnetic resonance imaging (MRI) showed no vertebral fractures, cord compression, or cauda equina lesions but did report widespread T1 hypointensity, and heterogeneous areas of T2/inversion recovery hyperintensity, consistent with possible leukemic infiltration of the bone marrow. A bone marrow aspiration/biopsy demonstrated plasma cell neoplasm with plasmablastic features replacing the bone marrow cellularity. The MM fluorescent in situ hybridization (FISH) was positive for 17p (TP53) deletion, along with presence of additional copies of chromosomes 5, 9, and 15. Final clinical diagnosis of primary PCL, with 17P deletion, was made. The Positron Emission Tomography (PET) scan (Figure 2A) revealed numerous, intensely fluorodeoxyglucose (FDG) avid, bone marrow lesions throughout the skeleton. A core needle biopsy of right 8th rib lesion (Figure 2A arrow) confirmed the presence of plasmablastic malignancy.
Figure 1. Peripheral blood smear at the time of diagnosis (A) and at the time of relapse (B). Peripheral blood smear, Wright-Giemsa stain, 10× shows circulating large neoplastic plasma cells and thrombocytopenia (A). Peripheral blood smear, Wright-Giemsa stain, 40× shows that the neoplastic plasma cells have blastoid features (B).
Figure 2. Attenuation corrected 3-D maximum intensity projections (MIP) positron emission tomography (PET) images of fluorine 18 FDG PET-CT scan: (A) baseline study, demonstrating numerous bone marrow tracer avid lesions involving cervical, thoracic and lumbar spine as well as bilateral ribs, scapula, humeri, pelvis, sacrum, and bilateral femurs. Maximum standard uptake value (SUVmax) in the sacrum = 27 and (B) follow up post-treatment study demonstrating resolution of previously noted tracer avid lesions. Moderate intensity heterogeneous tracer uptake throughout the bone marrow felt to be related to granulocyte colony stimulation factor therapy effect.
Immediate initialization of induction chemotherapy using a combination regimen with bortezomib, dexamethasone, lenalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE) achieved stringent complete response (sCR) as defined by previously published criteria9 after 3 cycles. The patient received additional 2 cycles of bortezomib, dexamethasone, and lenalidomide (RVD) while waiting for HSCT. To prevent skeletal-related events, he also received zoledronic acid. He underwent HSCT conditioning, with melphalan (200 mg/m2 (MEL 200)), with engraftment on day +11.
The post-HSCT course was complicated with profound physical deconditioning and prolonged hospitalization. The patient developed generalized bone pain and a repeat bone marrow biopsy was performed on day +90 post-HSCT, which reveled 40% blastoid monoclonal plasma cells with plasmablastic features consistent with relapsed PCL.
The patient started salvage chemotherapy using carfilzomib, pomalidomide, and dexamethasone (KPD) to treat relapsed PCL with palliative intention as the patient was not felt to be a candidate for second HSCT or allogeneic HSCT. Cycle 1 of KPD therapy was complicated by acute hypoxemic respiratory failure due to bilateral pneumonia, and severe thrombocytopenia. A Flow cytometry of peripheral blood detected a small plasma cell clone and the peripheral blood smear showed blastoid neoplastic plasma cells confirming the relapsed of the PCL. Later, pomalidomide was discontinued due to intolerance (profound fatigue and cytopenia). He resumed carfilzomib at an increased dose 56 mg/m2, weekly, with dexamethasone. Progressive PCL was noted in the next several weeks and the patient became transfusion-dependent for red blood cells and platelets. Subsequently, the patient performance status deteriorated. Anti-CD 38 monoclonal antibody immunotherapy with daratumumab was offered but the patient elected for hospice, at-home, and died peacefully 14 months after the initial diagnosis.
Discussion
Even with employing the novel agents available for treatment of clonal plasma cell neoplasms in combination regimen, the treatment of PCL remains challenging. A prompt diagnosis and early stabilization of metabolic challenges, tumor lysis syndrome (TLS), hypercalcemia, acute renal failure and immediate use of multi-agent induction therapy containing novel agents can reduce the risk of early morbidity and may help prolong survival. There is a high response rate with induction therapies containing bortezomib, lenalidomide or thalidomide. Cytotoxic chemotherapies can also be combined with novel agents, which may not be routinely available on the formulary of many USA hospitals as most myeloma care is delivered on the outpatient basis. Rapid and complete responses are often observed after multi-agent induction therapy containing novel agents, but early relapse is common in PCL. For a durable remission, the induction therapy containing proteasome inhibitor (PI) should follow immediately with consolidation therapy, often with HSCT for eligible candidates. In HSCT-ineligible patients, the optimal strategy is unknown but a several cycles of remission induction therapy, followed by long term multi-agent maintenance therapy containing PI and an immunomodulatory agent (IMiD) may provide durable remission. A recently published multicenter retrospective analysis of 348 patients with PCL by Dhakal et al10 concluded that despite incorporation of modern induction therapy containing novel agents and despite increased utilization of both autologous and allogeneic HSCT in the last several years, the survival of PCL patients has not improved in comparison to the historical cohort of PCL patients prior to the widespread use of novel agents. The study underscored that the main reason for the lack of improvement in the survival despite utilization of modern therapies is due to the high relapse rate after HSCT (~76% relapsed at 4 years post-HSCT).10 Allogeneic HSCT is only suitable for a minority of PCL patients as shown in a few small studies10 demonstrating initial good response, a small PFS benefit of 19% at 4 years and overall survival (OS) of only 31% at 4 years. Small studies of tandem double autologous or tandem autologous/allogeneic HSCT showed limited benefit as well.11,12 For autologous or allogeneic HSCT, relapse was the main cause of death in approximately 80% of patients after HSCT. Allogeneic HSCT may have a role for treatment of younger and fit patients, ideally in the context of a clinical trial. For example , Currently an ongoing clinical trial in Europe (EudraCT Number: 2016-003105-33) incorporates a potent second generation irreversible PI, carfilzomib and lenalidomide during remission induction, consolidation, and maintenance phase of therapy and offers allogeneic HSCT to younger, fit, and responding patients.13
The median overall survival of PCL patients, before the use of novel agents, was historically measured in only a few months.14 However, with the incorporation of novel agents (bortezomib, lenalidomide or thalidomide) and autologous HSCT, survival has been reported to improve to 12 months.15 While this represents favorable progress for this patient group, more improvement is necessary to improve outcomes in the treatment of PCL. There is signal showing that further improvement can be achieved with post-HSCT maintenance therapy with novel agents. This was demonstrated by Mina et al16 in their retrospective analysis of 38 patients with PCL treated with bortezomib plus either thalidomide or lenalidomide as induction therapy followed by HSCT and maintenance therapy with bortezomib and lenalidomide for 3 years in majority of the cohort. The median PFS was 20 months, and the median OS was 33 months with PFS better for those who received HSCT (25 vs 6 months). Most important finding was that the patients who received maintenance therapy after HSCT had prolonged median PFS (27 vs 11 months) and a trend toward prolonged OS (median, 38 vs 22 months) compared with those who did not receive maintenance therapy.16
Over half of patients with PCL harbor highly adverse prognostic factor of 17p deletion.17 Bortezomib and other proteasome inhibitors (carfilzomib, ixazomib) are postulated to help overcome the adverse prognostic impact of poor cytogenetics in MM, especially in 17p deletion/TP53 mutation and cytogenetic aberrations involving chromosome 14 in high risk MM.18 Due to this observation and the retrospective data in high risk MM, PI appears to be an important therapeutic tool to be used in the treatment of PCL. To conduct a well-funded randomized phase III study is challenging due to multiple logistic factors and relatively rare nature of PCL. Therefore, randomized phase III studies in PCL are lacking. A phase II study evaluated the effectiveness of bortezomib and chemotherapy (doxorubicin or cyclosphosphamide), followed by HSCT, and 1 year of maintenance therapy with RVD. The results thereof indicated a good response rate (the overall response rate to induction therapy was 69%) and improved median survival to 3 years.19 In another report Nooka et al20 reported encouraging results of RVD maintenance with 51% of patients achieving stringent complete response (sCR) and 96% achieving VGPR or better and median PFS of 32 months and a 3-year OS of 93%. These studies support induction therapy with regimen containing novel agents followed by early HSCT for consolidation and post-HSCT maintenance therapy with RVD for the best results. Only 27% of post-autologous HSCT and only 12% of post allo-HCT PCL patients had received maintenance therapy in the study by Dhakal et al10 which may have contributed to the high relapse rate in the HSCT survivors in their cohort.
In summary, patients who are fit enough to undergo HSCT, and who receive PI containing multi-agent maintenance therapy after HSCT, tend to exhibit improved survival compared to patients who did not undergo HSCT and did not receive maintenance therapy. The standard low dose lenalidomide maintenance monotherapy (10-15 mg daily), prescribed after HSCT in MM, appears to be inadequate in PCL due to reported 50% relapse rate within first year.21 The maintenance strategy with combination therapy of RVD appears to be more effective and is tolerated by majority of patients after HSCT in PCL.21,22 Three factors affecting survival outcomes in PCL appear to be (1) incorporating novel agents with PI and IMiD in the induction therapy, (2) consolidation with HSCT in fit stronger and younger patients, and (3) maintenance therapy containing multiple novel agents (bortezomib and lenalidomide). Patients who are able to tolerate these therapies tend to have the best possible outcomes but relapses still do occur including at unusual sites for example, meningeal relapses after both allogeneic and autologous HSCT.19
The timing and sequencing of newer generation proteasome inhibitors, carfilzomib and ixazomib, is still evolving in PCL and there are no published studies as of the writing of this review. Ixazomib, as an oral agent, may be suitable as a combination therapy with an IMiD, such as lenalidomide or pomalidomide, particularly for maintenance therapy. Both ixazomib and pomalidomide are effective agents against relapsed myeloma, but no study has been conducted to prospectively examine the efficacy of either in PCL. However, a phase II study of pomalidomide, ixazomib, and dexamethasone, in treating patients with previously treated MM or secondary PCL, is currently ongoing and will help answer questions surrounding the effectiveness of these biologic agents for patients with relapsed myeloma and secondary PCL (ClinicalTrials.gov Identifier: NCT02547662). Additionally, a phase I study of filanesib and carfilzomib in treating patients with relapsed or refractory MM, or secondary PCL, was completed and the final results of which are pending (ClinicalTrials.gov Identifier: NCT01372540). The results of a clinical study of carfilzomib, pomalidomide, and dexamethasone (KPD) for relapsed or refractory myeloma indicate that the regimen is a well-tolerated and highly active combination for patients with relapsed/refractory multiple myeloma22 and there is evolving preliminary safety and efficacy data from an ongoing phase II non-randomized clinical trial that examined carfilzomib, lenalidomide and dexamethasone (KRD) for first line treatment of PCL.23 In this study patients eligible for HSCT underwent 4 cycles of KRd induction followed by HSCT, KRd consolidation, and then maintenance with KD until progression. Patients not eligible for HSCT received KRd followed by KD maintenance. The final results are not published yet but preliminary results are encouraging with high response rate and acceptable safety (⩾VGPR in 80% and ⩾CR in 33%).23 The patient in this report received KPD therapy at the time of relapse, with less than partial response (Figure 3) attesting to the much more aggressive biology of relapsed PCL.
Figure 3. The levels of serum free lambda light chain (LLC), lactate dehydrogenase (LDH) and beta 2 microglobulin at the time of diagnosis, relapse, and disease progression.
RVD-PACE = lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; HSCT = hematopoietic stem cell transplantation; KPD = carfilzomib, pomalidomide, and dexamethasone; LDH = lactate dehydrogenase.
Daratumumab and isatuximab are highly effective anti-CD38 monoclonal antibodies approved for MM in combination with novel agents.24-27 Studies are needed to understand how and when to incorporate this highly active novel immunotherapy for treatment of PCL. Unfortunately, a phase I study of daratumumab, in combination with bortezomib, dexamethasone, pegylated liposomal doxorubicin hydrochloride, and lenalidomide in treating patients with PCL has been withdrawn citing budgetary constraints (ClinicalTrials.gov Identifier: NCT03591744). Similarly, antibody drug conjugates, bi-specific antibodies and CAR-T therapy may have a future for the treatment of PCL, but initial trials usually exclude PCL from the inclusion criteria (ClinicalTrials.gov Identifier: NCT03815383).
Venetoclax is an attractive molecule for patients with PCL given its good tolerability as an oral inhibitor of BCL-2 and the high prevalence (30-50%) of the t(11;14) in PCL population.17,18 When venetoclax was evaluated in a phase 1 study in relapsed/refractory MM, 86% of responders had the t(11;14) with overall response rate of 40%, with 27% of patients achieving very good partial response (VGPR) or better in this heavily pretreated population.28 Future studies of PCL should examine venetocalx either as single agent or in combination with novel agents, cellular therapies or immunotherapies.
Finally, due to the high frequency of extra-medullary involvement, international myeloma working group (IMWG) has recommended that PET scan be included in the diagnosis and monitoring of PCL.29
Conclusion
Primary plasma cell leukemia (PCL) is a rare and aggressive hematologic malignancy. Response to induction therapy, with a combination of novel agents (PI and IMiD) with or without cytotoxic chemotherapy, is common but durability of such response is brief unless consolidated with HSCT followed by maintenance therapy. A single agent lenalidomide, as maintenance therapy after HSCT, is inadequate due to high relapse rate. Therefore, it is recommended to incorporate both lenalidomide and bortezomib, in combination with dexamethasone (RVD), for maintenance in PCL when tolerated. For HSCT-ineligible patients, efficacious treatment remains a challenge and we recommend treating with multiple cycles of therapies containing lenalidomide and bortezomib or participation in a clinical trial when available. Employing immunotherapy with monoclonal antibodies, antibody drug conjugates, bi-specific antibodies and engineered cellular therapy such as CAR-T cell therapy, are all attractive concepts that require investigations in future in treatment of PCL. Incorporating newer generation proteasome inhibitors (carfilzomib, ixazomib) and immunomodulatory agent such as pomalidomide may further improve the outcomes. Venetoclax may also play an important role in future for the treatment of PCL harboring t(11;14) mutation. Prospective multicenter studies are required to further understand the definitions, pathogenesis, treatment and prognosis of PCL. Employing novel imaging technique such as PET scan when done at diagnosis and follow up may provide valuable insight in to the status of the disease outside of the bone marrow.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Informed Consent: Informed patient consent was not possible due to the death of the patient. Patient’s surviving spouse provided the verbal informed consent to publish the case report on 7/15/2020. This was documented in patient’s chart in the electronic medical record system of Cleveland Clinic per Cleveland Clinic IRB guidance.
Ethics Approval: Ethics approval is not required for case report because such report does not constitute a research per Cleveland Clinic Institutional Review Board (IRB).
ORCID iDs: Chakra P Chaulagain https://orcid.org/0000-0002-4641-2217
Faiz Anwer https://orcid.org/0000-0001-6914-7439 | CARFILZOMIB, DEXAMETHASONE | DrugsGivenReaction | CC BY-NC | 33716516 | 19,971,940 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug intolerance'. | Management of Primary Plasma Cell Leukemia Remains Challenging Even in the Era of Novel Agents.
Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.
Introduction
Primary plasma cell leukemia (PCL) is a rare and aggressive form of multiple myeloma (MM). The PCL accounts for 0.5% to 2% of MM cases with annual incidence ranging between 0.4 and 1.2 cases per million individuals per year.1,2 Although the definition of PCL is still evolving, a circulating plasma cell count that exceeds 20% of peripheral blood leukocytes, or an absolute plasma cell count >2000/mm3, has been the arbitrary but traditional definition of PCL.3 Multiple myeloma (MM) patients exhibiting circulating plasma cell levels as low as 2%, counted morphologically at the time of diagnosis, demonstrated poor survival, similar to that seen in PCL patients.4 Granell et al5 in another analysis of 482 newly diagnosed MM patients, demonstrated that the presence of ⩾5% circulating plasma cells counted in the peripheral blood has a similar adverse prognostic impact as that of PCL. As also reported, extremely low levels (~0.26%) of circulating clonal plasma cells (CPC) in MM patients, as detected by immunophenotyping (flow cytometry) at the time of diagnosis and treated with novel agents, was also associated with inferior overall survival (OS).6 For example, the 3-year OS for the MM patients with presence of CPC was 67% compared with 87% for those with no CPC.6 Currently, the optimal diagnostic threshold of CPC levels necessary to define PCL is being debated by multiple myeloma experts worldwide.
Primary PCL is rare and arises de novo, but secondary PCL occurs via clonal evolution from a pre-existing MM. This is typically observed following several lines of therapy and often as a terminal event as part of aggressive relapsed of multiple myeloma. Therefore, for the purpose of this report, “PCL” will refer to primary PCL only.
A brief comparison of the clinical features of PCL and MM is presented in Table 1. Compared to MM, PCL is more aggressive at presentation, patients more often than not present with bone marrow insufficiency (in the form of anemia, or thrombocytopenia,) and end organ damage (in the form of hypercalcemia or renal dysfunction) and multi-organ dysfunction. The clinical course is much more aggressive and outcome is associated with poorer prognosis despite treatment in PCL when compared to MM.5 Additionally, higher LDH and B2-microglobulin levels are often observed in PCL, indicating significantly higher disease burden and proliferation rate at the time of presentation. The higher propensity for extra-medullary involvement at diagnosis, in addition to a larger incidence of high-risk cytogenetics (eg, 17p deletion/TP53 mutation and t[14;16]) also reflects the biologically much more aggressive nature of PCL compared to MM.7,8
Table 1. Clinical features of primary plasma cell leukemia (PCL) compared to multiple myeloma.
Clinical features Multiple myeloma Plasma cell leukemia
Incidence 52 to 75 cases per million individuals per year1,2 0.4 to 1.2 cases per million individuals per year or 0.5% to 2% of all MM cases1,2
Age of onset (years) Older (median age, 65-74)23 Relatively younger (median age 55)1-3
Most common subtype IgG (46%) followed by IgA IgG (58%) followed by light chain only
Bone marrow failure (anemia, thrombocytopenia) Less common More common
Hypercalcemia Less common More common
B2-microglobulin + +++
LDH + +++
Renal dysfunction + +++
Tumor lysis syndrome Less common More common
Extra-medullary involvement (liver, spleen, other organs) at diagnosis Less common More common
Deletion 17p/TP53 mutation Less common (~10%) More common (~50%)12
t (11;14) Less common (10%-31%)24 More common 30%12 to 50%14
Prognosis (median overall survival) Better (median OS = 5.2 years with median follow up 5.9 years)25 Worse [median OS 28% at 4 years (range 22%-35%)]10
Abbreviations: LDH, lactate dehydrogenase; MM, multiple myeloma; OS, overall survival; PFS, progression free survival.
In this review, we present a patient with primary PCL who exhibited complete response to induction therapy with lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE), but relapsed quickly after autologous peripheral blood hematopoietic stem cell transplantation (HSCT). A second remission was not inducible with salvage therapy containing carfilzomib, pomalidomide, and dexamethasone, and the patient subsequently died from progression of PCL.
Case Presentation
A 62-year-old male with a history of bladder cancer status post transurethral resection of the bladder tumor 5 years prior, was seen in the emergency room for progressively worsening low back pain for 6 weeks prior to his presentation. His past medical history was complicated and included: anxiety/depression, Type II diabetes, hypertension, coronary artery disease, hypercholesterolemia, morbid obesity, obstructive sleep apnea, and cigaratte smoking(active smoker with 20-pack year history). In the emergency room, patient’s vital signs were normal and laboratory studies showed WBC 10 500/mm3, hemoglobin 13.7 gm/dL, platelets 66 000/mm3, absolute neutrophil count 4400/mm3, absolute lymphocyte count, 4200/mm3, and 13% blasts. The patient’s creatinine, uric acid, bilirubin, calcium, total protein, and serum albumin levels were normal. The LDH was elevated to 958 IU/L (normal range 135-225). A peripheral blood smear showed frequent (53%) atypical plasmacytoid cells (Figure 1A) and the flow cytometry of peripheral blood confirmed 50% monotypic lambda restricted clonal plasma cells consistent with PCL. The Serum protein electrophoresis with immunofixation revealed IgG lambda monoclonal gammopathy, with M spike 0.52 gm/dL, serum free kappa light chain level 4.3 mg/L (range 3.3-19.4), serum free lambda light chain level was 2695 mg/L (range 5.7-26.3), with lambda to kappa ratio of ~627. The Beta-2-microglobulin level was 4.5 mg/L (range 0.3-1.9), and levels of IgG, IgA, and IgM levels were 775, 31, and 13 mg/dL respectively. A lumbar spine magnetic resonance imaging (MRI) showed no vertebral fractures, cord compression, or cauda equina lesions but did report widespread T1 hypointensity, and heterogeneous areas of T2/inversion recovery hyperintensity, consistent with possible leukemic infiltration of the bone marrow. A bone marrow aspiration/biopsy demonstrated plasma cell neoplasm with plasmablastic features replacing the bone marrow cellularity. The MM fluorescent in situ hybridization (FISH) was positive for 17p (TP53) deletion, along with presence of additional copies of chromosomes 5, 9, and 15. Final clinical diagnosis of primary PCL, with 17P deletion, was made. The Positron Emission Tomography (PET) scan (Figure 2A) revealed numerous, intensely fluorodeoxyglucose (FDG) avid, bone marrow lesions throughout the skeleton. A core needle biopsy of right 8th rib lesion (Figure 2A arrow) confirmed the presence of plasmablastic malignancy.
Figure 1. Peripheral blood smear at the time of diagnosis (A) and at the time of relapse (B). Peripheral blood smear, Wright-Giemsa stain, 10× shows circulating large neoplastic plasma cells and thrombocytopenia (A). Peripheral blood smear, Wright-Giemsa stain, 40× shows that the neoplastic plasma cells have blastoid features (B).
Figure 2. Attenuation corrected 3-D maximum intensity projections (MIP) positron emission tomography (PET) images of fluorine 18 FDG PET-CT scan: (A) baseline study, demonstrating numerous bone marrow tracer avid lesions involving cervical, thoracic and lumbar spine as well as bilateral ribs, scapula, humeri, pelvis, sacrum, and bilateral femurs. Maximum standard uptake value (SUVmax) in the sacrum = 27 and (B) follow up post-treatment study demonstrating resolution of previously noted tracer avid lesions. Moderate intensity heterogeneous tracer uptake throughout the bone marrow felt to be related to granulocyte colony stimulation factor therapy effect.
Immediate initialization of induction chemotherapy using a combination regimen with bortezomib, dexamethasone, lenalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE) achieved stringent complete response (sCR) as defined by previously published criteria9 after 3 cycles. The patient received additional 2 cycles of bortezomib, dexamethasone, and lenalidomide (RVD) while waiting for HSCT. To prevent skeletal-related events, he also received zoledronic acid. He underwent HSCT conditioning, with melphalan (200 mg/m2 (MEL 200)), with engraftment on day +11.
The post-HSCT course was complicated with profound physical deconditioning and prolonged hospitalization. The patient developed generalized bone pain and a repeat bone marrow biopsy was performed on day +90 post-HSCT, which reveled 40% blastoid monoclonal plasma cells with plasmablastic features consistent with relapsed PCL.
The patient started salvage chemotherapy using carfilzomib, pomalidomide, and dexamethasone (KPD) to treat relapsed PCL with palliative intention as the patient was not felt to be a candidate for second HSCT or allogeneic HSCT. Cycle 1 of KPD therapy was complicated by acute hypoxemic respiratory failure due to bilateral pneumonia, and severe thrombocytopenia. A Flow cytometry of peripheral blood detected a small plasma cell clone and the peripheral blood smear showed blastoid neoplastic plasma cells confirming the relapsed of the PCL. Later, pomalidomide was discontinued due to intolerance (profound fatigue and cytopenia). He resumed carfilzomib at an increased dose 56 mg/m2, weekly, with dexamethasone. Progressive PCL was noted in the next several weeks and the patient became transfusion-dependent for red blood cells and platelets. Subsequently, the patient performance status deteriorated. Anti-CD 38 monoclonal antibody immunotherapy with daratumumab was offered but the patient elected for hospice, at-home, and died peacefully 14 months after the initial diagnosis.
Discussion
Even with employing the novel agents available for treatment of clonal plasma cell neoplasms in combination regimen, the treatment of PCL remains challenging. A prompt diagnosis and early stabilization of metabolic challenges, tumor lysis syndrome (TLS), hypercalcemia, acute renal failure and immediate use of multi-agent induction therapy containing novel agents can reduce the risk of early morbidity and may help prolong survival. There is a high response rate with induction therapies containing bortezomib, lenalidomide or thalidomide. Cytotoxic chemotherapies can also be combined with novel agents, which may not be routinely available on the formulary of many USA hospitals as most myeloma care is delivered on the outpatient basis. Rapid and complete responses are often observed after multi-agent induction therapy containing novel agents, but early relapse is common in PCL. For a durable remission, the induction therapy containing proteasome inhibitor (PI) should follow immediately with consolidation therapy, often with HSCT for eligible candidates. In HSCT-ineligible patients, the optimal strategy is unknown but a several cycles of remission induction therapy, followed by long term multi-agent maintenance therapy containing PI and an immunomodulatory agent (IMiD) may provide durable remission. A recently published multicenter retrospective analysis of 348 patients with PCL by Dhakal et al10 concluded that despite incorporation of modern induction therapy containing novel agents and despite increased utilization of both autologous and allogeneic HSCT in the last several years, the survival of PCL patients has not improved in comparison to the historical cohort of PCL patients prior to the widespread use of novel agents. The study underscored that the main reason for the lack of improvement in the survival despite utilization of modern therapies is due to the high relapse rate after HSCT (~76% relapsed at 4 years post-HSCT).10 Allogeneic HSCT is only suitable for a minority of PCL patients as shown in a few small studies10 demonstrating initial good response, a small PFS benefit of 19% at 4 years and overall survival (OS) of only 31% at 4 years. Small studies of tandem double autologous or tandem autologous/allogeneic HSCT showed limited benefit as well.11,12 For autologous or allogeneic HSCT, relapse was the main cause of death in approximately 80% of patients after HSCT. Allogeneic HSCT may have a role for treatment of younger and fit patients, ideally in the context of a clinical trial. For example , Currently an ongoing clinical trial in Europe (EudraCT Number: 2016-003105-33) incorporates a potent second generation irreversible PI, carfilzomib and lenalidomide during remission induction, consolidation, and maintenance phase of therapy and offers allogeneic HSCT to younger, fit, and responding patients.13
The median overall survival of PCL patients, before the use of novel agents, was historically measured in only a few months.14 However, with the incorporation of novel agents (bortezomib, lenalidomide or thalidomide) and autologous HSCT, survival has been reported to improve to 12 months.15 While this represents favorable progress for this patient group, more improvement is necessary to improve outcomes in the treatment of PCL. There is signal showing that further improvement can be achieved with post-HSCT maintenance therapy with novel agents. This was demonstrated by Mina et al16 in their retrospective analysis of 38 patients with PCL treated with bortezomib plus either thalidomide or lenalidomide as induction therapy followed by HSCT and maintenance therapy with bortezomib and lenalidomide for 3 years in majority of the cohort. The median PFS was 20 months, and the median OS was 33 months with PFS better for those who received HSCT (25 vs 6 months). Most important finding was that the patients who received maintenance therapy after HSCT had prolonged median PFS (27 vs 11 months) and a trend toward prolonged OS (median, 38 vs 22 months) compared with those who did not receive maintenance therapy.16
Over half of patients with PCL harbor highly adverse prognostic factor of 17p deletion.17 Bortezomib and other proteasome inhibitors (carfilzomib, ixazomib) are postulated to help overcome the adverse prognostic impact of poor cytogenetics in MM, especially in 17p deletion/TP53 mutation and cytogenetic aberrations involving chromosome 14 in high risk MM.18 Due to this observation and the retrospective data in high risk MM, PI appears to be an important therapeutic tool to be used in the treatment of PCL. To conduct a well-funded randomized phase III study is challenging due to multiple logistic factors and relatively rare nature of PCL. Therefore, randomized phase III studies in PCL are lacking. A phase II study evaluated the effectiveness of bortezomib and chemotherapy (doxorubicin or cyclosphosphamide), followed by HSCT, and 1 year of maintenance therapy with RVD. The results thereof indicated a good response rate (the overall response rate to induction therapy was 69%) and improved median survival to 3 years.19 In another report Nooka et al20 reported encouraging results of RVD maintenance with 51% of patients achieving stringent complete response (sCR) and 96% achieving VGPR or better and median PFS of 32 months and a 3-year OS of 93%. These studies support induction therapy with regimen containing novel agents followed by early HSCT for consolidation and post-HSCT maintenance therapy with RVD for the best results. Only 27% of post-autologous HSCT and only 12% of post allo-HCT PCL patients had received maintenance therapy in the study by Dhakal et al10 which may have contributed to the high relapse rate in the HSCT survivors in their cohort.
In summary, patients who are fit enough to undergo HSCT, and who receive PI containing multi-agent maintenance therapy after HSCT, tend to exhibit improved survival compared to patients who did not undergo HSCT and did not receive maintenance therapy. The standard low dose lenalidomide maintenance monotherapy (10-15 mg daily), prescribed after HSCT in MM, appears to be inadequate in PCL due to reported 50% relapse rate within first year.21 The maintenance strategy with combination therapy of RVD appears to be more effective and is tolerated by majority of patients after HSCT in PCL.21,22 Three factors affecting survival outcomes in PCL appear to be (1) incorporating novel agents with PI and IMiD in the induction therapy, (2) consolidation with HSCT in fit stronger and younger patients, and (3) maintenance therapy containing multiple novel agents (bortezomib and lenalidomide). Patients who are able to tolerate these therapies tend to have the best possible outcomes but relapses still do occur including at unusual sites for example, meningeal relapses after both allogeneic and autologous HSCT.19
The timing and sequencing of newer generation proteasome inhibitors, carfilzomib and ixazomib, is still evolving in PCL and there are no published studies as of the writing of this review. Ixazomib, as an oral agent, may be suitable as a combination therapy with an IMiD, such as lenalidomide or pomalidomide, particularly for maintenance therapy. Both ixazomib and pomalidomide are effective agents against relapsed myeloma, but no study has been conducted to prospectively examine the efficacy of either in PCL. However, a phase II study of pomalidomide, ixazomib, and dexamethasone, in treating patients with previously treated MM or secondary PCL, is currently ongoing and will help answer questions surrounding the effectiveness of these biologic agents for patients with relapsed myeloma and secondary PCL (ClinicalTrials.gov Identifier: NCT02547662). Additionally, a phase I study of filanesib and carfilzomib in treating patients with relapsed or refractory MM, or secondary PCL, was completed and the final results of which are pending (ClinicalTrials.gov Identifier: NCT01372540). The results of a clinical study of carfilzomib, pomalidomide, and dexamethasone (KPD) for relapsed or refractory myeloma indicate that the regimen is a well-tolerated and highly active combination for patients with relapsed/refractory multiple myeloma22 and there is evolving preliminary safety and efficacy data from an ongoing phase II non-randomized clinical trial that examined carfilzomib, lenalidomide and dexamethasone (KRD) for first line treatment of PCL.23 In this study patients eligible for HSCT underwent 4 cycles of KRd induction followed by HSCT, KRd consolidation, and then maintenance with KD until progression. Patients not eligible for HSCT received KRd followed by KD maintenance. The final results are not published yet but preliminary results are encouraging with high response rate and acceptable safety (⩾VGPR in 80% and ⩾CR in 33%).23 The patient in this report received KPD therapy at the time of relapse, with less than partial response (Figure 3) attesting to the much more aggressive biology of relapsed PCL.
Figure 3. The levels of serum free lambda light chain (LLC), lactate dehydrogenase (LDH) and beta 2 microglobulin at the time of diagnosis, relapse, and disease progression.
RVD-PACE = lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; HSCT = hematopoietic stem cell transplantation; KPD = carfilzomib, pomalidomide, and dexamethasone; LDH = lactate dehydrogenase.
Daratumumab and isatuximab are highly effective anti-CD38 monoclonal antibodies approved for MM in combination with novel agents.24-27 Studies are needed to understand how and when to incorporate this highly active novel immunotherapy for treatment of PCL. Unfortunately, a phase I study of daratumumab, in combination with bortezomib, dexamethasone, pegylated liposomal doxorubicin hydrochloride, and lenalidomide in treating patients with PCL has been withdrawn citing budgetary constraints (ClinicalTrials.gov Identifier: NCT03591744). Similarly, antibody drug conjugates, bi-specific antibodies and CAR-T therapy may have a future for the treatment of PCL, but initial trials usually exclude PCL from the inclusion criteria (ClinicalTrials.gov Identifier: NCT03815383).
Venetoclax is an attractive molecule for patients with PCL given its good tolerability as an oral inhibitor of BCL-2 and the high prevalence (30-50%) of the t(11;14) in PCL population.17,18 When venetoclax was evaluated in a phase 1 study in relapsed/refractory MM, 86% of responders had the t(11;14) with overall response rate of 40%, with 27% of patients achieving very good partial response (VGPR) or better in this heavily pretreated population.28 Future studies of PCL should examine venetocalx either as single agent or in combination with novel agents, cellular therapies or immunotherapies.
Finally, due to the high frequency of extra-medullary involvement, international myeloma working group (IMWG) has recommended that PET scan be included in the diagnosis and monitoring of PCL.29
Conclusion
Primary plasma cell leukemia (PCL) is a rare and aggressive hematologic malignancy. Response to induction therapy, with a combination of novel agents (PI and IMiD) with or without cytotoxic chemotherapy, is common but durability of such response is brief unless consolidated with HSCT followed by maintenance therapy. A single agent lenalidomide, as maintenance therapy after HSCT, is inadequate due to high relapse rate. Therefore, it is recommended to incorporate both lenalidomide and bortezomib, in combination with dexamethasone (RVD), for maintenance in PCL when tolerated. For HSCT-ineligible patients, efficacious treatment remains a challenge and we recommend treating with multiple cycles of therapies containing lenalidomide and bortezomib or participation in a clinical trial when available. Employing immunotherapy with monoclonal antibodies, antibody drug conjugates, bi-specific antibodies and engineered cellular therapy such as CAR-T cell therapy, are all attractive concepts that require investigations in future in treatment of PCL. Incorporating newer generation proteasome inhibitors (carfilzomib, ixazomib) and immunomodulatory agent such as pomalidomide may further improve the outcomes. Venetoclax may also play an important role in future for the treatment of PCL harboring t(11;14) mutation. Prospective multicenter studies are required to further understand the definitions, pathogenesis, treatment and prognosis of PCL. Employing novel imaging technique such as PET scan when done at diagnosis and follow up may provide valuable insight in to the status of the disease outside of the bone marrow.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Informed Consent: Informed patient consent was not possible due to the death of the patient. Patient’s surviving spouse provided the verbal informed consent to publish the case report on 7/15/2020. This was documented in patient’s chart in the electronic medical record system of Cleveland Clinic per Cleveland Clinic IRB guidance.
Ethics Approval: Ethics approval is not required for case report because such report does not constitute a research per Cleveland Clinic Institutional Review Board (IRB).
ORCID iDs: Chakra P Chaulagain https://orcid.org/0000-0002-4641-2217
Faiz Anwer https://orcid.org/0000-0001-6914-7439 | BORTEZOMIB, CARFILZOMIB, CISPLATIN, CYCLOPHOSPHAMIDE, DEXAMETHASONE, DOXORUBICIN, ETOPOSIDE, LENALIDOMIDE, MELPHALAN, POMALIDOMIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC | 33716516 | 19,065,425 | 2021 |
What was the administration route of drug 'LENALIDOMIDE'? | Management of Primary Plasma Cell Leukemia Remains Challenging Even in the Era of Novel Agents.
Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.
Introduction
Primary plasma cell leukemia (PCL) is a rare and aggressive form of multiple myeloma (MM). The PCL accounts for 0.5% to 2% of MM cases with annual incidence ranging between 0.4 and 1.2 cases per million individuals per year.1,2 Although the definition of PCL is still evolving, a circulating plasma cell count that exceeds 20% of peripheral blood leukocytes, or an absolute plasma cell count >2000/mm3, has been the arbitrary but traditional definition of PCL.3 Multiple myeloma (MM) patients exhibiting circulating plasma cell levels as low as 2%, counted morphologically at the time of diagnosis, demonstrated poor survival, similar to that seen in PCL patients.4 Granell et al5 in another analysis of 482 newly diagnosed MM patients, demonstrated that the presence of ⩾5% circulating plasma cells counted in the peripheral blood has a similar adverse prognostic impact as that of PCL. As also reported, extremely low levels (~0.26%) of circulating clonal plasma cells (CPC) in MM patients, as detected by immunophenotyping (flow cytometry) at the time of diagnosis and treated with novel agents, was also associated with inferior overall survival (OS).6 For example, the 3-year OS for the MM patients with presence of CPC was 67% compared with 87% for those with no CPC.6 Currently, the optimal diagnostic threshold of CPC levels necessary to define PCL is being debated by multiple myeloma experts worldwide.
Primary PCL is rare and arises de novo, but secondary PCL occurs via clonal evolution from a pre-existing MM. This is typically observed following several lines of therapy and often as a terminal event as part of aggressive relapsed of multiple myeloma. Therefore, for the purpose of this report, “PCL” will refer to primary PCL only.
A brief comparison of the clinical features of PCL and MM is presented in Table 1. Compared to MM, PCL is more aggressive at presentation, patients more often than not present with bone marrow insufficiency (in the form of anemia, or thrombocytopenia,) and end organ damage (in the form of hypercalcemia or renal dysfunction) and multi-organ dysfunction. The clinical course is much more aggressive and outcome is associated with poorer prognosis despite treatment in PCL when compared to MM.5 Additionally, higher LDH and B2-microglobulin levels are often observed in PCL, indicating significantly higher disease burden and proliferation rate at the time of presentation. The higher propensity for extra-medullary involvement at diagnosis, in addition to a larger incidence of high-risk cytogenetics (eg, 17p deletion/TP53 mutation and t[14;16]) also reflects the biologically much more aggressive nature of PCL compared to MM.7,8
Table 1. Clinical features of primary plasma cell leukemia (PCL) compared to multiple myeloma.
Clinical features Multiple myeloma Plasma cell leukemia
Incidence 52 to 75 cases per million individuals per year1,2 0.4 to 1.2 cases per million individuals per year or 0.5% to 2% of all MM cases1,2
Age of onset (years) Older (median age, 65-74)23 Relatively younger (median age 55)1-3
Most common subtype IgG (46%) followed by IgA IgG (58%) followed by light chain only
Bone marrow failure (anemia, thrombocytopenia) Less common More common
Hypercalcemia Less common More common
B2-microglobulin + +++
LDH + +++
Renal dysfunction + +++
Tumor lysis syndrome Less common More common
Extra-medullary involvement (liver, spleen, other organs) at diagnosis Less common More common
Deletion 17p/TP53 mutation Less common (~10%) More common (~50%)12
t (11;14) Less common (10%-31%)24 More common 30%12 to 50%14
Prognosis (median overall survival) Better (median OS = 5.2 years with median follow up 5.9 years)25 Worse [median OS 28% at 4 years (range 22%-35%)]10
Abbreviations: LDH, lactate dehydrogenase; MM, multiple myeloma; OS, overall survival; PFS, progression free survival.
In this review, we present a patient with primary PCL who exhibited complete response to induction therapy with lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE), but relapsed quickly after autologous peripheral blood hematopoietic stem cell transplantation (HSCT). A second remission was not inducible with salvage therapy containing carfilzomib, pomalidomide, and dexamethasone, and the patient subsequently died from progression of PCL.
Case Presentation
A 62-year-old male with a history of bladder cancer status post transurethral resection of the bladder tumor 5 years prior, was seen in the emergency room for progressively worsening low back pain for 6 weeks prior to his presentation. His past medical history was complicated and included: anxiety/depression, Type II diabetes, hypertension, coronary artery disease, hypercholesterolemia, morbid obesity, obstructive sleep apnea, and cigaratte smoking(active smoker with 20-pack year history). In the emergency room, patient’s vital signs were normal and laboratory studies showed WBC 10 500/mm3, hemoglobin 13.7 gm/dL, platelets 66 000/mm3, absolute neutrophil count 4400/mm3, absolute lymphocyte count, 4200/mm3, and 13% blasts. The patient’s creatinine, uric acid, bilirubin, calcium, total protein, and serum albumin levels were normal. The LDH was elevated to 958 IU/L (normal range 135-225). A peripheral blood smear showed frequent (53%) atypical plasmacytoid cells (Figure 1A) and the flow cytometry of peripheral blood confirmed 50% monotypic lambda restricted clonal plasma cells consistent with PCL. The Serum protein electrophoresis with immunofixation revealed IgG lambda monoclonal gammopathy, with M spike 0.52 gm/dL, serum free kappa light chain level 4.3 mg/L (range 3.3-19.4), serum free lambda light chain level was 2695 mg/L (range 5.7-26.3), with lambda to kappa ratio of ~627. The Beta-2-microglobulin level was 4.5 mg/L (range 0.3-1.9), and levels of IgG, IgA, and IgM levels were 775, 31, and 13 mg/dL respectively. A lumbar spine magnetic resonance imaging (MRI) showed no vertebral fractures, cord compression, or cauda equina lesions but did report widespread T1 hypointensity, and heterogeneous areas of T2/inversion recovery hyperintensity, consistent with possible leukemic infiltration of the bone marrow. A bone marrow aspiration/biopsy demonstrated plasma cell neoplasm with plasmablastic features replacing the bone marrow cellularity. The MM fluorescent in situ hybridization (FISH) was positive for 17p (TP53) deletion, along with presence of additional copies of chromosomes 5, 9, and 15. Final clinical diagnosis of primary PCL, with 17P deletion, was made. The Positron Emission Tomography (PET) scan (Figure 2A) revealed numerous, intensely fluorodeoxyglucose (FDG) avid, bone marrow lesions throughout the skeleton. A core needle biopsy of right 8th rib lesion (Figure 2A arrow) confirmed the presence of plasmablastic malignancy.
Figure 1. Peripheral blood smear at the time of diagnosis (A) and at the time of relapse (B). Peripheral blood smear, Wright-Giemsa stain, 10× shows circulating large neoplastic plasma cells and thrombocytopenia (A). Peripheral blood smear, Wright-Giemsa stain, 40× shows that the neoplastic plasma cells have blastoid features (B).
Figure 2. Attenuation corrected 3-D maximum intensity projections (MIP) positron emission tomography (PET) images of fluorine 18 FDG PET-CT scan: (A) baseline study, demonstrating numerous bone marrow tracer avid lesions involving cervical, thoracic and lumbar spine as well as bilateral ribs, scapula, humeri, pelvis, sacrum, and bilateral femurs. Maximum standard uptake value (SUVmax) in the sacrum = 27 and (B) follow up post-treatment study demonstrating resolution of previously noted tracer avid lesions. Moderate intensity heterogeneous tracer uptake throughout the bone marrow felt to be related to granulocyte colony stimulation factor therapy effect.
Immediate initialization of induction chemotherapy using a combination regimen with bortezomib, dexamethasone, lenalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE) achieved stringent complete response (sCR) as defined by previously published criteria9 after 3 cycles. The patient received additional 2 cycles of bortezomib, dexamethasone, and lenalidomide (RVD) while waiting for HSCT. To prevent skeletal-related events, he also received zoledronic acid. He underwent HSCT conditioning, with melphalan (200 mg/m2 (MEL 200)), with engraftment on day +11.
The post-HSCT course was complicated with profound physical deconditioning and prolonged hospitalization. The patient developed generalized bone pain and a repeat bone marrow biopsy was performed on day +90 post-HSCT, which reveled 40% blastoid monoclonal plasma cells with plasmablastic features consistent with relapsed PCL.
The patient started salvage chemotherapy using carfilzomib, pomalidomide, and dexamethasone (KPD) to treat relapsed PCL with palliative intention as the patient was not felt to be a candidate for second HSCT or allogeneic HSCT. Cycle 1 of KPD therapy was complicated by acute hypoxemic respiratory failure due to bilateral pneumonia, and severe thrombocytopenia. A Flow cytometry of peripheral blood detected a small plasma cell clone and the peripheral blood smear showed blastoid neoplastic plasma cells confirming the relapsed of the PCL. Later, pomalidomide was discontinued due to intolerance (profound fatigue and cytopenia). He resumed carfilzomib at an increased dose 56 mg/m2, weekly, with dexamethasone. Progressive PCL was noted in the next several weeks and the patient became transfusion-dependent for red blood cells and platelets. Subsequently, the patient performance status deteriorated. Anti-CD 38 monoclonal antibody immunotherapy with daratumumab was offered but the patient elected for hospice, at-home, and died peacefully 14 months after the initial diagnosis.
Discussion
Even with employing the novel agents available for treatment of clonal plasma cell neoplasms in combination regimen, the treatment of PCL remains challenging. A prompt diagnosis and early stabilization of metabolic challenges, tumor lysis syndrome (TLS), hypercalcemia, acute renal failure and immediate use of multi-agent induction therapy containing novel agents can reduce the risk of early morbidity and may help prolong survival. There is a high response rate with induction therapies containing bortezomib, lenalidomide or thalidomide. Cytotoxic chemotherapies can also be combined with novel agents, which may not be routinely available on the formulary of many USA hospitals as most myeloma care is delivered on the outpatient basis. Rapid and complete responses are often observed after multi-agent induction therapy containing novel agents, but early relapse is common in PCL. For a durable remission, the induction therapy containing proteasome inhibitor (PI) should follow immediately with consolidation therapy, often with HSCT for eligible candidates. In HSCT-ineligible patients, the optimal strategy is unknown but a several cycles of remission induction therapy, followed by long term multi-agent maintenance therapy containing PI and an immunomodulatory agent (IMiD) may provide durable remission. A recently published multicenter retrospective analysis of 348 patients with PCL by Dhakal et al10 concluded that despite incorporation of modern induction therapy containing novel agents and despite increased utilization of both autologous and allogeneic HSCT in the last several years, the survival of PCL patients has not improved in comparison to the historical cohort of PCL patients prior to the widespread use of novel agents. The study underscored that the main reason for the lack of improvement in the survival despite utilization of modern therapies is due to the high relapse rate after HSCT (~76% relapsed at 4 years post-HSCT).10 Allogeneic HSCT is only suitable for a minority of PCL patients as shown in a few small studies10 demonstrating initial good response, a small PFS benefit of 19% at 4 years and overall survival (OS) of only 31% at 4 years. Small studies of tandem double autologous or tandem autologous/allogeneic HSCT showed limited benefit as well.11,12 For autologous or allogeneic HSCT, relapse was the main cause of death in approximately 80% of patients after HSCT. Allogeneic HSCT may have a role for treatment of younger and fit patients, ideally in the context of a clinical trial. For example , Currently an ongoing clinical trial in Europe (EudraCT Number: 2016-003105-33) incorporates a potent second generation irreversible PI, carfilzomib and lenalidomide during remission induction, consolidation, and maintenance phase of therapy and offers allogeneic HSCT to younger, fit, and responding patients.13
The median overall survival of PCL patients, before the use of novel agents, was historically measured in only a few months.14 However, with the incorporation of novel agents (bortezomib, lenalidomide or thalidomide) and autologous HSCT, survival has been reported to improve to 12 months.15 While this represents favorable progress for this patient group, more improvement is necessary to improve outcomes in the treatment of PCL. There is signal showing that further improvement can be achieved with post-HSCT maintenance therapy with novel agents. This was demonstrated by Mina et al16 in their retrospective analysis of 38 patients with PCL treated with bortezomib plus either thalidomide or lenalidomide as induction therapy followed by HSCT and maintenance therapy with bortezomib and lenalidomide for 3 years in majority of the cohort. The median PFS was 20 months, and the median OS was 33 months with PFS better for those who received HSCT (25 vs 6 months). Most important finding was that the patients who received maintenance therapy after HSCT had prolonged median PFS (27 vs 11 months) and a trend toward prolonged OS (median, 38 vs 22 months) compared with those who did not receive maintenance therapy.16
Over half of patients with PCL harbor highly adverse prognostic factor of 17p deletion.17 Bortezomib and other proteasome inhibitors (carfilzomib, ixazomib) are postulated to help overcome the adverse prognostic impact of poor cytogenetics in MM, especially in 17p deletion/TP53 mutation and cytogenetic aberrations involving chromosome 14 in high risk MM.18 Due to this observation and the retrospective data in high risk MM, PI appears to be an important therapeutic tool to be used in the treatment of PCL. To conduct a well-funded randomized phase III study is challenging due to multiple logistic factors and relatively rare nature of PCL. Therefore, randomized phase III studies in PCL are lacking. A phase II study evaluated the effectiveness of bortezomib and chemotherapy (doxorubicin or cyclosphosphamide), followed by HSCT, and 1 year of maintenance therapy with RVD. The results thereof indicated a good response rate (the overall response rate to induction therapy was 69%) and improved median survival to 3 years.19 In another report Nooka et al20 reported encouraging results of RVD maintenance with 51% of patients achieving stringent complete response (sCR) and 96% achieving VGPR or better and median PFS of 32 months and a 3-year OS of 93%. These studies support induction therapy with regimen containing novel agents followed by early HSCT for consolidation and post-HSCT maintenance therapy with RVD for the best results. Only 27% of post-autologous HSCT and only 12% of post allo-HCT PCL patients had received maintenance therapy in the study by Dhakal et al10 which may have contributed to the high relapse rate in the HSCT survivors in their cohort.
In summary, patients who are fit enough to undergo HSCT, and who receive PI containing multi-agent maintenance therapy after HSCT, tend to exhibit improved survival compared to patients who did not undergo HSCT and did not receive maintenance therapy. The standard low dose lenalidomide maintenance monotherapy (10-15 mg daily), prescribed after HSCT in MM, appears to be inadequate in PCL due to reported 50% relapse rate within first year.21 The maintenance strategy with combination therapy of RVD appears to be more effective and is tolerated by majority of patients after HSCT in PCL.21,22 Three factors affecting survival outcomes in PCL appear to be (1) incorporating novel agents with PI and IMiD in the induction therapy, (2) consolidation with HSCT in fit stronger and younger patients, and (3) maintenance therapy containing multiple novel agents (bortezomib and lenalidomide). Patients who are able to tolerate these therapies tend to have the best possible outcomes but relapses still do occur including at unusual sites for example, meningeal relapses after both allogeneic and autologous HSCT.19
The timing and sequencing of newer generation proteasome inhibitors, carfilzomib and ixazomib, is still evolving in PCL and there are no published studies as of the writing of this review. Ixazomib, as an oral agent, may be suitable as a combination therapy with an IMiD, such as lenalidomide or pomalidomide, particularly for maintenance therapy. Both ixazomib and pomalidomide are effective agents against relapsed myeloma, but no study has been conducted to prospectively examine the efficacy of either in PCL. However, a phase II study of pomalidomide, ixazomib, and dexamethasone, in treating patients with previously treated MM or secondary PCL, is currently ongoing and will help answer questions surrounding the effectiveness of these biologic agents for patients with relapsed myeloma and secondary PCL (ClinicalTrials.gov Identifier: NCT02547662). Additionally, a phase I study of filanesib and carfilzomib in treating patients with relapsed or refractory MM, or secondary PCL, was completed and the final results of which are pending (ClinicalTrials.gov Identifier: NCT01372540). The results of a clinical study of carfilzomib, pomalidomide, and dexamethasone (KPD) for relapsed or refractory myeloma indicate that the regimen is a well-tolerated and highly active combination for patients with relapsed/refractory multiple myeloma22 and there is evolving preliminary safety and efficacy data from an ongoing phase II non-randomized clinical trial that examined carfilzomib, lenalidomide and dexamethasone (KRD) for first line treatment of PCL.23 In this study patients eligible for HSCT underwent 4 cycles of KRd induction followed by HSCT, KRd consolidation, and then maintenance with KD until progression. Patients not eligible for HSCT received KRd followed by KD maintenance. The final results are not published yet but preliminary results are encouraging with high response rate and acceptable safety (⩾VGPR in 80% and ⩾CR in 33%).23 The patient in this report received KPD therapy at the time of relapse, with less than partial response (Figure 3) attesting to the much more aggressive biology of relapsed PCL.
Figure 3. The levels of serum free lambda light chain (LLC), lactate dehydrogenase (LDH) and beta 2 microglobulin at the time of diagnosis, relapse, and disease progression.
RVD-PACE = lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; HSCT = hematopoietic stem cell transplantation; KPD = carfilzomib, pomalidomide, and dexamethasone; LDH = lactate dehydrogenase.
Daratumumab and isatuximab are highly effective anti-CD38 monoclonal antibodies approved for MM in combination with novel agents.24-27 Studies are needed to understand how and when to incorporate this highly active novel immunotherapy for treatment of PCL. Unfortunately, a phase I study of daratumumab, in combination with bortezomib, dexamethasone, pegylated liposomal doxorubicin hydrochloride, and lenalidomide in treating patients with PCL has been withdrawn citing budgetary constraints (ClinicalTrials.gov Identifier: NCT03591744). Similarly, antibody drug conjugates, bi-specific antibodies and CAR-T therapy may have a future for the treatment of PCL, but initial trials usually exclude PCL from the inclusion criteria (ClinicalTrials.gov Identifier: NCT03815383).
Venetoclax is an attractive molecule for patients with PCL given its good tolerability as an oral inhibitor of BCL-2 and the high prevalence (30-50%) of the t(11;14) in PCL population.17,18 When venetoclax was evaluated in a phase 1 study in relapsed/refractory MM, 86% of responders had the t(11;14) with overall response rate of 40%, with 27% of patients achieving very good partial response (VGPR) or better in this heavily pretreated population.28 Future studies of PCL should examine venetocalx either as single agent or in combination with novel agents, cellular therapies or immunotherapies.
Finally, due to the high frequency of extra-medullary involvement, international myeloma working group (IMWG) has recommended that PET scan be included in the diagnosis and monitoring of PCL.29
Conclusion
Primary plasma cell leukemia (PCL) is a rare and aggressive hematologic malignancy. Response to induction therapy, with a combination of novel agents (PI and IMiD) with or without cytotoxic chemotherapy, is common but durability of such response is brief unless consolidated with HSCT followed by maintenance therapy. A single agent lenalidomide, as maintenance therapy after HSCT, is inadequate due to high relapse rate. Therefore, it is recommended to incorporate both lenalidomide and bortezomib, in combination with dexamethasone (RVD), for maintenance in PCL when tolerated. For HSCT-ineligible patients, efficacious treatment remains a challenge and we recommend treating with multiple cycles of therapies containing lenalidomide and bortezomib or participation in a clinical trial when available. Employing immunotherapy with monoclonal antibodies, antibody drug conjugates, bi-specific antibodies and engineered cellular therapy such as CAR-T cell therapy, are all attractive concepts that require investigations in future in treatment of PCL. Incorporating newer generation proteasome inhibitors (carfilzomib, ixazomib) and immunomodulatory agent such as pomalidomide may further improve the outcomes. Venetoclax may also play an important role in future for the treatment of PCL harboring t(11;14) mutation. Prospective multicenter studies are required to further understand the definitions, pathogenesis, treatment and prognosis of PCL. Employing novel imaging technique such as PET scan when done at diagnosis and follow up may provide valuable insight in to the status of the disease outside of the bone marrow.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Informed Consent: Informed patient consent was not possible due to the death of the patient. Patient’s surviving spouse provided the verbal informed consent to publish the case report on 7/15/2020. This was documented in patient’s chart in the electronic medical record system of Cleveland Clinic per Cleveland Clinic IRB guidance.
Ethics Approval: Ethics approval is not required for case report because such report does not constitute a research per Cleveland Clinic Institutional Review Board (IRB).
ORCID iDs: Chakra P Chaulagain https://orcid.org/0000-0002-4641-2217
Faiz Anwer https://orcid.org/0000-0001-6914-7439 | Oral | DrugAdministrationRoute | CC BY-NC | 33716516 | 19,065,425 | 2021 |
What was the administration route of drug 'POMALIDOMIDE'? | Management of Primary Plasma Cell Leukemia Remains Challenging Even in the Era of Novel Agents.
Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.
Introduction
Primary plasma cell leukemia (PCL) is a rare and aggressive form of multiple myeloma (MM). The PCL accounts for 0.5% to 2% of MM cases with annual incidence ranging between 0.4 and 1.2 cases per million individuals per year.1,2 Although the definition of PCL is still evolving, a circulating plasma cell count that exceeds 20% of peripheral blood leukocytes, or an absolute plasma cell count >2000/mm3, has been the arbitrary but traditional definition of PCL.3 Multiple myeloma (MM) patients exhibiting circulating plasma cell levels as low as 2%, counted morphologically at the time of diagnosis, demonstrated poor survival, similar to that seen in PCL patients.4 Granell et al5 in another analysis of 482 newly diagnosed MM patients, demonstrated that the presence of ⩾5% circulating plasma cells counted in the peripheral blood has a similar adverse prognostic impact as that of PCL. As also reported, extremely low levels (~0.26%) of circulating clonal plasma cells (CPC) in MM patients, as detected by immunophenotyping (flow cytometry) at the time of diagnosis and treated with novel agents, was also associated with inferior overall survival (OS).6 For example, the 3-year OS for the MM patients with presence of CPC was 67% compared with 87% for those with no CPC.6 Currently, the optimal diagnostic threshold of CPC levels necessary to define PCL is being debated by multiple myeloma experts worldwide.
Primary PCL is rare and arises de novo, but secondary PCL occurs via clonal evolution from a pre-existing MM. This is typically observed following several lines of therapy and often as a terminal event as part of aggressive relapsed of multiple myeloma. Therefore, for the purpose of this report, “PCL” will refer to primary PCL only.
A brief comparison of the clinical features of PCL and MM is presented in Table 1. Compared to MM, PCL is more aggressive at presentation, patients more often than not present with bone marrow insufficiency (in the form of anemia, or thrombocytopenia,) and end organ damage (in the form of hypercalcemia or renal dysfunction) and multi-organ dysfunction. The clinical course is much more aggressive and outcome is associated with poorer prognosis despite treatment in PCL when compared to MM.5 Additionally, higher LDH and B2-microglobulin levels are often observed in PCL, indicating significantly higher disease burden and proliferation rate at the time of presentation. The higher propensity for extra-medullary involvement at diagnosis, in addition to a larger incidence of high-risk cytogenetics (eg, 17p deletion/TP53 mutation and t[14;16]) also reflects the biologically much more aggressive nature of PCL compared to MM.7,8
Table 1. Clinical features of primary plasma cell leukemia (PCL) compared to multiple myeloma.
Clinical features Multiple myeloma Plasma cell leukemia
Incidence 52 to 75 cases per million individuals per year1,2 0.4 to 1.2 cases per million individuals per year or 0.5% to 2% of all MM cases1,2
Age of onset (years) Older (median age, 65-74)23 Relatively younger (median age 55)1-3
Most common subtype IgG (46%) followed by IgA IgG (58%) followed by light chain only
Bone marrow failure (anemia, thrombocytopenia) Less common More common
Hypercalcemia Less common More common
B2-microglobulin + +++
LDH + +++
Renal dysfunction + +++
Tumor lysis syndrome Less common More common
Extra-medullary involvement (liver, spleen, other organs) at diagnosis Less common More common
Deletion 17p/TP53 mutation Less common (~10%) More common (~50%)12
t (11;14) Less common (10%-31%)24 More common 30%12 to 50%14
Prognosis (median overall survival) Better (median OS = 5.2 years with median follow up 5.9 years)25 Worse [median OS 28% at 4 years (range 22%-35%)]10
Abbreviations: LDH, lactate dehydrogenase; MM, multiple myeloma; OS, overall survival; PFS, progression free survival.
In this review, we present a patient with primary PCL who exhibited complete response to induction therapy with lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE), but relapsed quickly after autologous peripheral blood hematopoietic stem cell transplantation (HSCT). A second remission was not inducible with salvage therapy containing carfilzomib, pomalidomide, and dexamethasone, and the patient subsequently died from progression of PCL.
Case Presentation
A 62-year-old male with a history of bladder cancer status post transurethral resection of the bladder tumor 5 years prior, was seen in the emergency room for progressively worsening low back pain for 6 weeks prior to his presentation. His past medical history was complicated and included: anxiety/depression, Type II diabetes, hypertension, coronary artery disease, hypercholesterolemia, morbid obesity, obstructive sleep apnea, and cigaratte smoking(active smoker with 20-pack year history). In the emergency room, patient’s vital signs were normal and laboratory studies showed WBC 10 500/mm3, hemoglobin 13.7 gm/dL, platelets 66 000/mm3, absolute neutrophil count 4400/mm3, absolute lymphocyte count, 4200/mm3, and 13% blasts. The patient’s creatinine, uric acid, bilirubin, calcium, total protein, and serum albumin levels were normal. The LDH was elevated to 958 IU/L (normal range 135-225). A peripheral blood smear showed frequent (53%) atypical plasmacytoid cells (Figure 1A) and the flow cytometry of peripheral blood confirmed 50% monotypic lambda restricted clonal plasma cells consistent with PCL. The Serum protein electrophoresis with immunofixation revealed IgG lambda monoclonal gammopathy, with M spike 0.52 gm/dL, serum free kappa light chain level 4.3 mg/L (range 3.3-19.4), serum free lambda light chain level was 2695 mg/L (range 5.7-26.3), with lambda to kappa ratio of ~627. The Beta-2-microglobulin level was 4.5 mg/L (range 0.3-1.9), and levels of IgG, IgA, and IgM levels were 775, 31, and 13 mg/dL respectively. A lumbar spine magnetic resonance imaging (MRI) showed no vertebral fractures, cord compression, or cauda equina lesions but did report widespread T1 hypointensity, and heterogeneous areas of T2/inversion recovery hyperintensity, consistent with possible leukemic infiltration of the bone marrow. A bone marrow aspiration/biopsy demonstrated plasma cell neoplasm with plasmablastic features replacing the bone marrow cellularity. The MM fluorescent in situ hybridization (FISH) was positive for 17p (TP53) deletion, along with presence of additional copies of chromosomes 5, 9, and 15. Final clinical diagnosis of primary PCL, with 17P deletion, was made. The Positron Emission Tomography (PET) scan (Figure 2A) revealed numerous, intensely fluorodeoxyglucose (FDG) avid, bone marrow lesions throughout the skeleton. A core needle biopsy of right 8th rib lesion (Figure 2A arrow) confirmed the presence of plasmablastic malignancy.
Figure 1. Peripheral blood smear at the time of diagnosis (A) and at the time of relapse (B). Peripheral blood smear, Wright-Giemsa stain, 10× shows circulating large neoplastic plasma cells and thrombocytopenia (A). Peripheral blood smear, Wright-Giemsa stain, 40× shows that the neoplastic plasma cells have blastoid features (B).
Figure 2. Attenuation corrected 3-D maximum intensity projections (MIP) positron emission tomography (PET) images of fluorine 18 FDG PET-CT scan: (A) baseline study, demonstrating numerous bone marrow tracer avid lesions involving cervical, thoracic and lumbar spine as well as bilateral ribs, scapula, humeri, pelvis, sacrum, and bilateral femurs. Maximum standard uptake value (SUVmax) in the sacrum = 27 and (B) follow up post-treatment study demonstrating resolution of previously noted tracer avid lesions. Moderate intensity heterogeneous tracer uptake throughout the bone marrow felt to be related to granulocyte colony stimulation factor therapy effect.
Immediate initialization of induction chemotherapy using a combination regimen with bortezomib, dexamethasone, lenalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE) achieved stringent complete response (sCR) as defined by previously published criteria9 after 3 cycles. The patient received additional 2 cycles of bortezomib, dexamethasone, and lenalidomide (RVD) while waiting for HSCT. To prevent skeletal-related events, he also received zoledronic acid. He underwent HSCT conditioning, with melphalan (200 mg/m2 (MEL 200)), with engraftment on day +11.
The post-HSCT course was complicated with profound physical deconditioning and prolonged hospitalization. The patient developed generalized bone pain and a repeat bone marrow biopsy was performed on day +90 post-HSCT, which reveled 40% blastoid monoclonal plasma cells with plasmablastic features consistent with relapsed PCL.
The patient started salvage chemotherapy using carfilzomib, pomalidomide, and dexamethasone (KPD) to treat relapsed PCL with palliative intention as the patient was not felt to be a candidate for second HSCT or allogeneic HSCT. Cycle 1 of KPD therapy was complicated by acute hypoxemic respiratory failure due to bilateral pneumonia, and severe thrombocytopenia. A Flow cytometry of peripheral blood detected a small plasma cell clone and the peripheral blood smear showed blastoid neoplastic plasma cells confirming the relapsed of the PCL. Later, pomalidomide was discontinued due to intolerance (profound fatigue and cytopenia). He resumed carfilzomib at an increased dose 56 mg/m2, weekly, with dexamethasone. Progressive PCL was noted in the next several weeks and the patient became transfusion-dependent for red blood cells and platelets. Subsequently, the patient performance status deteriorated. Anti-CD 38 monoclonal antibody immunotherapy with daratumumab was offered but the patient elected for hospice, at-home, and died peacefully 14 months after the initial diagnosis.
Discussion
Even with employing the novel agents available for treatment of clonal plasma cell neoplasms in combination regimen, the treatment of PCL remains challenging. A prompt diagnosis and early stabilization of metabolic challenges, tumor lysis syndrome (TLS), hypercalcemia, acute renal failure and immediate use of multi-agent induction therapy containing novel agents can reduce the risk of early morbidity and may help prolong survival. There is a high response rate with induction therapies containing bortezomib, lenalidomide or thalidomide. Cytotoxic chemotherapies can also be combined with novel agents, which may not be routinely available on the formulary of many USA hospitals as most myeloma care is delivered on the outpatient basis. Rapid and complete responses are often observed after multi-agent induction therapy containing novel agents, but early relapse is common in PCL. For a durable remission, the induction therapy containing proteasome inhibitor (PI) should follow immediately with consolidation therapy, often with HSCT for eligible candidates. In HSCT-ineligible patients, the optimal strategy is unknown but a several cycles of remission induction therapy, followed by long term multi-agent maintenance therapy containing PI and an immunomodulatory agent (IMiD) may provide durable remission. A recently published multicenter retrospective analysis of 348 patients with PCL by Dhakal et al10 concluded that despite incorporation of modern induction therapy containing novel agents and despite increased utilization of both autologous and allogeneic HSCT in the last several years, the survival of PCL patients has not improved in comparison to the historical cohort of PCL patients prior to the widespread use of novel agents. The study underscored that the main reason for the lack of improvement in the survival despite utilization of modern therapies is due to the high relapse rate after HSCT (~76% relapsed at 4 years post-HSCT).10 Allogeneic HSCT is only suitable for a minority of PCL patients as shown in a few small studies10 demonstrating initial good response, a small PFS benefit of 19% at 4 years and overall survival (OS) of only 31% at 4 years. Small studies of tandem double autologous or tandem autologous/allogeneic HSCT showed limited benefit as well.11,12 For autologous or allogeneic HSCT, relapse was the main cause of death in approximately 80% of patients after HSCT. Allogeneic HSCT may have a role for treatment of younger and fit patients, ideally in the context of a clinical trial. For example , Currently an ongoing clinical trial in Europe (EudraCT Number: 2016-003105-33) incorporates a potent second generation irreversible PI, carfilzomib and lenalidomide during remission induction, consolidation, and maintenance phase of therapy and offers allogeneic HSCT to younger, fit, and responding patients.13
The median overall survival of PCL patients, before the use of novel agents, was historically measured in only a few months.14 However, with the incorporation of novel agents (bortezomib, lenalidomide or thalidomide) and autologous HSCT, survival has been reported to improve to 12 months.15 While this represents favorable progress for this patient group, more improvement is necessary to improve outcomes in the treatment of PCL. There is signal showing that further improvement can be achieved with post-HSCT maintenance therapy with novel agents. This was demonstrated by Mina et al16 in their retrospective analysis of 38 patients with PCL treated with bortezomib plus either thalidomide or lenalidomide as induction therapy followed by HSCT and maintenance therapy with bortezomib and lenalidomide for 3 years in majority of the cohort. The median PFS was 20 months, and the median OS was 33 months with PFS better for those who received HSCT (25 vs 6 months). Most important finding was that the patients who received maintenance therapy after HSCT had prolonged median PFS (27 vs 11 months) and a trend toward prolonged OS (median, 38 vs 22 months) compared with those who did not receive maintenance therapy.16
Over half of patients with PCL harbor highly adverse prognostic factor of 17p deletion.17 Bortezomib and other proteasome inhibitors (carfilzomib, ixazomib) are postulated to help overcome the adverse prognostic impact of poor cytogenetics in MM, especially in 17p deletion/TP53 mutation and cytogenetic aberrations involving chromosome 14 in high risk MM.18 Due to this observation and the retrospective data in high risk MM, PI appears to be an important therapeutic tool to be used in the treatment of PCL. To conduct a well-funded randomized phase III study is challenging due to multiple logistic factors and relatively rare nature of PCL. Therefore, randomized phase III studies in PCL are lacking. A phase II study evaluated the effectiveness of bortezomib and chemotherapy (doxorubicin or cyclosphosphamide), followed by HSCT, and 1 year of maintenance therapy with RVD. The results thereof indicated a good response rate (the overall response rate to induction therapy was 69%) and improved median survival to 3 years.19 In another report Nooka et al20 reported encouraging results of RVD maintenance with 51% of patients achieving stringent complete response (sCR) and 96% achieving VGPR or better and median PFS of 32 months and a 3-year OS of 93%. These studies support induction therapy with regimen containing novel agents followed by early HSCT for consolidation and post-HSCT maintenance therapy with RVD for the best results. Only 27% of post-autologous HSCT and only 12% of post allo-HCT PCL patients had received maintenance therapy in the study by Dhakal et al10 which may have contributed to the high relapse rate in the HSCT survivors in their cohort.
In summary, patients who are fit enough to undergo HSCT, and who receive PI containing multi-agent maintenance therapy after HSCT, tend to exhibit improved survival compared to patients who did not undergo HSCT and did not receive maintenance therapy. The standard low dose lenalidomide maintenance monotherapy (10-15 mg daily), prescribed after HSCT in MM, appears to be inadequate in PCL due to reported 50% relapse rate within first year.21 The maintenance strategy with combination therapy of RVD appears to be more effective and is tolerated by majority of patients after HSCT in PCL.21,22 Three factors affecting survival outcomes in PCL appear to be (1) incorporating novel agents with PI and IMiD in the induction therapy, (2) consolidation with HSCT in fit stronger and younger patients, and (3) maintenance therapy containing multiple novel agents (bortezomib and lenalidomide). Patients who are able to tolerate these therapies tend to have the best possible outcomes but relapses still do occur including at unusual sites for example, meningeal relapses after both allogeneic and autologous HSCT.19
The timing and sequencing of newer generation proteasome inhibitors, carfilzomib and ixazomib, is still evolving in PCL and there are no published studies as of the writing of this review. Ixazomib, as an oral agent, may be suitable as a combination therapy with an IMiD, such as lenalidomide or pomalidomide, particularly for maintenance therapy. Both ixazomib and pomalidomide are effective agents against relapsed myeloma, but no study has been conducted to prospectively examine the efficacy of either in PCL. However, a phase II study of pomalidomide, ixazomib, and dexamethasone, in treating patients with previously treated MM or secondary PCL, is currently ongoing and will help answer questions surrounding the effectiveness of these biologic agents for patients with relapsed myeloma and secondary PCL (ClinicalTrials.gov Identifier: NCT02547662). Additionally, a phase I study of filanesib and carfilzomib in treating patients with relapsed or refractory MM, or secondary PCL, was completed and the final results of which are pending (ClinicalTrials.gov Identifier: NCT01372540). The results of a clinical study of carfilzomib, pomalidomide, and dexamethasone (KPD) for relapsed or refractory myeloma indicate that the regimen is a well-tolerated and highly active combination for patients with relapsed/refractory multiple myeloma22 and there is evolving preliminary safety and efficacy data from an ongoing phase II non-randomized clinical trial that examined carfilzomib, lenalidomide and dexamethasone (KRD) for first line treatment of PCL.23 In this study patients eligible for HSCT underwent 4 cycles of KRd induction followed by HSCT, KRd consolidation, and then maintenance with KD until progression. Patients not eligible for HSCT received KRd followed by KD maintenance. The final results are not published yet but preliminary results are encouraging with high response rate and acceptable safety (⩾VGPR in 80% and ⩾CR in 33%).23 The patient in this report received KPD therapy at the time of relapse, with less than partial response (Figure 3) attesting to the much more aggressive biology of relapsed PCL.
Figure 3. The levels of serum free lambda light chain (LLC), lactate dehydrogenase (LDH) and beta 2 microglobulin at the time of diagnosis, relapse, and disease progression.
RVD-PACE = lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; HSCT = hematopoietic stem cell transplantation; KPD = carfilzomib, pomalidomide, and dexamethasone; LDH = lactate dehydrogenase.
Daratumumab and isatuximab are highly effective anti-CD38 monoclonal antibodies approved for MM in combination with novel agents.24-27 Studies are needed to understand how and when to incorporate this highly active novel immunotherapy for treatment of PCL. Unfortunately, a phase I study of daratumumab, in combination with bortezomib, dexamethasone, pegylated liposomal doxorubicin hydrochloride, and lenalidomide in treating patients with PCL has been withdrawn citing budgetary constraints (ClinicalTrials.gov Identifier: NCT03591744). Similarly, antibody drug conjugates, bi-specific antibodies and CAR-T therapy may have a future for the treatment of PCL, but initial trials usually exclude PCL from the inclusion criteria (ClinicalTrials.gov Identifier: NCT03815383).
Venetoclax is an attractive molecule for patients with PCL given its good tolerability as an oral inhibitor of BCL-2 and the high prevalence (30-50%) of the t(11;14) in PCL population.17,18 When venetoclax was evaluated in a phase 1 study in relapsed/refractory MM, 86% of responders had the t(11;14) with overall response rate of 40%, with 27% of patients achieving very good partial response (VGPR) or better in this heavily pretreated population.28 Future studies of PCL should examine venetocalx either as single agent or in combination with novel agents, cellular therapies or immunotherapies.
Finally, due to the high frequency of extra-medullary involvement, international myeloma working group (IMWG) has recommended that PET scan be included in the diagnosis and monitoring of PCL.29
Conclusion
Primary plasma cell leukemia (PCL) is a rare and aggressive hematologic malignancy. Response to induction therapy, with a combination of novel agents (PI and IMiD) with or without cytotoxic chemotherapy, is common but durability of such response is brief unless consolidated with HSCT followed by maintenance therapy. A single agent lenalidomide, as maintenance therapy after HSCT, is inadequate due to high relapse rate. Therefore, it is recommended to incorporate both lenalidomide and bortezomib, in combination with dexamethasone (RVD), for maintenance in PCL when tolerated. For HSCT-ineligible patients, efficacious treatment remains a challenge and we recommend treating with multiple cycles of therapies containing lenalidomide and bortezomib or participation in a clinical trial when available. Employing immunotherapy with monoclonal antibodies, antibody drug conjugates, bi-specific antibodies and engineered cellular therapy such as CAR-T cell therapy, are all attractive concepts that require investigations in future in treatment of PCL. Incorporating newer generation proteasome inhibitors (carfilzomib, ixazomib) and immunomodulatory agent such as pomalidomide may further improve the outcomes. Venetoclax may also play an important role in future for the treatment of PCL harboring t(11;14) mutation. Prospective multicenter studies are required to further understand the definitions, pathogenesis, treatment and prognosis of PCL. Employing novel imaging technique such as PET scan when done at diagnosis and follow up may provide valuable insight in to the status of the disease outside of the bone marrow.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Informed Consent: Informed patient consent was not possible due to the death of the patient. Patient’s surviving spouse provided the verbal informed consent to publish the case report on 7/15/2020. This was documented in patient’s chart in the electronic medical record system of Cleveland Clinic per Cleveland Clinic IRB guidance.
Ethics Approval: Ethics approval is not required for case report because such report does not constitute a research per Cleveland Clinic Institutional Review Board (IRB).
ORCID iDs: Chakra P Chaulagain https://orcid.org/0000-0002-4641-2217
Faiz Anwer https://orcid.org/0000-0001-6914-7439 | Oral | DrugAdministrationRoute | CC BY-NC | 33716516 | 19,065,425 | 2021 |
What was the dosage of drug 'DEXAMETHASONE'? | Management of Primary Plasma Cell Leukemia Remains Challenging Even in the Era of Novel Agents.
Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.
Introduction
Primary plasma cell leukemia (PCL) is a rare and aggressive form of multiple myeloma (MM). The PCL accounts for 0.5% to 2% of MM cases with annual incidence ranging between 0.4 and 1.2 cases per million individuals per year.1,2 Although the definition of PCL is still evolving, a circulating plasma cell count that exceeds 20% of peripheral blood leukocytes, or an absolute plasma cell count >2000/mm3, has been the arbitrary but traditional definition of PCL.3 Multiple myeloma (MM) patients exhibiting circulating plasma cell levels as low as 2%, counted morphologically at the time of diagnosis, demonstrated poor survival, similar to that seen in PCL patients.4 Granell et al5 in another analysis of 482 newly diagnosed MM patients, demonstrated that the presence of ⩾5% circulating plasma cells counted in the peripheral blood has a similar adverse prognostic impact as that of PCL. As also reported, extremely low levels (~0.26%) of circulating clonal plasma cells (CPC) in MM patients, as detected by immunophenotyping (flow cytometry) at the time of diagnosis and treated with novel agents, was also associated with inferior overall survival (OS).6 For example, the 3-year OS for the MM patients with presence of CPC was 67% compared with 87% for those with no CPC.6 Currently, the optimal diagnostic threshold of CPC levels necessary to define PCL is being debated by multiple myeloma experts worldwide.
Primary PCL is rare and arises de novo, but secondary PCL occurs via clonal evolution from a pre-existing MM. This is typically observed following several lines of therapy and often as a terminal event as part of aggressive relapsed of multiple myeloma. Therefore, for the purpose of this report, “PCL” will refer to primary PCL only.
A brief comparison of the clinical features of PCL and MM is presented in Table 1. Compared to MM, PCL is more aggressive at presentation, patients more often than not present with bone marrow insufficiency (in the form of anemia, or thrombocytopenia,) and end organ damage (in the form of hypercalcemia or renal dysfunction) and multi-organ dysfunction. The clinical course is much more aggressive and outcome is associated with poorer prognosis despite treatment in PCL when compared to MM.5 Additionally, higher LDH and B2-microglobulin levels are often observed in PCL, indicating significantly higher disease burden and proliferation rate at the time of presentation. The higher propensity for extra-medullary involvement at diagnosis, in addition to a larger incidence of high-risk cytogenetics (eg, 17p deletion/TP53 mutation and t[14;16]) also reflects the biologically much more aggressive nature of PCL compared to MM.7,8
Table 1. Clinical features of primary plasma cell leukemia (PCL) compared to multiple myeloma.
Clinical features Multiple myeloma Plasma cell leukemia
Incidence 52 to 75 cases per million individuals per year1,2 0.4 to 1.2 cases per million individuals per year or 0.5% to 2% of all MM cases1,2
Age of onset (years) Older (median age, 65-74)23 Relatively younger (median age 55)1-3
Most common subtype IgG (46%) followed by IgA IgG (58%) followed by light chain only
Bone marrow failure (anemia, thrombocytopenia) Less common More common
Hypercalcemia Less common More common
B2-microglobulin + +++
LDH + +++
Renal dysfunction + +++
Tumor lysis syndrome Less common More common
Extra-medullary involvement (liver, spleen, other organs) at diagnosis Less common More common
Deletion 17p/TP53 mutation Less common (~10%) More common (~50%)12
t (11;14) Less common (10%-31%)24 More common 30%12 to 50%14
Prognosis (median overall survival) Better (median OS = 5.2 years with median follow up 5.9 years)25 Worse [median OS 28% at 4 years (range 22%-35%)]10
Abbreviations: LDH, lactate dehydrogenase; MM, multiple myeloma; OS, overall survival; PFS, progression free survival.
In this review, we present a patient with primary PCL who exhibited complete response to induction therapy with lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE), but relapsed quickly after autologous peripheral blood hematopoietic stem cell transplantation (HSCT). A second remission was not inducible with salvage therapy containing carfilzomib, pomalidomide, and dexamethasone, and the patient subsequently died from progression of PCL.
Case Presentation
A 62-year-old male with a history of bladder cancer status post transurethral resection of the bladder tumor 5 years prior, was seen in the emergency room for progressively worsening low back pain for 6 weeks prior to his presentation. His past medical history was complicated and included: anxiety/depression, Type II diabetes, hypertension, coronary artery disease, hypercholesterolemia, morbid obesity, obstructive sleep apnea, and cigaratte smoking(active smoker with 20-pack year history). In the emergency room, patient’s vital signs were normal and laboratory studies showed WBC 10 500/mm3, hemoglobin 13.7 gm/dL, platelets 66 000/mm3, absolute neutrophil count 4400/mm3, absolute lymphocyte count, 4200/mm3, and 13% blasts. The patient’s creatinine, uric acid, bilirubin, calcium, total protein, and serum albumin levels were normal. The LDH was elevated to 958 IU/L (normal range 135-225). A peripheral blood smear showed frequent (53%) atypical plasmacytoid cells (Figure 1A) and the flow cytometry of peripheral blood confirmed 50% monotypic lambda restricted clonal plasma cells consistent with PCL. The Serum protein electrophoresis with immunofixation revealed IgG lambda monoclonal gammopathy, with M spike 0.52 gm/dL, serum free kappa light chain level 4.3 mg/L (range 3.3-19.4), serum free lambda light chain level was 2695 mg/L (range 5.7-26.3), with lambda to kappa ratio of ~627. The Beta-2-microglobulin level was 4.5 mg/L (range 0.3-1.9), and levels of IgG, IgA, and IgM levels were 775, 31, and 13 mg/dL respectively. A lumbar spine magnetic resonance imaging (MRI) showed no vertebral fractures, cord compression, or cauda equina lesions but did report widespread T1 hypointensity, and heterogeneous areas of T2/inversion recovery hyperintensity, consistent with possible leukemic infiltration of the bone marrow. A bone marrow aspiration/biopsy demonstrated plasma cell neoplasm with plasmablastic features replacing the bone marrow cellularity. The MM fluorescent in situ hybridization (FISH) was positive for 17p (TP53) deletion, along with presence of additional copies of chromosomes 5, 9, and 15. Final clinical diagnosis of primary PCL, with 17P deletion, was made. The Positron Emission Tomography (PET) scan (Figure 2A) revealed numerous, intensely fluorodeoxyglucose (FDG) avid, bone marrow lesions throughout the skeleton. A core needle biopsy of right 8th rib lesion (Figure 2A arrow) confirmed the presence of plasmablastic malignancy.
Figure 1. Peripheral blood smear at the time of diagnosis (A) and at the time of relapse (B). Peripheral blood smear, Wright-Giemsa stain, 10× shows circulating large neoplastic plasma cells and thrombocytopenia (A). Peripheral blood smear, Wright-Giemsa stain, 40× shows that the neoplastic plasma cells have blastoid features (B).
Figure 2. Attenuation corrected 3-D maximum intensity projections (MIP) positron emission tomography (PET) images of fluorine 18 FDG PET-CT scan: (A) baseline study, demonstrating numerous bone marrow tracer avid lesions involving cervical, thoracic and lumbar spine as well as bilateral ribs, scapula, humeri, pelvis, sacrum, and bilateral femurs. Maximum standard uptake value (SUVmax) in the sacrum = 27 and (B) follow up post-treatment study demonstrating resolution of previously noted tracer avid lesions. Moderate intensity heterogeneous tracer uptake throughout the bone marrow felt to be related to granulocyte colony stimulation factor therapy effect.
Immediate initialization of induction chemotherapy using a combination regimen with bortezomib, dexamethasone, lenalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE) achieved stringent complete response (sCR) as defined by previously published criteria9 after 3 cycles. The patient received additional 2 cycles of bortezomib, dexamethasone, and lenalidomide (RVD) while waiting for HSCT. To prevent skeletal-related events, he also received zoledronic acid. He underwent HSCT conditioning, with melphalan (200 mg/m2 (MEL 200)), with engraftment on day +11.
The post-HSCT course was complicated with profound physical deconditioning and prolonged hospitalization. The patient developed generalized bone pain and a repeat bone marrow biopsy was performed on day +90 post-HSCT, which reveled 40% blastoid monoclonal plasma cells with plasmablastic features consistent with relapsed PCL.
The patient started salvage chemotherapy using carfilzomib, pomalidomide, and dexamethasone (KPD) to treat relapsed PCL with palliative intention as the patient was not felt to be a candidate for second HSCT or allogeneic HSCT. Cycle 1 of KPD therapy was complicated by acute hypoxemic respiratory failure due to bilateral pneumonia, and severe thrombocytopenia. A Flow cytometry of peripheral blood detected a small plasma cell clone and the peripheral blood smear showed blastoid neoplastic plasma cells confirming the relapsed of the PCL. Later, pomalidomide was discontinued due to intolerance (profound fatigue and cytopenia). He resumed carfilzomib at an increased dose 56 mg/m2, weekly, with dexamethasone. Progressive PCL was noted in the next several weeks and the patient became transfusion-dependent for red blood cells and platelets. Subsequently, the patient performance status deteriorated. Anti-CD 38 monoclonal antibody immunotherapy with daratumumab was offered but the patient elected for hospice, at-home, and died peacefully 14 months after the initial diagnosis.
Discussion
Even with employing the novel agents available for treatment of clonal plasma cell neoplasms in combination regimen, the treatment of PCL remains challenging. A prompt diagnosis and early stabilization of metabolic challenges, tumor lysis syndrome (TLS), hypercalcemia, acute renal failure and immediate use of multi-agent induction therapy containing novel agents can reduce the risk of early morbidity and may help prolong survival. There is a high response rate with induction therapies containing bortezomib, lenalidomide or thalidomide. Cytotoxic chemotherapies can also be combined with novel agents, which may not be routinely available on the formulary of many USA hospitals as most myeloma care is delivered on the outpatient basis. Rapid and complete responses are often observed after multi-agent induction therapy containing novel agents, but early relapse is common in PCL. For a durable remission, the induction therapy containing proteasome inhibitor (PI) should follow immediately with consolidation therapy, often with HSCT for eligible candidates. In HSCT-ineligible patients, the optimal strategy is unknown but a several cycles of remission induction therapy, followed by long term multi-agent maintenance therapy containing PI and an immunomodulatory agent (IMiD) may provide durable remission. A recently published multicenter retrospective analysis of 348 patients with PCL by Dhakal et al10 concluded that despite incorporation of modern induction therapy containing novel agents and despite increased utilization of both autologous and allogeneic HSCT in the last several years, the survival of PCL patients has not improved in comparison to the historical cohort of PCL patients prior to the widespread use of novel agents. The study underscored that the main reason for the lack of improvement in the survival despite utilization of modern therapies is due to the high relapse rate after HSCT (~76% relapsed at 4 years post-HSCT).10 Allogeneic HSCT is only suitable for a minority of PCL patients as shown in a few small studies10 demonstrating initial good response, a small PFS benefit of 19% at 4 years and overall survival (OS) of only 31% at 4 years. Small studies of tandem double autologous or tandem autologous/allogeneic HSCT showed limited benefit as well.11,12 For autologous or allogeneic HSCT, relapse was the main cause of death in approximately 80% of patients after HSCT. Allogeneic HSCT may have a role for treatment of younger and fit patients, ideally in the context of a clinical trial. For example , Currently an ongoing clinical trial in Europe (EudraCT Number: 2016-003105-33) incorporates a potent second generation irreversible PI, carfilzomib and lenalidomide during remission induction, consolidation, and maintenance phase of therapy and offers allogeneic HSCT to younger, fit, and responding patients.13
The median overall survival of PCL patients, before the use of novel agents, was historically measured in only a few months.14 However, with the incorporation of novel agents (bortezomib, lenalidomide or thalidomide) and autologous HSCT, survival has been reported to improve to 12 months.15 While this represents favorable progress for this patient group, more improvement is necessary to improve outcomes in the treatment of PCL. There is signal showing that further improvement can be achieved with post-HSCT maintenance therapy with novel agents. This was demonstrated by Mina et al16 in their retrospective analysis of 38 patients with PCL treated with bortezomib plus either thalidomide or lenalidomide as induction therapy followed by HSCT and maintenance therapy with bortezomib and lenalidomide for 3 years in majority of the cohort. The median PFS was 20 months, and the median OS was 33 months with PFS better for those who received HSCT (25 vs 6 months). Most important finding was that the patients who received maintenance therapy after HSCT had prolonged median PFS (27 vs 11 months) and a trend toward prolonged OS (median, 38 vs 22 months) compared with those who did not receive maintenance therapy.16
Over half of patients with PCL harbor highly adverse prognostic factor of 17p deletion.17 Bortezomib and other proteasome inhibitors (carfilzomib, ixazomib) are postulated to help overcome the adverse prognostic impact of poor cytogenetics in MM, especially in 17p deletion/TP53 mutation and cytogenetic aberrations involving chromosome 14 in high risk MM.18 Due to this observation and the retrospective data in high risk MM, PI appears to be an important therapeutic tool to be used in the treatment of PCL. To conduct a well-funded randomized phase III study is challenging due to multiple logistic factors and relatively rare nature of PCL. Therefore, randomized phase III studies in PCL are lacking. A phase II study evaluated the effectiveness of bortezomib and chemotherapy (doxorubicin or cyclosphosphamide), followed by HSCT, and 1 year of maintenance therapy with RVD. The results thereof indicated a good response rate (the overall response rate to induction therapy was 69%) and improved median survival to 3 years.19 In another report Nooka et al20 reported encouraging results of RVD maintenance with 51% of patients achieving stringent complete response (sCR) and 96% achieving VGPR or better and median PFS of 32 months and a 3-year OS of 93%. These studies support induction therapy with regimen containing novel agents followed by early HSCT for consolidation and post-HSCT maintenance therapy with RVD for the best results. Only 27% of post-autologous HSCT and only 12% of post allo-HCT PCL patients had received maintenance therapy in the study by Dhakal et al10 which may have contributed to the high relapse rate in the HSCT survivors in their cohort.
In summary, patients who are fit enough to undergo HSCT, and who receive PI containing multi-agent maintenance therapy after HSCT, tend to exhibit improved survival compared to patients who did not undergo HSCT and did not receive maintenance therapy. The standard low dose lenalidomide maintenance monotherapy (10-15 mg daily), prescribed after HSCT in MM, appears to be inadequate in PCL due to reported 50% relapse rate within first year.21 The maintenance strategy with combination therapy of RVD appears to be more effective and is tolerated by majority of patients after HSCT in PCL.21,22 Three factors affecting survival outcomes in PCL appear to be (1) incorporating novel agents with PI and IMiD in the induction therapy, (2) consolidation with HSCT in fit stronger and younger patients, and (3) maintenance therapy containing multiple novel agents (bortezomib and lenalidomide). Patients who are able to tolerate these therapies tend to have the best possible outcomes but relapses still do occur including at unusual sites for example, meningeal relapses after both allogeneic and autologous HSCT.19
The timing and sequencing of newer generation proteasome inhibitors, carfilzomib and ixazomib, is still evolving in PCL and there are no published studies as of the writing of this review. Ixazomib, as an oral agent, may be suitable as a combination therapy with an IMiD, such as lenalidomide or pomalidomide, particularly for maintenance therapy. Both ixazomib and pomalidomide are effective agents against relapsed myeloma, but no study has been conducted to prospectively examine the efficacy of either in PCL. However, a phase II study of pomalidomide, ixazomib, and dexamethasone, in treating patients with previously treated MM or secondary PCL, is currently ongoing and will help answer questions surrounding the effectiveness of these biologic agents for patients with relapsed myeloma and secondary PCL (ClinicalTrials.gov Identifier: NCT02547662). Additionally, a phase I study of filanesib and carfilzomib in treating patients with relapsed or refractory MM, or secondary PCL, was completed and the final results of which are pending (ClinicalTrials.gov Identifier: NCT01372540). The results of a clinical study of carfilzomib, pomalidomide, and dexamethasone (KPD) for relapsed or refractory myeloma indicate that the regimen is a well-tolerated and highly active combination for patients with relapsed/refractory multiple myeloma22 and there is evolving preliminary safety and efficacy data from an ongoing phase II non-randomized clinical trial that examined carfilzomib, lenalidomide and dexamethasone (KRD) for first line treatment of PCL.23 In this study patients eligible for HSCT underwent 4 cycles of KRd induction followed by HSCT, KRd consolidation, and then maintenance with KD until progression. Patients not eligible for HSCT received KRd followed by KD maintenance. The final results are not published yet but preliminary results are encouraging with high response rate and acceptable safety (⩾VGPR in 80% and ⩾CR in 33%).23 The patient in this report received KPD therapy at the time of relapse, with less than partial response (Figure 3) attesting to the much more aggressive biology of relapsed PCL.
Figure 3. The levels of serum free lambda light chain (LLC), lactate dehydrogenase (LDH) and beta 2 microglobulin at the time of diagnosis, relapse, and disease progression.
RVD-PACE = lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; HSCT = hematopoietic stem cell transplantation; KPD = carfilzomib, pomalidomide, and dexamethasone; LDH = lactate dehydrogenase.
Daratumumab and isatuximab are highly effective anti-CD38 monoclonal antibodies approved for MM in combination with novel agents.24-27 Studies are needed to understand how and when to incorporate this highly active novel immunotherapy for treatment of PCL. Unfortunately, a phase I study of daratumumab, in combination with bortezomib, dexamethasone, pegylated liposomal doxorubicin hydrochloride, and lenalidomide in treating patients with PCL has been withdrawn citing budgetary constraints (ClinicalTrials.gov Identifier: NCT03591744). Similarly, antibody drug conjugates, bi-specific antibodies and CAR-T therapy may have a future for the treatment of PCL, but initial trials usually exclude PCL from the inclusion criteria (ClinicalTrials.gov Identifier: NCT03815383).
Venetoclax is an attractive molecule for patients with PCL given its good tolerability as an oral inhibitor of BCL-2 and the high prevalence (30-50%) of the t(11;14) in PCL population.17,18 When venetoclax was evaluated in a phase 1 study in relapsed/refractory MM, 86% of responders had the t(11;14) with overall response rate of 40%, with 27% of patients achieving very good partial response (VGPR) or better in this heavily pretreated population.28 Future studies of PCL should examine venetocalx either as single agent or in combination with novel agents, cellular therapies or immunotherapies.
Finally, due to the high frequency of extra-medullary involvement, international myeloma working group (IMWG) has recommended that PET scan be included in the diagnosis and monitoring of PCL.29
Conclusion
Primary plasma cell leukemia (PCL) is a rare and aggressive hematologic malignancy. Response to induction therapy, with a combination of novel agents (PI and IMiD) with or without cytotoxic chemotherapy, is common but durability of such response is brief unless consolidated with HSCT followed by maintenance therapy. A single agent lenalidomide, as maintenance therapy after HSCT, is inadequate due to high relapse rate. Therefore, it is recommended to incorporate both lenalidomide and bortezomib, in combination with dexamethasone (RVD), for maintenance in PCL when tolerated. For HSCT-ineligible patients, efficacious treatment remains a challenge and we recommend treating with multiple cycles of therapies containing lenalidomide and bortezomib or participation in a clinical trial when available. Employing immunotherapy with monoclonal antibodies, antibody drug conjugates, bi-specific antibodies and engineered cellular therapy such as CAR-T cell therapy, are all attractive concepts that require investigations in future in treatment of PCL. Incorporating newer generation proteasome inhibitors (carfilzomib, ixazomib) and immunomodulatory agent such as pomalidomide may further improve the outcomes. Venetoclax may also play an important role in future for the treatment of PCL harboring t(11;14) mutation. Prospective multicenter studies are required to further understand the definitions, pathogenesis, treatment and prognosis of PCL. Employing novel imaging technique such as PET scan when done at diagnosis and follow up may provide valuable insight in to the status of the disease outside of the bone marrow.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Informed Consent: Informed patient consent was not possible due to the death of the patient. Patient’s surviving spouse provided the verbal informed consent to publish the case report on 7/15/2020. This was documented in patient’s chart in the electronic medical record system of Cleveland Clinic per Cleveland Clinic IRB guidance.
Ethics Approval: Ethics approval is not required for case report because such report does not constitute a research per Cleveland Clinic Institutional Review Board (IRB).
ORCID iDs: Chakra P Chaulagain https://orcid.org/0000-0002-4641-2217
Faiz Anwer https://orcid.org/0000-0001-6914-7439 | AS PART OF RVD-PACE, KVD AND KPD REGIMEN | DrugDosageText | CC BY-NC | 33716516 | 19,963,391 | 2021 |
What was the dosage of drug 'MELPHALAN'? | Management of Primary Plasma Cell Leukemia Remains Challenging Even in the Era of Novel Agents.
Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.
Introduction
Primary plasma cell leukemia (PCL) is a rare and aggressive form of multiple myeloma (MM). The PCL accounts for 0.5% to 2% of MM cases with annual incidence ranging between 0.4 and 1.2 cases per million individuals per year.1,2 Although the definition of PCL is still evolving, a circulating plasma cell count that exceeds 20% of peripheral blood leukocytes, or an absolute plasma cell count >2000/mm3, has been the arbitrary but traditional definition of PCL.3 Multiple myeloma (MM) patients exhibiting circulating plasma cell levels as low as 2%, counted morphologically at the time of diagnosis, demonstrated poor survival, similar to that seen in PCL patients.4 Granell et al5 in another analysis of 482 newly diagnosed MM patients, demonstrated that the presence of ⩾5% circulating plasma cells counted in the peripheral blood has a similar adverse prognostic impact as that of PCL. As also reported, extremely low levels (~0.26%) of circulating clonal plasma cells (CPC) in MM patients, as detected by immunophenotyping (flow cytometry) at the time of diagnosis and treated with novel agents, was also associated with inferior overall survival (OS).6 For example, the 3-year OS for the MM patients with presence of CPC was 67% compared with 87% for those with no CPC.6 Currently, the optimal diagnostic threshold of CPC levels necessary to define PCL is being debated by multiple myeloma experts worldwide.
Primary PCL is rare and arises de novo, but secondary PCL occurs via clonal evolution from a pre-existing MM. This is typically observed following several lines of therapy and often as a terminal event as part of aggressive relapsed of multiple myeloma. Therefore, for the purpose of this report, “PCL” will refer to primary PCL only.
A brief comparison of the clinical features of PCL and MM is presented in Table 1. Compared to MM, PCL is more aggressive at presentation, patients more often than not present with bone marrow insufficiency (in the form of anemia, or thrombocytopenia,) and end organ damage (in the form of hypercalcemia or renal dysfunction) and multi-organ dysfunction. The clinical course is much more aggressive and outcome is associated with poorer prognosis despite treatment in PCL when compared to MM.5 Additionally, higher LDH and B2-microglobulin levels are often observed in PCL, indicating significantly higher disease burden and proliferation rate at the time of presentation. The higher propensity for extra-medullary involvement at diagnosis, in addition to a larger incidence of high-risk cytogenetics (eg, 17p deletion/TP53 mutation and t[14;16]) also reflects the biologically much more aggressive nature of PCL compared to MM.7,8
Table 1. Clinical features of primary plasma cell leukemia (PCL) compared to multiple myeloma.
Clinical features Multiple myeloma Plasma cell leukemia
Incidence 52 to 75 cases per million individuals per year1,2 0.4 to 1.2 cases per million individuals per year or 0.5% to 2% of all MM cases1,2
Age of onset (years) Older (median age, 65-74)23 Relatively younger (median age 55)1-3
Most common subtype IgG (46%) followed by IgA IgG (58%) followed by light chain only
Bone marrow failure (anemia, thrombocytopenia) Less common More common
Hypercalcemia Less common More common
B2-microglobulin + +++
LDH + +++
Renal dysfunction + +++
Tumor lysis syndrome Less common More common
Extra-medullary involvement (liver, spleen, other organs) at diagnosis Less common More common
Deletion 17p/TP53 mutation Less common (~10%) More common (~50%)12
t (11;14) Less common (10%-31%)24 More common 30%12 to 50%14
Prognosis (median overall survival) Better (median OS = 5.2 years with median follow up 5.9 years)25 Worse [median OS 28% at 4 years (range 22%-35%)]10
Abbreviations: LDH, lactate dehydrogenase; MM, multiple myeloma; OS, overall survival; PFS, progression free survival.
In this review, we present a patient with primary PCL who exhibited complete response to induction therapy with lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE), but relapsed quickly after autologous peripheral blood hematopoietic stem cell transplantation (HSCT). A second remission was not inducible with salvage therapy containing carfilzomib, pomalidomide, and dexamethasone, and the patient subsequently died from progression of PCL.
Case Presentation
A 62-year-old male with a history of bladder cancer status post transurethral resection of the bladder tumor 5 years prior, was seen in the emergency room for progressively worsening low back pain for 6 weeks prior to his presentation. His past medical history was complicated and included: anxiety/depression, Type II diabetes, hypertension, coronary artery disease, hypercholesterolemia, morbid obesity, obstructive sleep apnea, and cigaratte smoking(active smoker with 20-pack year history). In the emergency room, patient’s vital signs were normal and laboratory studies showed WBC 10 500/mm3, hemoglobin 13.7 gm/dL, platelets 66 000/mm3, absolute neutrophil count 4400/mm3, absolute lymphocyte count, 4200/mm3, and 13% blasts. The patient’s creatinine, uric acid, bilirubin, calcium, total protein, and serum albumin levels were normal. The LDH was elevated to 958 IU/L (normal range 135-225). A peripheral blood smear showed frequent (53%) atypical plasmacytoid cells (Figure 1A) and the flow cytometry of peripheral blood confirmed 50% monotypic lambda restricted clonal plasma cells consistent with PCL. The Serum protein electrophoresis with immunofixation revealed IgG lambda monoclonal gammopathy, with M spike 0.52 gm/dL, serum free kappa light chain level 4.3 mg/L (range 3.3-19.4), serum free lambda light chain level was 2695 mg/L (range 5.7-26.3), with lambda to kappa ratio of ~627. The Beta-2-microglobulin level was 4.5 mg/L (range 0.3-1.9), and levels of IgG, IgA, and IgM levels were 775, 31, and 13 mg/dL respectively. A lumbar spine magnetic resonance imaging (MRI) showed no vertebral fractures, cord compression, or cauda equina lesions but did report widespread T1 hypointensity, and heterogeneous areas of T2/inversion recovery hyperintensity, consistent with possible leukemic infiltration of the bone marrow. A bone marrow aspiration/biopsy demonstrated plasma cell neoplasm with plasmablastic features replacing the bone marrow cellularity. The MM fluorescent in situ hybridization (FISH) was positive for 17p (TP53) deletion, along with presence of additional copies of chromosomes 5, 9, and 15. Final clinical diagnosis of primary PCL, with 17P deletion, was made. The Positron Emission Tomography (PET) scan (Figure 2A) revealed numerous, intensely fluorodeoxyglucose (FDG) avid, bone marrow lesions throughout the skeleton. A core needle biopsy of right 8th rib lesion (Figure 2A arrow) confirmed the presence of plasmablastic malignancy.
Figure 1. Peripheral blood smear at the time of diagnosis (A) and at the time of relapse (B). Peripheral blood smear, Wright-Giemsa stain, 10× shows circulating large neoplastic plasma cells and thrombocytopenia (A). Peripheral blood smear, Wright-Giemsa stain, 40× shows that the neoplastic plasma cells have blastoid features (B).
Figure 2. Attenuation corrected 3-D maximum intensity projections (MIP) positron emission tomography (PET) images of fluorine 18 FDG PET-CT scan: (A) baseline study, demonstrating numerous bone marrow tracer avid lesions involving cervical, thoracic and lumbar spine as well as bilateral ribs, scapula, humeri, pelvis, sacrum, and bilateral femurs. Maximum standard uptake value (SUVmax) in the sacrum = 27 and (B) follow up post-treatment study demonstrating resolution of previously noted tracer avid lesions. Moderate intensity heterogeneous tracer uptake throughout the bone marrow felt to be related to granulocyte colony stimulation factor therapy effect.
Immediate initialization of induction chemotherapy using a combination regimen with bortezomib, dexamethasone, lenalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE) achieved stringent complete response (sCR) as defined by previously published criteria9 after 3 cycles. The patient received additional 2 cycles of bortezomib, dexamethasone, and lenalidomide (RVD) while waiting for HSCT. To prevent skeletal-related events, he also received zoledronic acid. He underwent HSCT conditioning, with melphalan (200 mg/m2 (MEL 200)), with engraftment on day +11.
The post-HSCT course was complicated with profound physical deconditioning and prolonged hospitalization. The patient developed generalized bone pain and a repeat bone marrow biopsy was performed on day +90 post-HSCT, which reveled 40% blastoid monoclonal plasma cells with plasmablastic features consistent with relapsed PCL.
The patient started salvage chemotherapy using carfilzomib, pomalidomide, and dexamethasone (KPD) to treat relapsed PCL with palliative intention as the patient was not felt to be a candidate for second HSCT or allogeneic HSCT. Cycle 1 of KPD therapy was complicated by acute hypoxemic respiratory failure due to bilateral pneumonia, and severe thrombocytopenia. A Flow cytometry of peripheral blood detected a small plasma cell clone and the peripheral blood smear showed blastoid neoplastic plasma cells confirming the relapsed of the PCL. Later, pomalidomide was discontinued due to intolerance (profound fatigue and cytopenia). He resumed carfilzomib at an increased dose 56 mg/m2, weekly, with dexamethasone. Progressive PCL was noted in the next several weeks and the patient became transfusion-dependent for red blood cells and platelets. Subsequently, the patient performance status deteriorated. Anti-CD 38 monoclonal antibody immunotherapy with daratumumab was offered but the patient elected for hospice, at-home, and died peacefully 14 months after the initial diagnosis.
Discussion
Even with employing the novel agents available for treatment of clonal plasma cell neoplasms in combination regimen, the treatment of PCL remains challenging. A prompt diagnosis and early stabilization of metabolic challenges, tumor lysis syndrome (TLS), hypercalcemia, acute renal failure and immediate use of multi-agent induction therapy containing novel agents can reduce the risk of early morbidity and may help prolong survival. There is a high response rate with induction therapies containing bortezomib, lenalidomide or thalidomide. Cytotoxic chemotherapies can also be combined with novel agents, which may not be routinely available on the formulary of many USA hospitals as most myeloma care is delivered on the outpatient basis. Rapid and complete responses are often observed after multi-agent induction therapy containing novel agents, but early relapse is common in PCL. For a durable remission, the induction therapy containing proteasome inhibitor (PI) should follow immediately with consolidation therapy, often with HSCT for eligible candidates. In HSCT-ineligible patients, the optimal strategy is unknown but a several cycles of remission induction therapy, followed by long term multi-agent maintenance therapy containing PI and an immunomodulatory agent (IMiD) may provide durable remission. A recently published multicenter retrospective analysis of 348 patients with PCL by Dhakal et al10 concluded that despite incorporation of modern induction therapy containing novel agents and despite increased utilization of both autologous and allogeneic HSCT in the last several years, the survival of PCL patients has not improved in comparison to the historical cohort of PCL patients prior to the widespread use of novel agents. The study underscored that the main reason for the lack of improvement in the survival despite utilization of modern therapies is due to the high relapse rate after HSCT (~76% relapsed at 4 years post-HSCT).10 Allogeneic HSCT is only suitable for a minority of PCL patients as shown in a few small studies10 demonstrating initial good response, a small PFS benefit of 19% at 4 years and overall survival (OS) of only 31% at 4 years. Small studies of tandem double autologous or tandem autologous/allogeneic HSCT showed limited benefit as well.11,12 For autologous or allogeneic HSCT, relapse was the main cause of death in approximately 80% of patients after HSCT. Allogeneic HSCT may have a role for treatment of younger and fit patients, ideally in the context of a clinical trial. For example , Currently an ongoing clinical trial in Europe (EudraCT Number: 2016-003105-33) incorporates a potent second generation irreversible PI, carfilzomib and lenalidomide during remission induction, consolidation, and maintenance phase of therapy and offers allogeneic HSCT to younger, fit, and responding patients.13
The median overall survival of PCL patients, before the use of novel agents, was historically measured in only a few months.14 However, with the incorporation of novel agents (bortezomib, lenalidomide or thalidomide) and autologous HSCT, survival has been reported to improve to 12 months.15 While this represents favorable progress for this patient group, more improvement is necessary to improve outcomes in the treatment of PCL. There is signal showing that further improvement can be achieved with post-HSCT maintenance therapy with novel agents. This was demonstrated by Mina et al16 in their retrospective analysis of 38 patients with PCL treated with bortezomib plus either thalidomide or lenalidomide as induction therapy followed by HSCT and maintenance therapy with bortezomib and lenalidomide for 3 years in majority of the cohort. The median PFS was 20 months, and the median OS was 33 months with PFS better for those who received HSCT (25 vs 6 months). Most important finding was that the patients who received maintenance therapy after HSCT had prolonged median PFS (27 vs 11 months) and a trend toward prolonged OS (median, 38 vs 22 months) compared with those who did not receive maintenance therapy.16
Over half of patients with PCL harbor highly adverse prognostic factor of 17p deletion.17 Bortezomib and other proteasome inhibitors (carfilzomib, ixazomib) are postulated to help overcome the adverse prognostic impact of poor cytogenetics in MM, especially in 17p deletion/TP53 mutation and cytogenetic aberrations involving chromosome 14 in high risk MM.18 Due to this observation and the retrospective data in high risk MM, PI appears to be an important therapeutic tool to be used in the treatment of PCL. To conduct a well-funded randomized phase III study is challenging due to multiple logistic factors and relatively rare nature of PCL. Therefore, randomized phase III studies in PCL are lacking. A phase II study evaluated the effectiveness of bortezomib and chemotherapy (doxorubicin or cyclosphosphamide), followed by HSCT, and 1 year of maintenance therapy with RVD. The results thereof indicated a good response rate (the overall response rate to induction therapy was 69%) and improved median survival to 3 years.19 In another report Nooka et al20 reported encouraging results of RVD maintenance with 51% of patients achieving stringent complete response (sCR) and 96% achieving VGPR or better and median PFS of 32 months and a 3-year OS of 93%. These studies support induction therapy with regimen containing novel agents followed by early HSCT for consolidation and post-HSCT maintenance therapy with RVD for the best results. Only 27% of post-autologous HSCT and only 12% of post allo-HCT PCL patients had received maintenance therapy in the study by Dhakal et al10 which may have contributed to the high relapse rate in the HSCT survivors in their cohort.
In summary, patients who are fit enough to undergo HSCT, and who receive PI containing multi-agent maintenance therapy after HSCT, tend to exhibit improved survival compared to patients who did not undergo HSCT and did not receive maintenance therapy. The standard low dose lenalidomide maintenance monotherapy (10-15 mg daily), prescribed after HSCT in MM, appears to be inadequate in PCL due to reported 50% relapse rate within first year.21 The maintenance strategy with combination therapy of RVD appears to be more effective and is tolerated by majority of patients after HSCT in PCL.21,22 Three factors affecting survival outcomes in PCL appear to be (1) incorporating novel agents with PI and IMiD in the induction therapy, (2) consolidation with HSCT in fit stronger and younger patients, and (3) maintenance therapy containing multiple novel agents (bortezomib and lenalidomide). Patients who are able to tolerate these therapies tend to have the best possible outcomes but relapses still do occur including at unusual sites for example, meningeal relapses after both allogeneic and autologous HSCT.19
The timing and sequencing of newer generation proteasome inhibitors, carfilzomib and ixazomib, is still evolving in PCL and there are no published studies as of the writing of this review. Ixazomib, as an oral agent, may be suitable as a combination therapy with an IMiD, such as lenalidomide or pomalidomide, particularly for maintenance therapy. Both ixazomib and pomalidomide are effective agents against relapsed myeloma, but no study has been conducted to prospectively examine the efficacy of either in PCL. However, a phase II study of pomalidomide, ixazomib, and dexamethasone, in treating patients with previously treated MM or secondary PCL, is currently ongoing and will help answer questions surrounding the effectiveness of these biologic agents for patients with relapsed myeloma and secondary PCL (ClinicalTrials.gov Identifier: NCT02547662). Additionally, a phase I study of filanesib and carfilzomib in treating patients with relapsed or refractory MM, or secondary PCL, was completed and the final results of which are pending (ClinicalTrials.gov Identifier: NCT01372540). The results of a clinical study of carfilzomib, pomalidomide, and dexamethasone (KPD) for relapsed or refractory myeloma indicate that the regimen is a well-tolerated and highly active combination for patients with relapsed/refractory multiple myeloma22 and there is evolving preliminary safety and efficacy data from an ongoing phase II non-randomized clinical trial that examined carfilzomib, lenalidomide and dexamethasone (KRD) for first line treatment of PCL.23 In this study patients eligible for HSCT underwent 4 cycles of KRd induction followed by HSCT, KRd consolidation, and then maintenance with KD until progression. Patients not eligible for HSCT received KRd followed by KD maintenance. The final results are not published yet but preliminary results are encouraging with high response rate and acceptable safety (⩾VGPR in 80% and ⩾CR in 33%).23 The patient in this report received KPD therapy at the time of relapse, with less than partial response (Figure 3) attesting to the much more aggressive biology of relapsed PCL.
Figure 3. The levels of serum free lambda light chain (LLC), lactate dehydrogenase (LDH) and beta 2 microglobulin at the time of diagnosis, relapse, and disease progression.
RVD-PACE = lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; HSCT = hematopoietic stem cell transplantation; KPD = carfilzomib, pomalidomide, and dexamethasone; LDH = lactate dehydrogenase.
Daratumumab and isatuximab are highly effective anti-CD38 monoclonal antibodies approved for MM in combination with novel agents.24-27 Studies are needed to understand how and when to incorporate this highly active novel immunotherapy for treatment of PCL. Unfortunately, a phase I study of daratumumab, in combination with bortezomib, dexamethasone, pegylated liposomal doxorubicin hydrochloride, and lenalidomide in treating patients with PCL has been withdrawn citing budgetary constraints (ClinicalTrials.gov Identifier: NCT03591744). Similarly, antibody drug conjugates, bi-specific antibodies and CAR-T therapy may have a future for the treatment of PCL, but initial trials usually exclude PCL from the inclusion criteria (ClinicalTrials.gov Identifier: NCT03815383).
Venetoclax is an attractive molecule for patients with PCL given its good tolerability as an oral inhibitor of BCL-2 and the high prevalence (30-50%) of the t(11;14) in PCL population.17,18 When venetoclax was evaluated in a phase 1 study in relapsed/refractory MM, 86% of responders had the t(11;14) with overall response rate of 40%, with 27% of patients achieving very good partial response (VGPR) or better in this heavily pretreated population.28 Future studies of PCL should examine venetocalx either as single agent or in combination with novel agents, cellular therapies or immunotherapies.
Finally, due to the high frequency of extra-medullary involvement, international myeloma working group (IMWG) has recommended that PET scan be included in the diagnosis and monitoring of PCL.29
Conclusion
Primary plasma cell leukemia (PCL) is a rare and aggressive hematologic malignancy. Response to induction therapy, with a combination of novel agents (PI and IMiD) with or without cytotoxic chemotherapy, is common but durability of such response is brief unless consolidated with HSCT followed by maintenance therapy. A single agent lenalidomide, as maintenance therapy after HSCT, is inadequate due to high relapse rate. Therefore, it is recommended to incorporate both lenalidomide and bortezomib, in combination with dexamethasone (RVD), for maintenance in PCL when tolerated. For HSCT-ineligible patients, efficacious treatment remains a challenge and we recommend treating with multiple cycles of therapies containing lenalidomide and bortezomib or participation in a clinical trial when available. Employing immunotherapy with monoclonal antibodies, antibody drug conjugates, bi-specific antibodies and engineered cellular therapy such as CAR-T cell therapy, are all attractive concepts that require investigations in future in treatment of PCL. Incorporating newer generation proteasome inhibitors (carfilzomib, ixazomib) and immunomodulatory agent such as pomalidomide may further improve the outcomes. Venetoclax may also play an important role in future for the treatment of PCL harboring t(11;14) mutation. Prospective multicenter studies are required to further understand the definitions, pathogenesis, treatment and prognosis of PCL. Employing novel imaging technique such as PET scan when done at diagnosis and follow up may provide valuable insight in to the status of the disease outside of the bone marrow.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Informed Consent: Informed patient consent was not possible due to the death of the patient. Patient’s surviving spouse provided the verbal informed consent to publish the case report on 7/15/2020. This was documented in patient’s chart in the electronic medical record system of Cleveland Clinic per Cleveland Clinic IRB guidance.
Ethics Approval: Ethics approval is not required for case report because such report does not constitute a research per Cleveland Clinic Institutional Review Board (IRB).
ORCID iDs: Chakra P Chaulagain https://orcid.org/0000-0002-4641-2217
Faiz Anwer https://orcid.org/0000-0001-6914-7439 | 200 MILLIGRAM/SQ. METER | DrugDosageText | CC BY-NC | 33716516 | 20,010,918 | 2021 |
What was the outcome of reaction 'Disease progression'? | Management of Primary Plasma Cell Leukemia Remains Challenging Even in the Era of Novel Agents.
Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.
Introduction
Primary plasma cell leukemia (PCL) is a rare and aggressive form of multiple myeloma (MM). The PCL accounts for 0.5% to 2% of MM cases with annual incidence ranging between 0.4 and 1.2 cases per million individuals per year.1,2 Although the definition of PCL is still evolving, a circulating plasma cell count that exceeds 20% of peripheral blood leukocytes, or an absolute plasma cell count >2000/mm3, has been the arbitrary but traditional definition of PCL.3 Multiple myeloma (MM) patients exhibiting circulating plasma cell levels as low as 2%, counted morphologically at the time of diagnosis, demonstrated poor survival, similar to that seen in PCL patients.4 Granell et al5 in another analysis of 482 newly diagnosed MM patients, demonstrated that the presence of ⩾5% circulating plasma cells counted in the peripheral blood has a similar adverse prognostic impact as that of PCL. As also reported, extremely low levels (~0.26%) of circulating clonal plasma cells (CPC) in MM patients, as detected by immunophenotyping (flow cytometry) at the time of diagnosis and treated with novel agents, was also associated with inferior overall survival (OS).6 For example, the 3-year OS for the MM patients with presence of CPC was 67% compared with 87% for those with no CPC.6 Currently, the optimal diagnostic threshold of CPC levels necessary to define PCL is being debated by multiple myeloma experts worldwide.
Primary PCL is rare and arises de novo, but secondary PCL occurs via clonal evolution from a pre-existing MM. This is typically observed following several lines of therapy and often as a terminal event as part of aggressive relapsed of multiple myeloma. Therefore, for the purpose of this report, “PCL” will refer to primary PCL only.
A brief comparison of the clinical features of PCL and MM is presented in Table 1. Compared to MM, PCL is more aggressive at presentation, patients more often than not present with bone marrow insufficiency (in the form of anemia, or thrombocytopenia,) and end organ damage (in the form of hypercalcemia or renal dysfunction) and multi-organ dysfunction. The clinical course is much more aggressive and outcome is associated with poorer prognosis despite treatment in PCL when compared to MM.5 Additionally, higher LDH and B2-microglobulin levels are often observed in PCL, indicating significantly higher disease burden and proliferation rate at the time of presentation. The higher propensity for extra-medullary involvement at diagnosis, in addition to a larger incidence of high-risk cytogenetics (eg, 17p deletion/TP53 mutation and t[14;16]) also reflects the biologically much more aggressive nature of PCL compared to MM.7,8
Table 1. Clinical features of primary plasma cell leukemia (PCL) compared to multiple myeloma.
Clinical features Multiple myeloma Plasma cell leukemia
Incidence 52 to 75 cases per million individuals per year1,2 0.4 to 1.2 cases per million individuals per year or 0.5% to 2% of all MM cases1,2
Age of onset (years) Older (median age, 65-74)23 Relatively younger (median age 55)1-3
Most common subtype IgG (46%) followed by IgA IgG (58%) followed by light chain only
Bone marrow failure (anemia, thrombocytopenia) Less common More common
Hypercalcemia Less common More common
B2-microglobulin + +++
LDH + +++
Renal dysfunction + +++
Tumor lysis syndrome Less common More common
Extra-medullary involvement (liver, spleen, other organs) at diagnosis Less common More common
Deletion 17p/TP53 mutation Less common (~10%) More common (~50%)12
t (11;14) Less common (10%-31%)24 More common 30%12 to 50%14
Prognosis (median overall survival) Better (median OS = 5.2 years with median follow up 5.9 years)25 Worse [median OS 28% at 4 years (range 22%-35%)]10
Abbreviations: LDH, lactate dehydrogenase; MM, multiple myeloma; OS, overall survival; PFS, progression free survival.
In this review, we present a patient with primary PCL who exhibited complete response to induction therapy with lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE), but relapsed quickly after autologous peripheral blood hematopoietic stem cell transplantation (HSCT). A second remission was not inducible with salvage therapy containing carfilzomib, pomalidomide, and dexamethasone, and the patient subsequently died from progression of PCL.
Case Presentation
A 62-year-old male with a history of bladder cancer status post transurethral resection of the bladder tumor 5 years prior, was seen in the emergency room for progressively worsening low back pain for 6 weeks prior to his presentation. His past medical history was complicated and included: anxiety/depression, Type II diabetes, hypertension, coronary artery disease, hypercholesterolemia, morbid obesity, obstructive sleep apnea, and cigaratte smoking(active smoker with 20-pack year history). In the emergency room, patient’s vital signs were normal and laboratory studies showed WBC 10 500/mm3, hemoglobin 13.7 gm/dL, platelets 66 000/mm3, absolute neutrophil count 4400/mm3, absolute lymphocyte count, 4200/mm3, and 13% blasts. The patient’s creatinine, uric acid, bilirubin, calcium, total protein, and serum albumin levels were normal. The LDH was elevated to 958 IU/L (normal range 135-225). A peripheral blood smear showed frequent (53%) atypical plasmacytoid cells (Figure 1A) and the flow cytometry of peripheral blood confirmed 50% monotypic lambda restricted clonal plasma cells consistent with PCL. The Serum protein electrophoresis with immunofixation revealed IgG lambda monoclonal gammopathy, with M spike 0.52 gm/dL, serum free kappa light chain level 4.3 mg/L (range 3.3-19.4), serum free lambda light chain level was 2695 mg/L (range 5.7-26.3), with lambda to kappa ratio of ~627. The Beta-2-microglobulin level was 4.5 mg/L (range 0.3-1.9), and levels of IgG, IgA, and IgM levels were 775, 31, and 13 mg/dL respectively. A lumbar spine magnetic resonance imaging (MRI) showed no vertebral fractures, cord compression, or cauda equina lesions but did report widespread T1 hypointensity, and heterogeneous areas of T2/inversion recovery hyperintensity, consistent with possible leukemic infiltration of the bone marrow. A bone marrow aspiration/biopsy demonstrated plasma cell neoplasm with plasmablastic features replacing the bone marrow cellularity. The MM fluorescent in situ hybridization (FISH) was positive for 17p (TP53) deletion, along with presence of additional copies of chromosomes 5, 9, and 15. Final clinical diagnosis of primary PCL, with 17P deletion, was made. The Positron Emission Tomography (PET) scan (Figure 2A) revealed numerous, intensely fluorodeoxyglucose (FDG) avid, bone marrow lesions throughout the skeleton. A core needle biopsy of right 8th rib lesion (Figure 2A arrow) confirmed the presence of plasmablastic malignancy.
Figure 1. Peripheral blood smear at the time of diagnosis (A) and at the time of relapse (B). Peripheral blood smear, Wright-Giemsa stain, 10× shows circulating large neoplastic plasma cells and thrombocytopenia (A). Peripheral blood smear, Wright-Giemsa stain, 40× shows that the neoplastic plasma cells have blastoid features (B).
Figure 2. Attenuation corrected 3-D maximum intensity projections (MIP) positron emission tomography (PET) images of fluorine 18 FDG PET-CT scan: (A) baseline study, demonstrating numerous bone marrow tracer avid lesions involving cervical, thoracic and lumbar spine as well as bilateral ribs, scapula, humeri, pelvis, sacrum, and bilateral femurs. Maximum standard uptake value (SUVmax) in the sacrum = 27 and (B) follow up post-treatment study demonstrating resolution of previously noted tracer avid lesions. Moderate intensity heterogeneous tracer uptake throughout the bone marrow felt to be related to granulocyte colony stimulation factor therapy effect.
Immediate initialization of induction chemotherapy using a combination regimen with bortezomib, dexamethasone, lenalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (RVD-PACE) achieved stringent complete response (sCR) as defined by previously published criteria9 after 3 cycles. The patient received additional 2 cycles of bortezomib, dexamethasone, and lenalidomide (RVD) while waiting for HSCT. To prevent skeletal-related events, he also received zoledronic acid. He underwent HSCT conditioning, with melphalan (200 mg/m2 (MEL 200)), with engraftment on day +11.
The post-HSCT course was complicated with profound physical deconditioning and prolonged hospitalization. The patient developed generalized bone pain and a repeat bone marrow biopsy was performed on day +90 post-HSCT, which reveled 40% blastoid monoclonal plasma cells with plasmablastic features consistent with relapsed PCL.
The patient started salvage chemotherapy using carfilzomib, pomalidomide, and dexamethasone (KPD) to treat relapsed PCL with palliative intention as the patient was not felt to be a candidate for second HSCT or allogeneic HSCT. Cycle 1 of KPD therapy was complicated by acute hypoxemic respiratory failure due to bilateral pneumonia, and severe thrombocytopenia. A Flow cytometry of peripheral blood detected a small plasma cell clone and the peripheral blood smear showed blastoid neoplastic plasma cells confirming the relapsed of the PCL. Later, pomalidomide was discontinued due to intolerance (profound fatigue and cytopenia). He resumed carfilzomib at an increased dose 56 mg/m2, weekly, with dexamethasone. Progressive PCL was noted in the next several weeks and the patient became transfusion-dependent for red blood cells and platelets. Subsequently, the patient performance status deteriorated. Anti-CD 38 monoclonal antibody immunotherapy with daratumumab was offered but the patient elected for hospice, at-home, and died peacefully 14 months after the initial diagnosis.
Discussion
Even with employing the novel agents available for treatment of clonal plasma cell neoplasms in combination regimen, the treatment of PCL remains challenging. A prompt diagnosis and early stabilization of metabolic challenges, tumor lysis syndrome (TLS), hypercalcemia, acute renal failure and immediate use of multi-agent induction therapy containing novel agents can reduce the risk of early morbidity and may help prolong survival. There is a high response rate with induction therapies containing bortezomib, lenalidomide or thalidomide. Cytotoxic chemotherapies can also be combined with novel agents, which may not be routinely available on the formulary of many USA hospitals as most myeloma care is delivered on the outpatient basis. Rapid and complete responses are often observed after multi-agent induction therapy containing novel agents, but early relapse is common in PCL. For a durable remission, the induction therapy containing proteasome inhibitor (PI) should follow immediately with consolidation therapy, often with HSCT for eligible candidates. In HSCT-ineligible patients, the optimal strategy is unknown but a several cycles of remission induction therapy, followed by long term multi-agent maintenance therapy containing PI and an immunomodulatory agent (IMiD) may provide durable remission. A recently published multicenter retrospective analysis of 348 patients with PCL by Dhakal et al10 concluded that despite incorporation of modern induction therapy containing novel agents and despite increased utilization of both autologous and allogeneic HSCT in the last several years, the survival of PCL patients has not improved in comparison to the historical cohort of PCL patients prior to the widespread use of novel agents. The study underscored that the main reason for the lack of improvement in the survival despite utilization of modern therapies is due to the high relapse rate after HSCT (~76% relapsed at 4 years post-HSCT).10 Allogeneic HSCT is only suitable for a minority of PCL patients as shown in a few small studies10 demonstrating initial good response, a small PFS benefit of 19% at 4 years and overall survival (OS) of only 31% at 4 years. Small studies of tandem double autologous or tandem autologous/allogeneic HSCT showed limited benefit as well.11,12 For autologous or allogeneic HSCT, relapse was the main cause of death in approximately 80% of patients after HSCT. Allogeneic HSCT may have a role for treatment of younger and fit patients, ideally in the context of a clinical trial. For example , Currently an ongoing clinical trial in Europe (EudraCT Number: 2016-003105-33) incorporates a potent second generation irreversible PI, carfilzomib and lenalidomide during remission induction, consolidation, and maintenance phase of therapy and offers allogeneic HSCT to younger, fit, and responding patients.13
The median overall survival of PCL patients, before the use of novel agents, was historically measured in only a few months.14 However, with the incorporation of novel agents (bortezomib, lenalidomide or thalidomide) and autologous HSCT, survival has been reported to improve to 12 months.15 While this represents favorable progress for this patient group, more improvement is necessary to improve outcomes in the treatment of PCL. There is signal showing that further improvement can be achieved with post-HSCT maintenance therapy with novel agents. This was demonstrated by Mina et al16 in their retrospective analysis of 38 patients with PCL treated with bortezomib plus either thalidomide or lenalidomide as induction therapy followed by HSCT and maintenance therapy with bortezomib and lenalidomide for 3 years in majority of the cohort. The median PFS was 20 months, and the median OS was 33 months with PFS better for those who received HSCT (25 vs 6 months). Most important finding was that the patients who received maintenance therapy after HSCT had prolonged median PFS (27 vs 11 months) and a trend toward prolonged OS (median, 38 vs 22 months) compared with those who did not receive maintenance therapy.16
Over half of patients with PCL harbor highly adverse prognostic factor of 17p deletion.17 Bortezomib and other proteasome inhibitors (carfilzomib, ixazomib) are postulated to help overcome the adverse prognostic impact of poor cytogenetics in MM, especially in 17p deletion/TP53 mutation and cytogenetic aberrations involving chromosome 14 in high risk MM.18 Due to this observation and the retrospective data in high risk MM, PI appears to be an important therapeutic tool to be used in the treatment of PCL. To conduct a well-funded randomized phase III study is challenging due to multiple logistic factors and relatively rare nature of PCL. Therefore, randomized phase III studies in PCL are lacking. A phase II study evaluated the effectiveness of bortezomib and chemotherapy (doxorubicin or cyclosphosphamide), followed by HSCT, and 1 year of maintenance therapy with RVD. The results thereof indicated a good response rate (the overall response rate to induction therapy was 69%) and improved median survival to 3 years.19 In another report Nooka et al20 reported encouraging results of RVD maintenance with 51% of patients achieving stringent complete response (sCR) and 96% achieving VGPR or better and median PFS of 32 months and a 3-year OS of 93%. These studies support induction therapy with regimen containing novel agents followed by early HSCT for consolidation and post-HSCT maintenance therapy with RVD for the best results. Only 27% of post-autologous HSCT and only 12% of post allo-HCT PCL patients had received maintenance therapy in the study by Dhakal et al10 which may have contributed to the high relapse rate in the HSCT survivors in their cohort.
In summary, patients who are fit enough to undergo HSCT, and who receive PI containing multi-agent maintenance therapy after HSCT, tend to exhibit improved survival compared to patients who did not undergo HSCT and did not receive maintenance therapy. The standard low dose lenalidomide maintenance monotherapy (10-15 mg daily), prescribed after HSCT in MM, appears to be inadequate in PCL due to reported 50% relapse rate within first year.21 The maintenance strategy with combination therapy of RVD appears to be more effective and is tolerated by majority of patients after HSCT in PCL.21,22 Three factors affecting survival outcomes in PCL appear to be (1) incorporating novel agents with PI and IMiD in the induction therapy, (2) consolidation with HSCT in fit stronger and younger patients, and (3) maintenance therapy containing multiple novel agents (bortezomib and lenalidomide). Patients who are able to tolerate these therapies tend to have the best possible outcomes but relapses still do occur including at unusual sites for example, meningeal relapses after both allogeneic and autologous HSCT.19
The timing and sequencing of newer generation proteasome inhibitors, carfilzomib and ixazomib, is still evolving in PCL and there are no published studies as of the writing of this review. Ixazomib, as an oral agent, may be suitable as a combination therapy with an IMiD, such as lenalidomide or pomalidomide, particularly for maintenance therapy. Both ixazomib and pomalidomide are effective agents against relapsed myeloma, but no study has been conducted to prospectively examine the efficacy of either in PCL. However, a phase II study of pomalidomide, ixazomib, and dexamethasone, in treating patients with previously treated MM or secondary PCL, is currently ongoing and will help answer questions surrounding the effectiveness of these biologic agents for patients with relapsed myeloma and secondary PCL (ClinicalTrials.gov Identifier: NCT02547662). Additionally, a phase I study of filanesib and carfilzomib in treating patients with relapsed or refractory MM, or secondary PCL, was completed and the final results of which are pending (ClinicalTrials.gov Identifier: NCT01372540). The results of a clinical study of carfilzomib, pomalidomide, and dexamethasone (KPD) for relapsed or refractory myeloma indicate that the regimen is a well-tolerated and highly active combination for patients with relapsed/refractory multiple myeloma22 and there is evolving preliminary safety and efficacy data from an ongoing phase II non-randomized clinical trial that examined carfilzomib, lenalidomide and dexamethasone (KRD) for first line treatment of PCL.23 In this study patients eligible for HSCT underwent 4 cycles of KRd induction followed by HSCT, KRd consolidation, and then maintenance with KD until progression. Patients not eligible for HSCT received KRd followed by KD maintenance. The final results are not published yet but preliminary results are encouraging with high response rate and acceptable safety (⩾VGPR in 80% and ⩾CR in 33%).23 The patient in this report received KPD therapy at the time of relapse, with less than partial response (Figure 3) attesting to the much more aggressive biology of relapsed PCL.
Figure 3. The levels of serum free lambda light chain (LLC), lactate dehydrogenase (LDH) and beta 2 microglobulin at the time of diagnosis, relapse, and disease progression.
RVD-PACE = lenalidomide, bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide; HSCT = hematopoietic stem cell transplantation; KPD = carfilzomib, pomalidomide, and dexamethasone; LDH = lactate dehydrogenase.
Daratumumab and isatuximab are highly effective anti-CD38 monoclonal antibodies approved for MM in combination with novel agents.24-27 Studies are needed to understand how and when to incorporate this highly active novel immunotherapy for treatment of PCL. Unfortunately, a phase I study of daratumumab, in combination with bortezomib, dexamethasone, pegylated liposomal doxorubicin hydrochloride, and lenalidomide in treating patients with PCL has been withdrawn citing budgetary constraints (ClinicalTrials.gov Identifier: NCT03591744). Similarly, antibody drug conjugates, bi-specific antibodies and CAR-T therapy may have a future for the treatment of PCL, but initial trials usually exclude PCL from the inclusion criteria (ClinicalTrials.gov Identifier: NCT03815383).
Venetoclax is an attractive molecule for patients with PCL given its good tolerability as an oral inhibitor of BCL-2 and the high prevalence (30-50%) of the t(11;14) in PCL population.17,18 When venetoclax was evaluated in a phase 1 study in relapsed/refractory MM, 86% of responders had the t(11;14) with overall response rate of 40%, with 27% of patients achieving very good partial response (VGPR) or better in this heavily pretreated population.28 Future studies of PCL should examine venetocalx either as single agent or in combination with novel agents, cellular therapies or immunotherapies.
Finally, due to the high frequency of extra-medullary involvement, international myeloma working group (IMWG) has recommended that PET scan be included in the diagnosis and monitoring of PCL.29
Conclusion
Primary plasma cell leukemia (PCL) is a rare and aggressive hematologic malignancy. Response to induction therapy, with a combination of novel agents (PI and IMiD) with or without cytotoxic chemotherapy, is common but durability of such response is brief unless consolidated with HSCT followed by maintenance therapy. A single agent lenalidomide, as maintenance therapy after HSCT, is inadequate due to high relapse rate. Therefore, it is recommended to incorporate both lenalidomide and bortezomib, in combination with dexamethasone (RVD), for maintenance in PCL when tolerated. For HSCT-ineligible patients, efficacious treatment remains a challenge and we recommend treating with multiple cycles of therapies containing lenalidomide and bortezomib or participation in a clinical trial when available. Employing immunotherapy with monoclonal antibodies, antibody drug conjugates, bi-specific antibodies and engineered cellular therapy such as CAR-T cell therapy, are all attractive concepts that require investigations in future in treatment of PCL. Incorporating newer generation proteasome inhibitors (carfilzomib, ixazomib) and immunomodulatory agent such as pomalidomide may further improve the outcomes. Venetoclax may also play an important role in future for the treatment of PCL harboring t(11;14) mutation. Prospective multicenter studies are required to further understand the definitions, pathogenesis, treatment and prognosis of PCL. Employing novel imaging technique such as PET scan when done at diagnosis and follow up may provide valuable insight in to the status of the disease outside of the bone marrow.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Informed Consent: Informed patient consent was not possible due to the death of the patient. Patient’s surviving spouse provided the verbal informed consent to publish the case report on 7/15/2020. This was documented in patient’s chart in the electronic medical record system of Cleveland Clinic per Cleveland Clinic IRB guidance.
Ethics Approval: Ethics approval is not required for case report because such report does not constitute a research per Cleveland Clinic Institutional Review Board (IRB).
ORCID iDs: Chakra P Chaulagain https://orcid.org/0000-0002-4641-2217
Faiz Anwer https://orcid.org/0000-0001-6914-7439 | Fatal | ReactionOutcome | CC BY-NC | 33716516 | 19,971,940 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Akathisia'. | A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine.
Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders-Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4-18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4-18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.
Introduction
Tetrabenazine (TBZ; Xenazine®) is a selective and reversible depletor of monoamines from synaptic terminals, preferentially dopamine but also norepinephrine, serotonin, histamine (1). TBZ has a short half-life, which lasts for about 16–24 h, and a rapid onset of action, which is useful in clinical applications (2). The antichorea efficacy of TBZ is related to dopamine depletion, whereas the risk of depression may be mediated by serotonin and norepinephrine depletion, and sedation may be explained by histamine depletion (1).
TBZ could determine a mild increase in the corrected QT (QTc) interval and should be used properly and carefully when combined with other drugs that also increase the interval of QTc or in patients with congenital long QT syndrome and a history of cardiac arrhythmias (3).
The dose of TBZ should be personalized for each patient (3), with significantly interindividual differences in reaching the “optimal dose,” which is the dose that provides the main clinical response with minimal or tolerable adverse events (1).
The principal most common and dose-limiting side effects of TBZ are known. These include sedation (28%), akathisia (13%), parkinsonism (7%), depression (5.5%), anxiety (4%), fatigue (2%), and diarrhea (2%), all of which are usually rapidly reversible upon dosage reduction (1, 2, 4).
To date, there is no consensus regarding the best clinical practice in the pediatric population; in this instance, the administration of TBZ to the adult population is empirically adapted to children and it is “off-label” (5) for a wide variety of hyperkinetic movement disorders (6–10), including dyskinetic cerebral palsy (DCP) (11).
DCP, the second most common type of cerebral palsy (CP) (almost 15%), typically caused by non-progressive basal ganglia and/or thalamus lesions, is characterized by abnormal postures or movements associated with compromised tone regulation and coordination. In DCP, the two typical movement disorders are dystonia and choreoathetosis, which are often co-occurring; dystonia is usually more severe than choreoathetosis, affecting daily activity, quality of life, and social participation (12).
A recent review has highlighted the inadequate evidence for pharmacological interventions in DCP due to the absence of any therapeutic algorithm and the lack of reliable, valid, and agreed-upon age-specific outcome measures (11). To fill this gap, in 2008, the Childhood Movement Disorders Rating Scale (MD-CRS) was proposed and has been recently updated in a revised form (MD-CRS 4-18 R). The scale aimed to define the functional impairment and the severity produced by movement disorder (e.g., dystonia and choreoathetosis) in the pediatric population (11, 13–15). The psychometric properties in DCP of MD-CRS 4–18 R have been recently published (15).
In this study, we have hypothesized that (i) the use of standardized outcome measures, such as MD-CRS, could provide useful data for a retrospective analysis of “off-label” treatment with TBZ obtained from routine clinical practice in the pediatric population affected by DCP; (ii) clinical data could provide a preliminary insight for evaluating the safety and effectiveness of TBZ treatment.
The primary purpose of this study was to retrospectively evaluate a sample of children with DCP who had been treated with TBZ in order to collect data on its efficacy using the MD-CRS 4–18 R as a standardized tool to assess movement disorders in childhood and to detect changes during treatment.
The secondary aims of the study were (1) to determine the impact of TBZ-associated side effects in children with DCP and (2) to analyze the long-term effectiveness and tolerability of TBZ in clinical practice, by evaluating the outcome on a sub-group with a follow-up >2 years.
Materials and Methods
Study Design
A multicenter retrospective longitudinal study was designed involving three Italian Research and Clinical Scientific Institutes: The Department of Developmental Neuroscience of Stella Maris Foundation (Pisa), The Developmental Neurology Unit Institute “C. Besta” (Milano), and The Pediatric Neurology Unit of Fondazione Policlinico “A. Gemelli” (Rome).
These scientific institutes cooperate in the research on movement disorders, sharing agreed clinical and pharmacological protocols, including outcome measures, as MD-CRS. Each Center has its own database for CP data collection, which accounts for at least 600 subjects. From these data sets, cases were selected according to the following inclusion criteria: (a) DCP diagnosis according to the Surveillance of Cerebral Palsy in Europe criteria (16); (b) age ≥4 years; (c) use of TBZ, in mono- or polytherapy—in the presence of polytherapy a stable dosage of other drugs was maintained during the 12 months of follow up, after starting TBZ; (d) videos of Movement Disorder-Childhood Rating Scale which had been collected between July 2007 and December 2019, at the following timing: baseline, i.e., before starting TBZ (T0), after 6 (T1), and 12 (T2) months of treatment. When available, a MD-CRS video after ≥2 years of treatment (long term—LT), was also included (Figure 1).
Figure 1 Design and management of the study with subjects selection.
Procedures
The clinical, demographic, and pharmacological data of each selected subject were extracted from medical records to fulfill the aims of the study.
All participants were classified according to the Gross Motor Function Classification System (GMFCS) for cerebral palsy which is based on self-initiated movement, with emphasis on sitting, transfers, and mobility. A five-level classification system is used to define the subject (from I to V increasing severity) and the distinctions are based on functional limitations, the need for hand-held mobility devices or wheeled mobility, and to a much lesser extent, quality of movement.
A neurological and psychiatric history assessment was carried out on all the subjects.
The psychiatric evaluation was carried out by anamnestic interview and, when available for subjects >6 years, with some items from a semi-structured interview, the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL).
These evaluations were checked before and during the follow up visit.
TBZ treatment indications for all the included subjects were based on multidisciplinary assessments made by child neurologists, an expert in movement disorders, and a pediatric physical therapist.
TBZ administration usually started with a low fixed dose of 6.25 mg (1/4 oral tablet of 25 mg) at least during the first week and was gradually and variably increased according to weight or the clinical neuromotor picture with an aim of reaching a “possible optimal dose,” as in previous reports (1, 4). The dosage was subdivided into 2 or 3 times daily.
Data collection of corrected QT (QTc) was considered if the subjects had performed an EKG before the study, during up-titration, and subsequently annually during follow-up to monitor the risk of a potential increase in the QTc interval or cardiac arrhythmias.
Outcome Measure
All the videos included were recorded according to a standardized videoprotocol and blind scored according to MD-CRS 4–18 R (15).
MD-CRS 4–18 R is a feasible tool to verify the natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP.
The MD-CRS 4–18 R was developed for the assessment of function and disability in various types of movement disorders. This scale requires that the evaluation be recorded according to a specific videoprotocol, and subsequently a score is assigned. The MD-CRS 4–18 R scale is divided into two parts: General Assessment (Part I) and Movement-Disorder Severity (Part II). In Part I, four areas are included: motor function, oral/verbal function, self-care, and attention/alertness, for a total of 15 items. In Part II, the intensity of the prevalent movement abnormality in seven body parts (eye and periorbital region, face, tongue and perioral region, neck, trunk, upper limb, lower limb) in two conditions, at rest and during the execution of specific tasks, is assessed. All items are scored on a 5-point ordinal scale (0–4): zero corresponds to no signs, and 4 corresponds to the most severe findings. The scores for part I and part II and the total score are calculated by statistical analysis obtaining Index I, Index II, and Global Index, respectively. Indexes range come from 0 (severe impairment) to 1 (normal).
The Stella Maris Foundation holds the copyright for the MD-CRS 4–18 R (MD-CRS copyright owner) which is distributed, worldwide, by Mapi Research Trust, a nonprofit organization. For further information and conditions of use of the MD-CRS 4–18 R, consult the online platform Mapi Research Trust, ePROVIDE (https://eprovide.mapi-trust.org).
Ethics Approval
The multicenter study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for treatment “off label” at baseline.
Statistical Analyses
A linear mixed model was used to evaluate the effects of the different timings (T0, T1, and T2 as fixed factors) on each Index (Index I, Index II, and Global Index) adding age and type of MD as random effect. Further analysis with the same approach was also carried out for the subgroup of subjects with the long-term follow-up to evaluate the effects of T0, T1, T2, and LT on each index. For both models, a post hoc analysis between different time points was performed.
Results
Participants
The study included 23 children and adolescents (19 male and 4 female) affected by DCP, age range 4.02–16.30 years at baseline observation (mean age 8.28 years, SD 3.59).
Clinical and demographic data are reported in Table 1.
Table 1 Clinical and demographic data of the sample.
Demographic Participants N = 23
Sex: n (%) Male: 19 (83%)
Female 4 (17%)
Mean age ± SD (range) at T0 (years) 8.28 ± 3.59 (4.02–16.30)
Mean weight ± SD (range) at T0 (kg) 25.13 ± 11.94 (12.00–62.00)
Type of MD: n (%) Dystonia and choreoathetosis: 19 (83%)
Choreoathetosis: 4 (17%)
Etiology: n (%) Hypoxic-ischemic encephalopathy: 17 (74%)
Kernicterus: 4 (17%) Cytomegalovirus infection: 2 (9%)
GMFCS level: n (%) I: 1 (4%)
II: 1 (4%)
III: 2 (9%)
IV: 5 (22%)
V: 14 (61%)
None of the participants presented clinically relevant psychiatric diseases (e.g., significant depression or history of suicidal intent) at baseline (T0).
At the beginning of TBZ treatment, seven subjects with DCP started TBZ in monotherapy, while the others were in polytherapy (e.g., oral baclofen, trihexyphenidyl, benzodiazepines).
A mean dosage of TBZ close to 1 mg/kg was reached (Table 2).
Table 2 Mean and range TBZ dosage at the different time points.
Timing Mean (mg/kg) ± SD Min (mg/kg) Max (mg/kg)
T1 (T0 +6 months) 0.70 ± 0.41 0.30 2.08
T2 (T0 +12 months) 0.84 ± 0.44 0.20 2.08
Long Term 0.97 ± 0.58 0.20 2.08
T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, > 2 year of therapy.
The reduction of the minimum dosage after 12 months and at long term after treatment was related to the maintenance of a stable oral dose between T1 and T2 (5 subjects) without considering the weight increase of the subjects. 4 of the other children reduced their dosage, 2 after 6 months, and 2 after 12 months respectively, due to the occurrence of adverse events (see specific section).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) of TBZ Treatment
A relevant effect of timing was found with a significant reduction of each index between T0 and T1 and between T0 and T2, but not between T1 and T2. Specifically, the mean value of Index I (General Assessment) at T0 0.60 ± 0.06, at T1 0.57 ± 0.06, and at T2 0.57 ± 0.06; the mean value for Index II (MD severity) at T0 was 0.63 ± 0.03, at T1 0.53 ± 0.03, and at T2 0.48 ± 0.03; finally, the mean value of for Global Index at T0 was 0.61 ± 0.05, at T1 0.56 ± 0.05, and at T2 0.54 ± 0.05.
The results of the analysis at T0, T1, and T2 are reported in Table 3.
Table 3 Linear mixed model results during 12 months of follow up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.60 (0.06) >0.05 0.98
T1 −0.03 (0.01) <0.01
T2 −0.03 (0.01) <0.01
Index II Intercept 0.63 (0.03) <0.01 0.73
T1 −0.10 (0.03) <0.01
T2 −0.15 (0.03) <0.01
Global index Intercept 0.61 (0.05) >0.05 0.95
T1 −0.05 (0.01) <0.01
T2 −0.07 (0.01) <0.01
MD-CRS R, movement disorders—childhood rating scale revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
As shown, a significant effect of timing was found at T1 and T2 (Table 3).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) and TBZ Long-Term (LT) Treatment
A small group, 10 subjects, had a long-term follow-up >2 years, and the efficacy of TBZ was still present and stable without important side effects.
In this long-term group (LT), a significant reduction of each Index was found between T0 and T2 but not between T2 and LT. Specifically, the MD-CRS R Index I (General Assessment) mean value was 0.52 ± 0.08 at T0, 0.48 ± 0.08 at T1, 0.49 ± 0.08 at T2, and 0.46 ± 0.08 at long term; the Index II (MD Severity) mean value was 0.62 ± 0.06 at T0, 0.52 ± 0.06 at T1, 0.49 ± 0.06 at T2, and 0.52 ± 0.06 at long term; the Global Index mean value was 0.55 ± 0.07 at T0, 0.49 ± 0.07 at T1, 0.48 ± 0.07 at T2, and 0.48 at long term.
The post hoc analysis between the different time points during 12 months follow up are reported in Table 4. The results of the analysis on the T0, T1, T2, and long-term subgroup are reported in Table 5. As shown, all-time points are significant (Table 5).
Table 4 Post-hoc analysis between the different time points during 12 months follow up.
Timing MD-CRS 4-18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
T0–T1 Index I 0.03 (0.01) 42 2.92 <0.05
Index II 0.10 (0.02) 42 3.81 <0.01
Global index 0.05 (0.01) 42 4.15 <0.01
T0–T2 Index I 0.03 (0.01) 42 3.06 <0.05
Index II 0.15 (0.03) 42.3 5.38 <0.01
Global index 0.07 (0.01) 42 5.40 <0.01
T1–T2 Index I 0.01 (0.01) 42 0.24 > 0.05
Index II 0.05 (0.02) 42.3 1.69 > 0.05
Global index 0.02 (0.01) 42 1.39 > 0.05
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
Table 5 Linear mixed model results during the long-term follow-up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.52 (0.08) <0.01 0.98
T1 −0.05 (0.01) <0.01
T2 −0.03 (0.01) <0.05
LT −0.07 (0.02) <0.01
Index II Intercept 0.62 (0.06) <0.01 0.75
T1 −0.10 (0.04) <0.05
T2 −0.13 (0.04) <0.05
LT −0.09 (0.04) <0.05
Global index Intercept 0.55 (0.07) <0.01 0.96
T1 −0.06 (0.02) <0.01
T2 −0.07 (0.02) <0.01
LT −0.08 (0.02) <0.01
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, >2 year of therapy.
In the following table, the result of the post-hoc analysis of long-term vs. baseline (T0) and T2 are represented (Table 6).
Table 6 Post-hoc analysis between the different time points during the long-term follow-up.
Timing MD-CRS 4–18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
LT–T0 Index I −0.07 (0.02) 28 −4.44 <0.01
Index II −0.09 (0.04) 28.2 −2.13 <0.05
Global index −0.08 (0.02) 28 −3.78 <0.01
LT–T2 Index I −0.03 (0.01) 28 −2.22 <0.05
Index II 0.04 (0.04) 28 0.79 > 0.05
Global index −0.01 (0.02) 28 −0.22 > 0.05
MD-CRS 4–18 R: movement disorders—childhood rating scale 4–18 revised; t0, baseline; t2, 12 months of therapy; lt, long term, >2 year of therapy.
TBZ-Associated Side Effects
TBZ was associated with side effects in 6/23 (26%) subjects: drowsiness in 3/23 (13.04%); dystonia in 2/23 (8.69%); parkinsonism/rigidity in 2/23 (8.69%), anxiety and depressive problems in 1 (4.35%), and akathisia in 1 (4.35%).
Three of these children showed two side effects: one child showed drowsiness after 6 months of treatment and parkinsonism/rigidity after 12 months; another showed dystonia after 6 months of therapy and anxious-depressive problems in the long-term follow-up while the third child presented dystonia and akathisia after 12 months of therapy. Of these subjects, 2 dropped out after T1, one due to dystonia and the other to parkinsonism/rigidity which was treated subsequently with the implantation of Intrathecal Baclofen Pump.
An ECG (included QTc) was performed on all individuals with QTc at baseline (T0) and during up-titration, T1, and T2. The QTc value remained in a normal range in all subjects. Two children reported no clinically significant tachycardia.
Discussion
To our knowledge, this is the first study dedicated to a homogeneous cohort of children with DCP treated with TBZ who were subsequently followed up for at least 1 year and evaluated with a standardized clinical outcome (MD-CRS). Specifically, it represents the results of a routine medical practice by monitoring, by a standardized outcome measure, the use of TBZ when prescribed to children with DCP.
In this study, the use of TBZ was determined by the ineffectiveness of other dystonia and chorea drugs or it was prescribed as an add-on to hyperkinetic movement disorder treatment specifically. The effects of TBZ in children with DCP, either in a dystonic or choreic form, were evaluated, and a clinical improvement was reported regarding both the severity and quantity of the movement disorder in different parts of the body. Improvement in general clinical functioning, such as the motor and self-care abilities and activities, was also detected.
During the titration period, the dose of TBZ was adjusted empirically according to the clinical benefit: the starting dose of 6.25 mg (1/4 oral tablet of 25 mg) was prescribed once daily, and it was titrated gradually increasing it to 6.25 mg weekly or bi-weekly until a maximum of 50 mg/day (2 mg/kg, twice or three times daily).
In order to identify a dose level that clinically reduced movement disorders and was well tolerated, a customized TBZ dose regimen was considered for each subject. This step is a very crucial achievement because it shows the common behavior of clinicians to customize the TBZ dose on the basis of the clinical improvement and functioning. In general, research impacts the clinical behavior, but in this case, as is important in evidence-based medicine (EBM), clinical expertise is essential and works in parallel with research evidence and patient preferences for guiding the EBM.
The data obtained by clinical observation were considered because there is no consensus in literature regarding the optimal medical treatment currently available (11), and the therapies are mainly related to “off-label” drugs anecdotally adapted to children (17).
With regard to the pediatric population, some authors, already many years ago, used a higher initial drug schedule: for age 3–10 years, the final dose was 25 mg twice a day, and for age >10 years the final dose was 50 mg twice a day, but due to the occurrence of drowsiness, the drug regimen was reduced to half dose (18). Other studies (5, 7, 19–21) on the use of TBZ treatment in the hyperkinetic movements, but not related to DCP or children, introduce a wide range of doses of TBZ which vary from 12.5 to 350 mg/day based on the positive drug response.
These findings were confirmed in the current study: in common clinical practice, the optimal dose of TBZ in the treatment of DCP in a pediatric population is individualized and not related to any specific dose per body weight but according to the clinical improvement.
This study, differently from those undertaken previously, also evaluated the efficacy of TBZ in children with DCP by using MD-CRS 4–18 R, a standardized and suitable tool to detect changes during pharmacological treatment.
Indeed, a significant clinical reduction of movement disorder after 6 months was detected, subsequently followed by a “plateau state.” A significant improvement in the general assessment (including Motor function, Oral/verbal function, Self-care and Attention/Alertness) and in the severity of movement disorders (including grading and spread of movement disorders for different body regions) was found after 6 and 12 months of TBZ treatment. No relevant differences were obtained during TBZ administration between 6 and 12 months. These results are crucial from a clinical point of view because they show how the children and parents can be assured that the use of TBZ impacts not only the reduction of movement disorder but also the clinical general functioning such as language and the self-care activities.
No relevant differences were observed in the type and frequency of adverse events reported in scientific literature and this study. The main side effect, in fact, was sedation, followed by dystonia-parkinsonism, depression, and akathisia.
In the long-term subgroup of the sample, a stable improvement was reached after a treatment period of more than 2 years and no important side effects were detected.
Although no side effects relating to heart rhythm abnormalities were detected, according to our experience, EKG evaluations, including QTc measurement, are advisable before starting TBZ, during up-titration (10 days after each dose increasing) and subsequently an annual follow-up.
The main limitations of this study are related to the small size of the sample and the low dosage of TBZ prescribed, compared to the previous reports. A retrospective design based on the review of each Center database and the inclusion criteria (i.e., polytherapy with stable dosage for at least 12 months during TBZ treatment) were probably responsible for the small size of the cohort and the concomitant use of other medications, which could have interfered with the obtained benefits. In addition, the lack of further clinical improvement after the initial reduction of hyperkinetic movements and the absence of severe side effects could be justified by the low dose used in the study cohort.
However, the present study reflects the common clinical practice in the management of an “off-label” drug in children while at the same time embedding valid and agreed-upon age-specific outcome measures.
In conclusion, this study shows that (a) the efficacy of TBZ in children with DCP through a gradual titration has been demonstrated when a standardized outcome measure is used; (b) an optimal TBZ dose should be individualized according to the clinical improvement, such as the reduction of movement disorders; (c) a standardized outcome measure, such as MD-CRS 4–18 R, is also essential during the clinical observational trial and not only in the randomized trial, since it is important to detect changes in an objective way; and (d) good safety and tolerability of TBZ in children has been proved while the occurrence of the side effects should be evaluated through a clinical neurological and psychiatric follow-up and periodic EKG monitoring.
Further studies, however, are needed in children with DCP by randomized clinical trials including parallel groups with different doses of the drug to determine the standardized dosage to be shared in clinical and research settings.
Data Availability Statement
The datasets presented in this article are not readily available because the they contain information that could compromise the privacy of the participants. Requests to access the datasets should be directed to rbattini@fsm.unipi.it.
Ethics Statement
The research was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and local laws. The study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for the treatment “off label” with tetrabenazine.
Author Contributions
RS contributed to the study concept and design and to the execution of the research project and wrote and edited the first draft of the manuscript. GS contributed to the study concept and design, execution and review of the statistical analysis, and manuscript revision. VM organized the database for data collection, generated the tables, and edited the manuscript. NC proofread the data and wrote a part of the manuscript. DR, FS, RD, EP, and MF contributed to the execution of the research project and data collection. GC read, critically revised, and approved the final manuscript. RB conceived the study concept and design, the execution of the research project, interpretation of results, and critical revision of the submitted version. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We wish to thank Miningful Studio for carrying out the statistical analysis and revising the manuscript; and Prof. Ailish Lynam for reviewing the English in the manuscript.
Funding. The authors have not received specific funding sources for this study. The study was partially supported by the Italian Ministry of Health (Grant No. RC2019) and taxpayers' contributions (5 × 1,000) to 2018 IRCCS Stella Maris Foundation. | TETRABENAZINE | DrugsGivenReaction | CC BY | 33716922 | 19,975,465 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Depression'. | A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine.
Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders-Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4-18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4-18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.
Introduction
Tetrabenazine (TBZ; Xenazine®) is a selective and reversible depletor of monoamines from synaptic terminals, preferentially dopamine but also norepinephrine, serotonin, histamine (1). TBZ has a short half-life, which lasts for about 16–24 h, and a rapid onset of action, which is useful in clinical applications (2). The antichorea efficacy of TBZ is related to dopamine depletion, whereas the risk of depression may be mediated by serotonin and norepinephrine depletion, and sedation may be explained by histamine depletion (1).
TBZ could determine a mild increase in the corrected QT (QTc) interval and should be used properly and carefully when combined with other drugs that also increase the interval of QTc or in patients with congenital long QT syndrome and a history of cardiac arrhythmias (3).
The dose of TBZ should be personalized for each patient (3), with significantly interindividual differences in reaching the “optimal dose,” which is the dose that provides the main clinical response with minimal or tolerable adverse events (1).
The principal most common and dose-limiting side effects of TBZ are known. These include sedation (28%), akathisia (13%), parkinsonism (7%), depression (5.5%), anxiety (4%), fatigue (2%), and diarrhea (2%), all of which are usually rapidly reversible upon dosage reduction (1, 2, 4).
To date, there is no consensus regarding the best clinical practice in the pediatric population; in this instance, the administration of TBZ to the adult population is empirically adapted to children and it is “off-label” (5) for a wide variety of hyperkinetic movement disorders (6–10), including dyskinetic cerebral palsy (DCP) (11).
DCP, the second most common type of cerebral palsy (CP) (almost 15%), typically caused by non-progressive basal ganglia and/or thalamus lesions, is characterized by abnormal postures or movements associated with compromised tone regulation and coordination. In DCP, the two typical movement disorders are dystonia and choreoathetosis, which are often co-occurring; dystonia is usually more severe than choreoathetosis, affecting daily activity, quality of life, and social participation (12).
A recent review has highlighted the inadequate evidence for pharmacological interventions in DCP due to the absence of any therapeutic algorithm and the lack of reliable, valid, and agreed-upon age-specific outcome measures (11). To fill this gap, in 2008, the Childhood Movement Disorders Rating Scale (MD-CRS) was proposed and has been recently updated in a revised form (MD-CRS 4-18 R). The scale aimed to define the functional impairment and the severity produced by movement disorder (e.g., dystonia and choreoathetosis) in the pediatric population (11, 13–15). The psychometric properties in DCP of MD-CRS 4–18 R have been recently published (15).
In this study, we have hypothesized that (i) the use of standardized outcome measures, such as MD-CRS, could provide useful data for a retrospective analysis of “off-label” treatment with TBZ obtained from routine clinical practice in the pediatric population affected by DCP; (ii) clinical data could provide a preliminary insight for evaluating the safety and effectiveness of TBZ treatment.
The primary purpose of this study was to retrospectively evaluate a sample of children with DCP who had been treated with TBZ in order to collect data on its efficacy using the MD-CRS 4–18 R as a standardized tool to assess movement disorders in childhood and to detect changes during treatment.
The secondary aims of the study were (1) to determine the impact of TBZ-associated side effects in children with DCP and (2) to analyze the long-term effectiveness and tolerability of TBZ in clinical practice, by evaluating the outcome on a sub-group with a follow-up >2 years.
Materials and Methods
Study Design
A multicenter retrospective longitudinal study was designed involving three Italian Research and Clinical Scientific Institutes: The Department of Developmental Neuroscience of Stella Maris Foundation (Pisa), The Developmental Neurology Unit Institute “C. Besta” (Milano), and The Pediatric Neurology Unit of Fondazione Policlinico “A. Gemelli” (Rome).
These scientific institutes cooperate in the research on movement disorders, sharing agreed clinical and pharmacological protocols, including outcome measures, as MD-CRS. Each Center has its own database for CP data collection, which accounts for at least 600 subjects. From these data sets, cases were selected according to the following inclusion criteria: (a) DCP diagnosis according to the Surveillance of Cerebral Palsy in Europe criteria (16); (b) age ≥4 years; (c) use of TBZ, in mono- or polytherapy—in the presence of polytherapy a stable dosage of other drugs was maintained during the 12 months of follow up, after starting TBZ; (d) videos of Movement Disorder-Childhood Rating Scale which had been collected between July 2007 and December 2019, at the following timing: baseline, i.e., before starting TBZ (T0), after 6 (T1), and 12 (T2) months of treatment. When available, a MD-CRS video after ≥2 years of treatment (long term—LT), was also included (Figure 1).
Figure 1 Design and management of the study with subjects selection.
Procedures
The clinical, demographic, and pharmacological data of each selected subject were extracted from medical records to fulfill the aims of the study.
All participants were classified according to the Gross Motor Function Classification System (GMFCS) for cerebral palsy which is based on self-initiated movement, with emphasis on sitting, transfers, and mobility. A five-level classification system is used to define the subject (from I to V increasing severity) and the distinctions are based on functional limitations, the need for hand-held mobility devices or wheeled mobility, and to a much lesser extent, quality of movement.
A neurological and psychiatric history assessment was carried out on all the subjects.
The psychiatric evaluation was carried out by anamnestic interview and, when available for subjects >6 years, with some items from a semi-structured interview, the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL).
These evaluations were checked before and during the follow up visit.
TBZ treatment indications for all the included subjects were based on multidisciplinary assessments made by child neurologists, an expert in movement disorders, and a pediatric physical therapist.
TBZ administration usually started with a low fixed dose of 6.25 mg (1/4 oral tablet of 25 mg) at least during the first week and was gradually and variably increased according to weight or the clinical neuromotor picture with an aim of reaching a “possible optimal dose,” as in previous reports (1, 4). The dosage was subdivided into 2 or 3 times daily.
Data collection of corrected QT (QTc) was considered if the subjects had performed an EKG before the study, during up-titration, and subsequently annually during follow-up to monitor the risk of a potential increase in the QTc interval or cardiac arrhythmias.
Outcome Measure
All the videos included were recorded according to a standardized videoprotocol and blind scored according to MD-CRS 4–18 R (15).
MD-CRS 4–18 R is a feasible tool to verify the natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP.
The MD-CRS 4–18 R was developed for the assessment of function and disability in various types of movement disorders. This scale requires that the evaluation be recorded according to a specific videoprotocol, and subsequently a score is assigned. The MD-CRS 4–18 R scale is divided into two parts: General Assessment (Part I) and Movement-Disorder Severity (Part II). In Part I, four areas are included: motor function, oral/verbal function, self-care, and attention/alertness, for a total of 15 items. In Part II, the intensity of the prevalent movement abnormality in seven body parts (eye and periorbital region, face, tongue and perioral region, neck, trunk, upper limb, lower limb) in two conditions, at rest and during the execution of specific tasks, is assessed. All items are scored on a 5-point ordinal scale (0–4): zero corresponds to no signs, and 4 corresponds to the most severe findings. The scores for part I and part II and the total score are calculated by statistical analysis obtaining Index I, Index II, and Global Index, respectively. Indexes range come from 0 (severe impairment) to 1 (normal).
The Stella Maris Foundation holds the copyright for the MD-CRS 4–18 R (MD-CRS copyright owner) which is distributed, worldwide, by Mapi Research Trust, a nonprofit organization. For further information and conditions of use of the MD-CRS 4–18 R, consult the online platform Mapi Research Trust, ePROVIDE (https://eprovide.mapi-trust.org).
Ethics Approval
The multicenter study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for treatment “off label” at baseline.
Statistical Analyses
A linear mixed model was used to evaluate the effects of the different timings (T0, T1, and T2 as fixed factors) on each Index (Index I, Index II, and Global Index) adding age and type of MD as random effect. Further analysis with the same approach was also carried out for the subgroup of subjects with the long-term follow-up to evaluate the effects of T0, T1, T2, and LT on each index. For both models, a post hoc analysis between different time points was performed.
Results
Participants
The study included 23 children and adolescents (19 male and 4 female) affected by DCP, age range 4.02–16.30 years at baseline observation (mean age 8.28 years, SD 3.59).
Clinical and demographic data are reported in Table 1.
Table 1 Clinical and demographic data of the sample.
Demographic Participants N = 23
Sex: n (%) Male: 19 (83%)
Female 4 (17%)
Mean age ± SD (range) at T0 (years) 8.28 ± 3.59 (4.02–16.30)
Mean weight ± SD (range) at T0 (kg) 25.13 ± 11.94 (12.00–62.00)
Type of MD: n (%) Dystonia and choreoathetosis: 19 (83%)
Choreoathetosis: 4 (17%)
Etiology: n (%) Hypoxic-ischemic encephalopathy: 17 (74%)
Kernicterus: 4 (17%) Cytomegalovirus infection: 2 (9%)
GMFCS level: n (%) I: 1 (4%)
II: 1 (4%)
III: 2 (9%)
IV: 5 (22%)
V: 14 (61%)
None of the participants presented clinically relevant psychiatric diseases (e.g., significant depression or history of suicidal intent) at baseline (T0).
At the beginning of TBZ treatment, seven subjects with DCP started TBZ in monotherapy, while the others were in polytherapy (e.g., oral baclofen, trihexyphenidyl, benzodiazepines).
A mean dosage of TBZ close to 1 mg/kg was reached (Table 2).
Table 2 Mean and range TBZ dosage at the different time points.
Timing Mean (mg/kg) ± SD Min (mg/kg) Max (mg/kg)
T1 (T0 +6 months) 0.70 ± 0.41 0.30 2.08
T2 (T0 +12 months) 0.84 ± 0.44 0.20 2.08
Long Term 0.97 ± 0.58 0.20 2.08
T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, > 2 year of therapy.
The reduction of the minimum dosage after 12 months and at long term after treatment was related to the maintenance of a stable oral dose between T1 and T2 (5 subjects) without considering the weight increase of the subjects. 4 of the other children reduced their dosage, 2 after 6 months, and 2 after 12 months respectively, due to the occurrence of adverse events (see specific section).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) of TBZ Treatment
A relevant effect of timing was found with a significant reduction of each index between T0 and T1 and between T0 and T2, but not between T1 and T2. Specifically, the mean value of Index I (General Assessment) at T0 0.60 ± 0.06, at T1 0.57 ± 0.06, and at T2 0.57 ± 0.06; the mean value for Index II (MD severity) at T0 was 0.63 ± 0.03, at T1 0.53 ± 0.03, and at T2 0.48 ± 0.03; finally, the mean value of for Global Index at T0 was 0.61 ± 0.05, at T1 0.56 ± 0.05, and at T2 0.54 ± 0.05.
The results of the analysis at T0, T1, and T2 are reported in Table 3.
Table 3 Linear mixed model results during 12 months of follow up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.60 (0.06) >0.05 0.98
T1 −0.03 (0.01) <0.01
T2 −0.03 (0.01) <0.01
Index II Intercept 0.63 (0.03) <0.01 0.73
T1 −0.10 (0.03) <0.01
T2 −0.15 (0.03) <0.01
Global index Intercept 0.61 (0.05) >0.05 0.95
T1 −0.05 (0.01) <0.01
T2 −0.07 (0.01) <0.01
MD-CRS R, movement disorders—childhood rating scale revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
As shown, a significant effect of timing was found at T1 and T2 (Table 3).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) and TBZ Long-Term (LT) Treatment
A small group, 10 subjects, had a long-term follow-up >2 years, and the efficacy of TBZ was still present and stable without important side effects.
In this long-term group (LT), a significant reduction of each Index was found between T0 and T2 but not between T2 and LT. Specifically, the MD-CRS R Index I (General Assessment) mean value was 0.52 ± 0.08 at T0, 0.48 ± 0.08 at T1, 0.49 ± 0.08 at T2, and 0.46 ± 0.08 at long term; the Index II (MD Severity) mean value was 0.62 ± 0.06 at T0, 0.52 ± 0.06 at T1, 0.49 ± 0.06 at T2, and 0.52 ± 0.06 at long term; the Global Index mean value was 0.55 ± 0.07 at T0, 0.49 ± 0.07 at T1, 0.48 ± 0.07 at T2, and 0.48 at long term.
The post hoc analysis between the different time points during 12 months follow up are reported in Table 4. The results of the analysis on the T0, T1, T2, and long-term subgroup are reported in Table 5. As shown, all-time points are significant (Table 5).
Table 4 Post-hoc analysis between the different time points during 12 months follow up.
Timing MD-CRS 4-18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
T0–T1 Index I 0.03 (0.01) 42 2.92 <0.05
Index II 0.10 (0.02) 42 3.81 <0.01
Global index 0.05 (0.01) 42 4.15 <0.01
T0–T2 Index I 0.03 (0.01) 42 3.06 <0.05
Index II 0.15 (0.03) 42.3 5.38 <0.01
Global index 0.07 (0.01) 42 5.40 <0.01
T1–T2 Index I 0.01 (0.01) 42 0.24 > 0.05
Index II 0.05 (0.02) 42.3 1.69 > 0.05
Global index 0.02 (0.01) 42 1.39 > 0.05
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
Table 5 Linear mixed model results during the long-term follow-up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.52 (0.08) <0.01 0.98
T1 −0.05 (0.01) <0.01
T2 −0.03 (0.01) <0.05
LT −0.07 (0.02) <0.01
Index II Intercept 0.62 (0.06) <0.01 0.75
T1 −0.10 (0.04) <0.05
T2 −0.13 (0.04) <0.05
LT −0.09 (0.04) <0.05
Global index Intercept 0.55 (0.07) <0.01 0.96
T1 −0.06 (0.02) <0.01
T2 −0.07 (0.02) <0.01
LT −0.08 (0.02) <0.01
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, >2 year of therapy.
In the following table, the result of the post-hoc analysis of long-term vs. baseline (T0) and T2 are represented (Table 6).
Table 6 Post-hoc analysis between the different time points during the long-term follow-up.
Timing MD-CRS 4–18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
LT–T0 Index I −0.07 (0.02) 28 −4.44 <0.01
Index II −0.09 (0.04) 28.2 −2.13 <0.05
Global index −0.08 (0.02) 28 −3.78 <0.01
LT–T2 Index I −0.03 (0.01) 28 −2.22 <0.05
Index II 0.04 (0.04) 28 0.79 > 0.05
Global index −0.01 (0.02) 28 −0.22 > 0.05
MD-CRS 4–18 R: movement disorders—childhood rating scale 4–18 revised; t0, baseline; t2, 12 months of therapy; lt, long term, >2 year of therapy.
TBZ-Associated Side Effects
TBZ was associated with side effects in 6/23 (26%) subjects: drowsiness in 3/23 (13.04%); dystonia in 2/23 (8.69%); parkinsonism/rigidity in 2/23 (8.69%), anxiety and depressive problems in 1 (4.35%), and akathisia in 1 (4.35%).
Three of these children showed two side effects: one child showed drowsiness after 6 months of treatment and parkinsonism/rigidity after 12 months; another showed dystonia after 6 months of therapy and anxious-depressive problems in the long-term follow-up while the third child presented dystonia and akathisia after 12 months of therapy. Of these subjects, 2 dropped out after T1, one due to dystonia and the other to parkinsonism/rigidity which was treated subsequently with the implantation of Intrathecal Baclofen Pump.
An ECG (included QTc) was performed on all individuals with QTc at baseline (T0) and during up-titration, T1, and T2. The QTc value remained in a normal range in all subjects. Two children reported no clinically significant tachycardia.
Discussion
To our knowledge, this is the first study dedicated to a homogeneous cohort of children with DCP treated with TBZ who were subsequently followed up for at least 1 year and evaluated with a standardized clinical outcome (MD-CRS). Specifically, it represents the results of a routine medical practice by monitoring, by a standardized outcome measure, the use of TBZ when prescribed to children with DCP.
In this study, the use of TBZ was determined by the ineffectiveness of other dystonia and chorea drugs or it was prescribed as an add-on to hyperkinetic movement disorder treatment specifically. The effects of TBZ in children with DCP, either in a dystonic or choreic form, were evaluated, and a clinical improvement was reported regarding both the severity and quantity of the movement disorder in different parts of the body. Improvement in general clinical functioning, such as the motor and self-care abilities and activities, was also detected.
During the titration period, the dose of TBZ was adjusted empirically according to the clinical benefit: the starting dose of 6.25 mg (1/4 oral tablet of 25 mg) was prescribed once daily, and it was titrated gradually increasing it to 6.25 mg weekly or bi-weekly until a maximum of 50 mg/day (2 mg/kg, twice or three times daily).
In order to identify a dose level that clinically reduced movement disorders and was well tolerated, a customized TBZ dose regimen was considered for each subject. This step is a very crucial achievement because it shows the common behavior of clinicians to customize the TBZ dose on the basis of the clinical improvement and functioning. In general, research impacts the clinical behavior, but in this case, as is important in evidence-based medicine (EBM), clinical expertise is essential and works in parallel with research evidence and patient preferences for guiding the EBM.
The data obtained by clinical observation were considered because there is no consensus in literature regarding the optimal medical treatment currently available (11), and the therapies are mainly related to “off-label” drugs anecdotally adapted to children (17).
With regard to the pediatric population, some authors, already many years ago, used a higher initial drug schedule: for age 3–10 years, the final dose was 25 mg twice a day, and for age >10 years the final dose was 50 mg twice a day, but due to the occurrence of drowsiness, the drug regimen was reduced to half dose (18). Other studies (5, 7, 19–21) on the use of TBZ treatment in the hyperkinetic movements, but not related to DCP or children, introduce a wide range of doses of TBZ which vary from 12.5 to 350 mg/day based on the positive drug response.
These findings were confirmed in the current study: in common clinical practice, the optimal dose of TBZ in the treatment of DCP in a pediatric population is individualized and not related to any specific dose per body weight but according to the clinical improvement.
This study, differently from those undertaken previously, also evaluated the efficacy of TBZ in children with DCP by using MD-CRS 4–18 R, a standardized and suitable tool to detect changes during pharmacological treatment.
Indeed, a significant clinical reduction of movement disorder after 6 months was detected, subsequently followed by a “plateau state.” A significant improvement in the general assessment (including Motor function, Oral/verbal function, Self-care and Attention/Alertness) and in the severity of movement disorders (including grading and spread of movement disorders for different body regions) was found after 6 and 12 months of TBZ treatment. No relevant differences were obtained during TBZ administration between 6 and 12 months. These results are crucial from a clinical point of view because they show how the children and parents can be assured that the use of TBZ impacts not only the reduction of movement disorder but also the clinical general functioning such as language and the self-care activities.
No relevant differences were observed in the type and frequency of adverse events reported in scientific literature and this study. The main side effect, in fact, was sedation, followed by dystonia-parkinsonism, depression, and akathisia.
In the long-term subgroup of the sample, a stable improvement was reached after a treatment period of more than 2 years and no important side effects were detected.
Although no side effects relating to heart rhythm abnormalities were detected, according to our experience, EKG evaluations, including QTc measurement, are advisable before starting TBZ, during up-titration (10 days after each dose increasing) and subsequently an annual follow-up.
The main limitations of this study are related to the small size of the sample and the low dosage of TBZ prescribed, compared to the previous reports. A retrospective design based on the review of each Center database and the inclusion criteria (i.e., polytherapy with stable dosage for at least 12 months during TBZ treatment) were probably responsible for the small size of the cohort and the concomitant use of other medications, which could have interfered with the obtained benefits. In addition, the lack of further clinical improvement after the initial reduction of hyperkinetic movements and the absence of severe side effects could be justified by the low dose used in the study cohort.
However, the present study reflects the common clinical practice in the management of an “off-label” drug in children while at the same time embedding valid and agreed-upon age-specific outcome measures.
In conclusion, this study shows that (a) the efficacy of TBZ in children with DCP through a gradual titration has been demonstrated when a standardized outcome measure is used; (b) an optimal TBZ dose should be individualized according to the clinical improvement, such as the reduction of movement disorders; (c) a standardized outcome measure, such as MD-CRS 4–18 R, is also essential during the clinical observational trial and not only in the randomized trial, since it is important to detect changes in an objective way; and (d) good safety and tolerability of TBZ in children has been proved while the occurrence of the side effects should be evaluated through a clinical neurological and psychiatric follow-up and periodic EKG monitoring.
Further studies, however, are needed in children with DCP by randomized clinical trials including parallel groups with different doses of the drug to determine the standardized dosage to be shared in clinical and research settings.
Data Availability Statement
The datasets presented in this article are not readily available because the they contain information that could compromise the privacy of the participants. Requests to access the datasets should be directed to rbattini@fsm.unipi.it.
Ethics Statement
The research was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and local laws. The study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for the treatment “off label” with tetrabenazine.
Author Contributions
RS contributed to the study concept and design and to the execution of the research project and wrote and edited the first draft of the manuscript. GS contributed to the study concept and design, execution and review of the statistical analysis, and manuscript revision. VM organized the database for data collection, generated the tables, and edited the manuscript. NC proofread the data and wrote a part of the manuscript. DR, FS, RD, EP, and MF contributed to the execution of the research project and data collection. GC read, critically revised, and approved the final manuscript. RB conceived the study concept and design, the execution of the research project, interpretation of results, and critical revision of the submitted version. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We wish to thank Miningful Studio for carrying out the statistical analysis and revising the manuscript; and Prof. Ailish Lynam for reviewing the English in the manuscript.
Funding. The authors have not received specific funding sources for this study. The study was partially supported by the Italian Ministry of Health (Grant No. RC2019) and taxpayers' contributions (5 × 1,000) to 2018 IRCCS Stella Maris Foundation. | TETRABENAZINE | DrugsGivenReaction | CC BY | 33716922 | 19,975,765 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dystonia'. | A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine.
Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders-Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4-18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4-18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.
Introduction
Tetrabenazine (TBZ; Xenazine®) is a selective and reversible depletor of monoamines from synaptic terminals, preferentially dopamine but also norepinephrine, serotonin, histamine (1). TBZ has a short half-life, which lasts for about 16–24 h, and a rapid onset of action, which is useful in clinical applications (2). The antichorea efficacy of TBZ is related to dopamine depletion, whereas the risk of depression may be mediated by serotonin and norepinephrine depletion, and sedation may be explained by histamine depletion (1).
TBZ could determine a mild increase in the corrected QT (QTc) interval and should be used properly and carefully when combined with other drugs that also increase the interval of QTc or in patients with congenital long QT syndrome and a history of cardiac arrhythmias (3).
The dose of TBZ should be personalized for each patient (3), with significantly interindividual differences in reaching the “optimal dose,” which is the dose that provides the main clinical response with minimal or tolerable adverse events (1).
The principal most common and dose-limiting side effects of TBZ are known. These include sedation (28%), akathisia (13%), parkinsonism (7%), depression (5.5%), anxiety (4%), fatigue (2%), and diarrhea (2%), all of which are usually rapidly reversible upon dosage reduction (1, 2, 4).
To date, there is no consensus regarding the best clinical practice in the pediatric population; in this instance, the administration of TBZ to the adult population is empirically adapted to children and it is “off-label” (5) for a wide variety of hyperkinetic movement disorders (6–10), including dyskinetic cerebral palsy (DCP) (11).
DCP, the second most common type of cerebral palsy (CP) (almost 15%), typically caused by non-progressive basal ganglia and/or thalamus lesions, is characterized by abnormal postures or movements associated with compromised tone regulation and coordination. In DCP, the two typical movement disorders are dystonia and choreoathetosis, which are often co-occurring; dystonia is usually more severe than choreoathetosis, affecting daily activity, quality of life, and social participation (12).
A recent review has highlighted the inadequate evidence for pharmacological interventions in DCP due to the absence of any therapeutic algorithm and the lack of reliable, valid, and agreed-upon age-specific outcome measures (11). To fill this gap, in 2008, the Childhood Movement Disorders Rating Scale (MD-CRS) was proposed and has been recently updated in a revised form (MD-CRS 4-18 R). The scale aimed to define the functional impairment and the severity produced by movement disorder (e.g., dystonia and choreoathetosis) in the pediatric population (11, 13–15). The psychometric properties in DCP of MD-CRS 4–18 R have been recently published (15).
In this study, we have hypothesized that (i) the use of standardized outcome measures, such as MD-CRS, could provide useful data for a retrospective analysis of “off-label” treatment with TBZ obtained from routine clinical practice in the pediatric population affected by DCP; (ii) clinical data could provide a preliminary insight for evaluating the safety and effectiveness of TBZ treatment.
The primary purpose of this study was to retrospectively evaluate a sample of children with DCP who had been treated with TBZ in order to collect data on its efficacy using the MD-CRS 4–18 R as a standardized tool to assess movement disorders in childhood and to detect changes during treatment.
The secondary aims of the study were (1) to determine the impact of TBZ-associated side effects in children with DCP and (2) to analyze the long-term effectiveness and tolerability of TBZ in clinical practice, by evaluating the outcome on a sub-group with a follow-up >2 years.
Materials and Methods
Study Design
A multicenter retrospective longitudinal study was designed involving three Italian Research and Clinical Scientific Institutes: The Department of Developmental Neuroscience of Stella Maris Foundation (Pisa), The Developmental Neurology Unit Institute “C. Besta” (Milano), and The Pediatric Neurology Unit of Fondazione Policlinico “A. Gemelli” (Rome).
These scientific institutes cooperate in the research on movement disorders, sharing agreed clinical and pharmacological protocols, including outcome measures, as MD-CRS. Each Center has its own database for CP data collection, which accounts for at least 600 subjects. From these data sets, cases were selected according to the following inclusion criteria: (a) DCP diagnosis according to the Surveillance of Cerebral Palsy in Europe criteria (16); (b) age ≥4 years; (c) use of TBZ, in mono- or polytherapy—in the presence of polytherapy a stable dosage of other drugs was maintained during the 12 months of follow up, after starting TBZ; (d) videos of Movement Disorder-Childhood Rating Scale which had been collected between July 2007 and December 2019, at the following timing: baseline, i.e., before starting TBZ (T0), after 6 (T1), and 12 (T2) months of treatment. When available, a MD-CRS video after ≥2 years of treatment (long term—LT), was also included (Figure 1).
Figure 1 Design and management of the study with subjects selection.
Procedures
The clinical, demographic, and pharmacological data of each selected subject were extracted from medical records to fulfill the aims of the study.
All participants were classified according to the Gross Motor Function Classification System (GMFCS) for cerebral palsy which is based on self-initiated movement, with emphasis on sitting, transfers, and mobility. A five-level classification system is used to define the subject (from I to V increasing severity) and the distinctions are based on functional limitations, the need for hand-held mobility devices or wheeled mobility, and to a much lesser extent, quality of movement.
A neurological and psychiatric history assessment was carried out on all the subjects.
The psychiatric evaluation was carried out by anamnestic interview and, when available for subjects >6 years, with some items from a semi-structured interview, the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL).
These evaluations were checked before and during the follow up visit.
TBZ treatment indications for all the included subjects were based on multidisciplinary assessments made by child neurologists, an expert in movement disorders, and a pediatric physical therapist.
TBZ administration usually started with a low fixed dose of 6.25 mg (1/4 oral tablet of 25 mg) at least during the first week and was gradually and variably increased according to weight or the clinical neuromotor picture with an aim of reaching a “possible optimal dose,” as in previous reports (1, 4). The dosage was subdivided into 2 or 3 times daily.
Data collection of corrected QT (QTc) was considered if the subjects had performed an EKG before the study, during up-titration, and subsequently annually during follow-up to monitor the risk of a potential increase in the QTc interval or cardiac arrhythmias.
Outcome Measure
All the videos included were recorded according to a standardized videoprotocol and blind scored according to MD-CRS 4–18 R (15).
MD-CRS 4–18 R is a feasible tool to verify the natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP.
The MD-CRS 4–18 R was developed for the assessment of function and disability in various types of movement disorders. This scale requires that the evaluation be recorded according to a specific videoprotocol, and subsequently a score is assigned. The MD-CRS 4–18 R scale is divided into two parts: General Assessment (Part I) and Movement-Disorder Severity (Part II). In Part I, four areas are included: motor function, oral/verbal function, self-care, and attention/alertness, for a total of 15 items. In Part II, the intensity of the prevalent movement abnormality in seven body parts (eye and periorbital region, face, tongue and perioral region, neck, trunk, upper limb, lower limb) in two conditions, at rest and during the execution of specific tasks, is assessed. All items are scored on a 5-point ordinal scale (0–4): zero corresponds to no signs, and 4 corresponds to the most severe findings. The scores for part I and part II and the total score are calculated by statistical analysis obtaining Index I, Index II, and Global Index, respectively. Indexes range come from 0 (severe impairment) to 1 (normal).
The Stella Maris Foundation holds the copyright for the MD-CRS 4–18 R (MD-CRS copyright owner) which is distributed, worldwide, by Mapi Research Trust, a nonprofit organization. For further information and conditions of use of the MD-CRS 4–18 R, consult the online platform Mapi Research Trust, ePROVIDE (https://eprovide.mapi-trust.org).
Ethics Approval
The multicenter study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for treatment “off label” at baseline.
Statistical Analyses
A linear mixed model was used to evaluate the effects of the different timings (T0, T1, and T2 as fixed factors) on each Index (Index I, Index II, and Global Index) adding age and type of MD as random effect. Further analysis with the same approach was also carried out for the subgroup of subjects with the long-term follow-up to evaluate the effects of T0, T1, T2, and LT on each index. For both models, a post hoc analysis between different time points was performed.
Results
Participants
The study included 23 children and adolescents (19 male and 4 female) affected by DCP, age range 4.02–16.30 years at baseline observation (mean age 8.28 years, SD 3.59).
Clinical and demographic data are reported in Table 1.
Table 1 Clinical and demographic data of the sample.
Demographic Participants N = 23
Sex: n (%) Male: 19 (83%)
Female 4 (17%)
Mean age ± SD (range) at T0 (years) 8.28 ± 3.59 (4.02–16.30)
Mean weight ± SD (range) at T0 (kg) 25.13 ± 11.94 (12.00–62.00)
Type of MD: n (%) Dystonia and choreoathetosis: 19 (83%)
Choreoathetosis: 4 (17%)
Etiology: n (%) Hypoxic-ischemic encephalopathy: 17 (74%)
Kernicterus: 4 (17%) Cytomegalovirus infection: 2 (9%)
GMFCS level: n (%) I: 1 (4%)
II: 1 (4%)
III: 2 (9%)
IV: 5 (22%)
V: 14 (61%)
None of the participants presented clinically relevant psychiatric diseases (e.g., significant depression or history of suicidal intent) at baseline (T0).
At the beginning of TBZ treatment, seven subjects with DCP started TBZ in monotherapy, while the others were in polytherapy (e.g., oral baclofen, trihexyphenidyl, benzodiazepines).
A mean dosage of TBZ close to 1 mg/kg was reached (Table 2).
Table 2 Mean and range TBZ dosage at the different time points.
Timing Mean (mg/kg) ± SD Min (mg/kg) Max (mg/kg)
T1 (T0 +6 months) 0.70 ± 0.41 0.30 2.08
T2 (T0 +12 months) 0.84 ± 0.44 0.20 2.08
Long Term 0.97 ± 0.58 0.20 2.08
T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, > 2 year of therapy.
The reduction of the minimum dosage after 12 months and at long term after treatment was related to the maintenance of a stable oral dose between T1 and T2 (5 subjects) without considering the weight increase of the subjects. 4 of the other children reduced their dosage, 2 after 6 months, and 2 after 12 months respectively, due to the occurrence of adverse events (see specific section).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) of TBZ Treatment
A relevant effect of timing was found with a significant reduction of each index between T0 and T1 and between T0 and T2, but not between T1 and T2. Specifically, the mean value of Index I (General Assessment) at T0 0.60 ± 0.06, at T1 0.57 ± 0.06, and at T2 0.57 ± 0.06; the mean value for Index II (MD severity) at T0 was 0.63 ± 0.03, at T1 0.53 ± 0.03, and at T2 0.48 ± 0.03; finally, the mean value of for Global Index at T0 was 0.61 ± 0.05, at T1 0.56 ± 0.05, and at T2 0.54 ± 0.05.
The results of the analysis at T0, T1, and T2 are reported in Table 3.
Table 3 Linear mixed model results during 12 months of follow up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.60 (0.06) >0.05 0.98
T1 −0.03 (0.01) <0.01
T2 −0.03 (0.01) <0.01
Index II Intercept 0.63 (0.03) <0.01 0.73
T1 −0.10 (0.03) <0.01
T2 −0.15 (0.03) <0.01
Global index Intercept 0.61 (0.05) >0.05 0.95
T1 −0.05 (0.01) <0.01
T2 −0.07 (0.01) <0.01
MD-CRS R, movement disorders—childhood rating scale revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
As shown, a significant effect of timing was found at T1 and T2 (Table 3).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) and TBZ Long-Term (LT) Treatment
A small group, 10 subjects, had a long-term follow-up >2 years, and the efficacy of TBZ was still present and stable without important side effects.
In this long-term group (LT), a significant reduction of each Index was found between T0 and T2 but not between T2 and LT. Specifically, the MD-CRS R Index I (General Assessment) mean value was 0.52 ± 0.08 at T0, 0.48 ± 0.08 at T1, 0.49 ± 0.08 at T2, and 0.46 ± 0.08 at long term; the Index II (MD Severity) mean value was 0.62 ± 0.06 at T0, 0.52 ± 0.06 at T1, 0.49 ± 0.06 at T2, and 0.52 ± 0.06 at long term; the Global Index mean value was 0.55 ± 0.07 at T0, 0.49 ± 0.07 at T1, 0.48 ± 0.07 at T2, and 0.48 at long term.
The post hoc analysis between the different time points during 12 months follow up are reported in Table 4. The results of the analysis on the T0, T1, T2, and long-term subgroup are reported in Table 5. As shown, all-time points are significant (Table 5).
Table 4 Post-hoc analysis between the different time points during 12 months follow up.
Timing MD-CRS 4-18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
T0–T1 Index I 0.03 (0.01) 42 2.92 <0.05
Index II 0.10 (0.02) 42 3.81 <0.01
Global index 0.05 (0.01) 42 4.15 <0.01
T0–T2 Index I 0.03 (0.01) 42 3.06 <0.05
Index II 0.15 (0.03) 42.3 5.38 <0.01
Global index 0.07 (0.01) 42 5.40 <0.01
T1–T2 Index I 0.01 (0.01) 42 0.24 > 0.05
Index II 0.05 (0.02) 42.3 1.69 > 0.05
Global index 0.02 (0.01) 42 1.39 > 0.05
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
Table 5 Linear mixed model results during the long-term follow-up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.52 (0.08) <0.01 0.98
T1 −0.05 (0.01) <0.01
T2 −0.03 (0.01) <0.05
LT −0.07 (0.02) <0.01
Index II Intercept 0.62 (0.06) <0.01 0.75
T1 −0.10 (0.04) <0.05
T2 −0.13 (0.04) <0.05
LT −0.09 (0.04) <0.05
Global index Intercept 0.55 (0.07) <0.01 0.96
T1 −0.06 (0.02) <0.01
T2 −0.07 (0.02) <0.01
LT −0.08 (0.02) <0.01
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, >2 year of therapy.
In the following table, the result of the post-hoc analysis of long-term vs. baseline (T0) and T2 are represented (Table 6).
Table 6 Post-hoc analysis between the different time points during the long-term follow-up.
Timing MD-CRS 4–18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
LT–T0 Index I −0.07 (0.02) 28 −4.44 <0.01
Index II −0.09 (0.04) 28.2 −2.13 <0.05
Global index −0.08 (0.02) 28 −3.78 <0.01
LT–T2 Index I −0.03 (0.01) 28 −2.22 <0.05
Index II 0.04 (0.04) 28 0.79 > 0.05
Global index −0.01 (0.02) 28 −0.22 > 0.05
MD-CRS 4–18 R: movement disorders—childhood rating scale 4–18 revised; t0, baseline; t2, 12 months of therapy; lt, long term, >2 year of therapy.
TBZ-Associated Side Effects
TBZ was associated with side effects in 6/23 (26%) subjects: drowsiness in 3/23 (13.04%); dystonia in 2/23 (8.69%); parkinsonism/rigidity in 2/23 (8.69%), anxiety and depressive problems in 1 (4.35%), and akathisia in 1 (4.35%).
Three of these children showed two side effects: one child showed drowsiness after 6 months of treatment and parkinsonism/rigidity after 12 months; another showed dystonia after 6 months of therapy and anxious-depressive problems in the long-term follow-up while the third child presented dystonia and akathisia after 12 months of therapy. Of these subjects, 2 dropped out after T1, one due to dystonia and the other to parkinsonism/rigidity which was treated subsequently with the implantation of Intrathecal Baclofen Pump.
An ECG (included QTc) was performed on all individuals with QTc at baseline (T0) and during up-titration, T1, and T2. The QTc value remained in a normal range in all subjects. Two children reported no clinically significant tachycardia.
Discussion
To our knowledge, this is the first study dedicated to a homogeneous cohort of children with DCP treated with TBZ who were subsequently followed up for at least 1 year and evaluated with a standardized clinical outcome (MD-CRS). Specifically, it represents the results of a routine medical practice by monitoring, by a standardized outcome measure, the use of TBZ when prescribed to children with DCP.
In this study, the use of TBZ was determined by the ineffectiveness of other dystonia and chorea drugs or it was prescribed as an add-on to hyperkinetic movement disorder treatment specifically. The effects of TBZ in children with DCP, either in a dystonic or choreic form, were evaluated, and a clinical improvement was reported regarding both the severity and quantity of the movement disorder in different parts of the body. Improvement in general clinical functioning, such as the motor and self-care abilities and activities, was also detected.
During the titration period, the dose of TBZ was adjusted empirically according to the clinical benefit: the starting dose of 6.25 mg (1/4 oral tablet of 25 mg) was prescribed once daily, and it was titrated gradually increasing it to 6.25 mg weekly or bi-weekly until a maximum of 50 mg/day (2 mg/kg, twice or three times daily).
In order to identify a dose level that clinically reduced movement disorders and was well tolerated, a customized TBZ dose regimen was considered for each subject. This step is a very crucial achievement because it shows the common behavior of clinicians to customize the TBZ dose on the basis of the clinical improvement and functioning. In general, research impacts the clinical behavior, but in this case, as is important in evidence-based medicine (EBM), clinical expertise is essential and works in parallel with research evidence and patient preferences for guiding the EBM.
The data obtained by clinical observation were considered because there is no consensus in literature regarding the optimal medical treatment currently available (11), and the therapies are mainly related to “off-label” drugs anecdotally adapted to children (17).
With regard to the pediatric population, some authors, already many years ago, used a higher initial drug schedule: for age 3–10 years, the final dose was 25 mg twice a day, and for age >10 years the final dose was 50 mg twice a day, but due to the occurrence of drowsiness, the drug regimen was reduced to half dose (18). Other studies (5, 7, 19–21) on the use of TBZ treatment in the hyperkinetic movements, but not related to DCP or children, introduce a wide range of doses of TBZ which vary from 12.5 to 350 mg/day based on the positive drug response.
These findings were confirmed in the current study: in common clinical practice, the optimal dose of TBZ in the treatment of DCP in a pediatric population is individualized and not related to any specific dose per body weight but according to the clinical improvement.
This study, differently from those undertaken previously, also evaluated the efficacy of TBZ in children with DCP by using MD-CRS 4–18 R, a standardized and suitable tool to detect changes during pharmacological treatment.
Indeed, a significant clinical reduction of movement disorder after 6 months was detected, subsequently followed by a “plateau state.” A significant improvement in the general assessment (including Motor function, Oral/verbal function, Self-care and Attention/Alertness) and in the severity of movement disorders (including grading and spread of movement disorders for different body regions) was found after 6 and 12 months of TBZ treatment. No relevant differences were obtained during TBZ administration between 6 and 12 months. These results are crucial from a clinical point of view because they show how the children and parents can be assured that the use of TBZ impacts not only the reduction of movement disorder but also the clinical general functioning such as language and the self-care activities.
No relevant differences were observed in the type and frequency of adverse events reported in scientific literature and this study. The main side effect, in fact, was sedation, followed by dystonia-parkinsonism, depression, and akathisia.
In the long-term subgroup of the sample, a stable improvement was reached after a treatment period of more than 2 years and no important side effects were detected.
Although no side effects relating to heart rhythm abnormalities were detected, according to our experience, EKG evaluations, including QTc measurement, are advisable before starting TBZ, during up-titration (10 days after each dose increasing) and subsequently an annual follow-up.
The main limitations of this study are related to the small size of the sample and the low dosage of TBZ prescribed, compared to the previous reports. A retrospective design based on the review of each Center database and the inclusion criteria (i.e., polytherapy with stable dosage for at least 12 months during TBZ treatment) were probably responsible for the small size of the cohort and the concomitant use of other medications, which could have interfered with the obtained benefits. In addition, the lack of further clinical improvement after the initial reduction of hyperkinetic movements and the absence of severe side effects could be justified by the low dose used in the study cohort.
However, the present study reflects the common clinical practice in the management of an “off-label” drug in children while at the same time embedding valid and agreed-upon age-specific outcome measures.
In conclusion, this study shows that (a) the efficacy of TBZ in children with DCP through a gradual titration has been demonstrated when a standardized outcome measure is used; (b) an optimal TBZ dose should be individualized according to the clinical improvement, such as the reduction of movement disorders; (c) a standardized outcome measure, such as MD-CRS 4–18 R, is also essential during the clinical observational trial and not only in the randomized trial, since it is important to detect changes in an objective way; and (d) good safety and tolerability of TBZ in children has been proved while the occurrence of the side effects should be evaluated through a clinical neurological and psychiatric follow-up and periodic EKG monitoring.
Further studies, however, are needed in children with DCP by randomized clinical trials including parallel groups with different doses of the drug to determine the standardized dosage to be shared in clinical and research settings.
Data Availability Statement
The datasets presented in this article are not readily available because the they contain information that could compromise the privacy of the participants. Requests to access the datasets should be directed to rbattini@fsm.unipi.it.
Ethics Statement
The research was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and local laws. The study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for the treatment “off label” with tetrabenazine.
Author Contributions
RS contributed to the study concept and design and to the execution of the research project and wrote and edited the first draft of the manuscript. GS contributed to the study concept and design, execution and review of the statistical analysis, and manuscript revision. VM organized the database for data collection, generated the tables, and edited the manuscript. NC proofread the data and wrote a part of the manuscript. DR, FS, RD, EP, and MF contributed to the execution of the research project and data collection. GC read, critically revised, and approved the final manuscript. RB conceived the study concept and design, the execution of the research project, interpretation of results, and critical revision of the submitted version. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We wish to thank Miningful Studio for carrying out the statistical analysis and revising the manuscript; and Prof. Ailish Lynam for reviewing the English in the manuscript.
Funding. The authors have not received specific funding sources for this study. The study was partially supported by the Italian Ministry of Health (Grant No. RC2019) and taxpayers' contributions (5 × 1,000) to 2018 IRCCS Stella Maris Foundation. | TETRABENAZINE | DrugsGivenReaction | CC BY | 33716922 | 19,975,765 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Muscle rigidity'. | A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine.
Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders-Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4-18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4-18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.
Introduction
Tetrabenazine (TBZ; Xenazine®) is a selective and reversible depletor of monoamines from synaptic terminals, preferentially dopamine but also norepinephrine, serotonin, histamine (1). TBZ has a short half-life, which lasts for about 16–24 h, and a rapid onset of action, which is useful in clinical applications (2). The antichorea efficacy of TBZ is related to dopamine depletion, whereas the risk of depression may be mediated by serotonin and norepinephrine depletion, and sedation may be explained by histamine depletion (1).
TBZ could determine a mild increase in the corrected QT (QTc) interval and should be used properly and carefully when combined with other drugs that also increase the interval of QTc or in patients with congenital long QT syndrome and a history of cardiac arrhythmias (3).
The dose of TBZ should be personalized for each patient (3), with significantly interindividual differences in reaching the “optimal dose,” which is the dose that provides the main clinical response with minimal or tolerable adverse events (1).
The principal most common and dose-limiting side effects of TBZ are known. These include sedation (28%), akathisia (13%), parkinsonism (7%), depression (5.5%), anxiety (4%), fatigue (2%), and diarrhea (2%), all of which are usually rapidly reversible upon dosage reduction (1, 2, 4).
To date, there is no consensus regarding the best clinical practice in the pediatric population; in this instance, the administration of TBZ to the adult population is empirically adapted to children and it is “off-label” (5) for a wide variety of hyperkinetic movement disorders (6–10), including dyskinetic cerebral palsy (DCP) (11).
DCP, the second most common type of cerebral palsy (CP) (almost 15%), typically caused by non-progressive basal ganglia and/or thalamus lesions, is characterized by abnormal postures or movements associated with compromised tone regulation and coordination. In DCP, the two typical movement disorders are dystonia and choreoathetosis, which are often co-occurring; dystonia is usually more severe than choreoathetosis, affecting daily activity, quality of life, and social participation (12).
A recent review has highlighted the inadequate evidence for pharmacological interventions in DCP due to the absence of any therapeutic algorithm and the lack of reliable, valid, and agreed-upon age-specific outcome measures (11). To fill this gap, in 2008, the Childhood Movement Disorders Rating Scale (MD-CRS) was proposed and has been recently updated in a revised form (MD-CRS 4-18 R). The scale aimed to define the functional impairment and the severity produced by movement disorder (e.g., dystonia and choreoathetosis) in the pediatric population (11, 13–15). The psychometric properties in DCP of MD-CRS 4–18 R have been recently published (15).
In this study, we have hypothesized that (i) the use of standardized outcome measures, such as MD-CRS, could provide useful data for a retrospective analysis of “off-label” treatment with TBZ obtained from routine clinical practice in the pediatric population affected by DCP; (ii) clinical data could provide a preliminary insight for evaluating the safety and effectiveness of TBZ treatment.
The primary purpose of this study was to retrospectively evaluate a sample of children with DCP who had been treated with TBZ in order to collect data on its efficacy using the MD-CRS 4–18 R as a standardized tool to assess movement disorders in childhood and to detect changes during treatment.
The secondary aims of the study were (1) to determine the impact of TBZ-associated side effects in children with DCP and (2) to analyze the long-term effectiveness and tolerability of TBZ in clinical practice, by evaluating the outcome on a sub-group with a follow-up >2 years.
Materials and Methods
Study Design
A multicenter retrospective longitudinal study was designed involving three Italian Research and Clinical Scientific Institutes: The Department of Developmental Neuroscience of Stella Maris Foundation (Pisa), The Developmental Neurology Unit Institute “C. Besta” (Milano), and The Pediatric Neurology Unit of Fondazione Policlinico “A. Gemelli” (Rome).
These scientific institutes cooperate in the research on movement disorders, sharing agreed clinical and pharmacological protocols, including outcome measures, as MD-CRS. Each Center has its own database for CP data collection, which accounts for at least 600 subjects. From these data sets, cases were selected according to the following inclusion criteria: (a) DCP diagnosis according to the Surveillance of Cerebral Palsy in Europe criteria (16); (b) age ≥4 years; (c) use of TBZ, in mono- or polytherapy—in the presence of polytherapy a stable dosage of other drugs was maintained during the 12 months of follow up, after starting TBZ; (d) videos of Movement Disorder-Childhood Rating Scale which had been collected between July 2007 and December 2019, at the following timing: baseline, i.e., before starting TBZ (T0), after 6 (T1), and 12 (T2) months of treatment. When available, a MD-CRS video after ≥2 years of treatment (long term—LT), was also included (Figure 1).
Figure 1 Design and management of the study with subjects selection.
Procedures
The clinical, demographic, and pharmacological data of each selected subject were extracted from medical records to fulfill the aims of the study.
All participants were classified according to the Gross Motor Function Classification System (GMFCS) for cerebral palsy which is based on self-initiated movement, with emphasis on sitting, transfers, and mobility. A five-level classification system is used to define the subject (from I to V increasing severity) and the distinctions are based on functional limitations, the need for hand-held mobility devices or wheeled mobility, and to a much lesser extent, quality of movement.
A neurological and psychiatric history assessment was carried out on all the subjects.
The psychiatric evaluation was carried out by anamnestic interview and, when available for subjects >6 years, with some items from a semi-structured interview, the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL).
These evaluations were checked before and during the follow up visit.
TBZ treatment indications for all the included subjects were based on multidisciplinary assessments made by child neurologists, an expert in movement disorders, and a pediatric physical therapist.
TBZ administration usually started with a low fixed dose of 6.25 mg (1/4 oral tablet of 25 mg) at least during the first week and was gradually and variably increased according to weight or the clinical neuromotor picture with an aim of reaching a “possible optimal dose,” as in previous reports (1, 4). The dosage was subdivided into 2 or 3 times daily.
Data collection of corrected QT (QTc) was considered if the subjects had performed an EKG before the study, during up-titration, and subsequently annually during follow-up to monitor the risk of a potential increase in the QTc interval or cardiac arrhythmias.
Outcome Measure
All the videos included were recorded according to a standardized videoprotocol and blind scored according to MD-CRS 4–18 R (15).
MD-CRS 4–18 R is a feasible tool to verify the natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP.
The MD-CRS 4–18 R was developed for the assessment of function and disability in various types of movement disorders. This scale requires that the evaluation be recorded according to a specific videoprotocol, and subsequently a score is assigned. The MD-CRS 4–18 R scale is divided into two parts: General Assessment (Part I) and Movement-Disorder Severity (Part II). In Part I, four areas are included: motor function, oral/verbal function, self-care, and attention/alertness, for a total of 15 items. In Part II, the intensity of the prevalent movement abnormality in seven body parts (eye and periorbital region, face, tongue and perioral region, neck, trunk, upper limb, lower limb) in two conditions, at rest and during the execution of specific tasks, is assessed. All items are scored on a 5-point ordinal scale (0–4): zero corresponds to no signs, and 4 corresponds to the most severe findings. The scores for part I and part II and the total score are calculated by statistical analysis obtaining Index I, Index II, and Global Index, respectively. Indexes range come from 0 (severe impairment) to 1 (normal).
The Stella Maris Foundation holds the copyright for the MD-CRS 4–18 R (MD-CRS copyright owner) which is distributed, worldwide, by Mapi Research Trust, a nonprofit organization. For further information and conditions of use of the MD-CRS 4–18 R, consult the online platform Mapi Research Trust, ePROVIDE (https://eprovide.mapi-trust.org).
Ethics Approval
The multicenter study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for treatment “off label” at baseline.
Statistical Analyses
A linear mixed model was used to evaluate the effects of the different timings (T0, T1, and T2 as fixed factors) on each Index (Index I, Index II, and Global Index) adding age and type of MD as random effect. Further analysis with the same approach was also carried out for the subgroup of subjects with the long-term follow-up to evaluate the effects of T0, T1, T2, and LT on each index. For both models, a post hoc analysis between different time points was performed.
Results
Participants
The study included 23 children and adolescents (19 male and 4 female) affected by DCP, age range 4.02–16.30 years at baseline observation (mean age 8.28 years, SD 3.59).
Clinical and demographic data are reported in Table 1.
Table 1 Clinical and demographic data of the sample.
Demographic Participants N = 23
Sex: n (%) Male: 19 (83%)
Female 4 (17%)
Mean age ± SD (range) at T0 (years) 8.28 ± 3.59 (4.02–16.30)
Mean weight ± SD (range) at T0 (kg) 25.13 ± 11.94 (12.00–62.00)
Type of MD: n (%) Dystonia and choreoathetosis: 19 (83%)
Choreoathetosis: 4 (17%)
Etiology: n (%) Hypoxic-ischemic encephalopathy: 17 (74%)
Kernicterus: 4 (17%) Cytomegalovirus infection: 2 (9%)
GMFCS level: n (%) I: 1 (4%)
II: 1 (4%)
III: 2 (9%)
IV: 5 (22%)
V: 14 (61%)
None of the participants presented clinically relevant psychiatric diseases (e.g., significant depression or history of suicidal intent) at baseline (T0).
At the beginning of TBZ treatment, seven subjects with DCP started TBZ in monotherapy, while the others were in polytherapy (e.g., oral baclofen, trihexyphenidyl, benzodiazepines).
A mean dosage of TBZ close to 1 mg/kg was reached (Table 2).
Table 2 Mean and range TBZ dosage at the different time points.
Timing Mean (mg/kg) ± SD Min (mg/kg) Max (mg/kg)
T1 (T0 +6 months) 0.70 ± 0.41 0.30 2.08
T2 (T0 +12 months) 0.84 ± 0.44 0.20 2.08
Long Term 0.97 ± 0.58 0.20 2.08
T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, > 2 year of therapy.
The reduction of the minimum dosage after 12 months and at long term after treatment was related to the maintenance of a stable oral dose between T1 and T2 (5 subjects) without considering the weight increase of the subjects. 4 of the other children reduced their dosage, 2 after 6 months, and 2 after 12 months respectively, due to the occurrence of adverse events (see specific section).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) of TBZ Treatment
A relevant effect of timing was found with a significant reduction of each index between T0 and T1 and between T0 and T2, but not between T1 and T2. Specifically, the mean value of Index I (General Assessment) at T0 0.60 ± 0.06, at T1 0.57 ± 0.06, and at T2 0.57 ± 0.06; the mean value for Index II (MD severity) at T0 was 0.63 ± 0.03, at T1 0.53 ± 0.03, and at T2 0.48 ± 0.03; finally, the mean value of for Global Index at T0 was 0.61 ± 0.05, at T1 0.56 ± 0.05, and at T2 0.54 ± 0.05.
The results of the analysis at T0, T1, and T2 are reported in Table 3.
Table 3 Linear mixed model results during 12 months of follow up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.60 (0.06) >0.05 0.98
T1 −0.03 (0.01) <0.01
T2 −0.03 (0.01) <0.01
Index II Intercept 0.63 (0.03) <0.01 0.73
T1 −0.10 (0.03) <0.01
T2 −0.15 (0.03) <0.01
Global index Intercept 0.61 (0.05) >0.05 0.95
T1 −0.05 (0.01) <0.01
T2 −0.07 (0.01) <0.01
MD-CRS R, movement disorders—childhood rating scale revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
As shown, a significant effect of timing was found at T1 and T2 (Table 3).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) and TBZ Long-Term (LT) Treatment
A small group, 10 subjects, had a long-term follow-up >2 years, and the efficacy of TBZ was still present and stable without important side effects.
In this long-term group (LT), a significant reduction of each Index was found between T0 and T2 but not between T2 and LT. Specifically, the MD-CRS R Index I (General Assessment) mean value was 0.52 ± 0.08 at T0, 0.48 ± 0.08 at T1, 0.49 ± 0.08 at T2, and 0.46 ± 0.08 at long term; the Index II (MD Severity) mean value was 0.62 ± 0.06 at T0, 0.52 ± 0.06 at T1, 0.49 ± 0.06 at T2, and 0.52 ± 0.06 at long term; the Global Index mean value was 0.55 ± 0.07 at T0, 0.49 ± 0.07 at T1, 0.48 ± 0.07 at T2, and 0.48 at long term.
The post hoc analysis between the different time points during 12 months follow up are reported in Table 4. The results of the analysis on the T0, T1, T2, and long-term subgroup are reported in Table 5. As shown, all-time points are significant (Table 5).
Table 4 Post-hoc analysis between the different time points during 12 months follow up.
Timing MD-CRS 4-18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
T0–T1 Index I 0.03 (0.01) 42 2.92 <0.05
Index II 0.10 (0.02) 42 3.81 <0.01
Global index 0.05 (0.01) 42 4.15 <0.01
T0–T2 Index I 0.03 (0.01) 42 3.06 <0.05
Index II 0.15 (0.03) 42.3 5.38 <0.01
Global index 0.07 (0.01) 42 5.40 <0.01
T1–T2 Index I 0.01 (0.01) 42 0.24 > 0.05
Index II 0.05 (0.02) 42.3 1.69 > 0.05
Global index 0.02 (0.01) 42 1.39 > 0.05
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
Table 5 Linear mixed model results during the long-term follow-up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.52 (0.08) <0.01 0.98
T1 −0.05 (0.01) <0.01
T2 −0.03 (0.01) <0.05
LT −0.07 (0.02) <0.01
Index II Intercept 0.62 (0.06) <0.01 0.75
T1 −0.10 (0.04) <0.05
T2 −0.13 (0.04) <0.05
LT −0.09 (0.04) <0.05
Global index Intercept 0.55 (0.07) <0.01 0.96
T1 −0.06 (0.02) <0.01
T2 −0.07 (0.02) <0.01
LT −0.08 (0.02) <0.01
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, >2 year of therapy.
In the following table, the result of the post-hoc analysis of long-term vs. baseline (T0) and T2 are represented (Table 6).
Table 6 Post-hoc analysis between the different time points during the long-term follow-up.
Timing MD-CRS 4–18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
LT–T0 Index I −0.07 (0.02) 28 −4.44 <0.01
Index II −0.09 (0.04) 28.2 −2.13 <0.05
Global index −0.08 (0.02) 28 −3.78 <0.01
LT–T2 Index I −0.03 (0.01) 28 −2.22 <0.05
Index II 0.04 (0.04) 28 0.79 > 0.05
Global index −0.01 (0.02) 28 −0.22 > 0.05
MD-CRS 4–18 R: movement disorders—childhood rating scale 4–18 revised; t0, baseline; t2, 12 months of therapy; lt, long term, >2 year of therapy.
TBZ-Associated Side Effects
TBZ was associated with side effects in 6/23 (26%) subjects: drowsiness in 3/23 (13.04%); dystonia in 2/23 (8.69%); parkinsonism/rigidity in 2/23 (8.69%), anxiety and depressive problems in 1 (4.35%), and akathisia in 1 (4.35%).
Three of these children showed two side effects: one child showed drowsiness after 6 months of treatment and parkinsonism/rigidity after 12 months; another showed dystonia after 6 months of therapy and anxious-depressive problems in the long-term follow-up while the third child presented dystonia and akathisia after 12 months of therapy. Of these subjects, 2 dropped out after T1, one due to dystonia and the other to parkinsonism/rigidity which was treated subsequently with the implantation of Intrathecal Baclofen Pump.
An ECG (included QTc) was performed on all individuals with QTc at baseline (T0) and during up-titration, T1, and T2. The QTc value remained in a normal range in all subjects. Two children reported no clinically significant tachycardia.
Discussion
To our knowledge, this is the first study dedicated to a homogeneous cohort of children with DCP treated with TBZ who were subsequently followed up for at least 1 year and evaluated with a standardized clinical outcome (MD-CRS). Specifically, it represents the results of a routine medical practice by monitoring, by a standardized outcome measure, the use of TBZ when prescribed to children with DCP.
In this study, the use of TBZ was determined by the ineffectiveness of other dystonia and chorea drugs or it was prescribed as an add-on to hyperkinetic movement disorder treatment specifically. The effects of TBZ in children with DCP, either in a dystonic or choreic form, were evaluated, and a clinical improvement was reported regarding both the severity and quantity of the movement disorder in different parts of the body. Improvement in general clinical functioning, such as the motor and self-care abilities and activities, was also detected.
During the titration period, the dose of TBZ was adjusted empirically according to the clinical benefit: the starting dose of 6.25 mg (1/4 oral tablet of 25 mg) was prescribed once daily, and it was titrated gradually increasing it to 6.25 mg weekly or bi-weekly until a maximum of 50 mg/day (2 mg/kg, twice or three times daily).
In order to identify a dose level that clinically reduced movement disorders and was well tolerated, a customized TBZ dose regimen was considered for each subject. This step is a very crucial achievement because it shows the common behavior of clinicians to customize the TBZ dose on the basis of the clinical improvement and functioning. In general, research impacts the clinical behavior, but in this case, as is important in evidence-based medicine (EBM), clinical expertise is essential and works in parallel with research evidence and patient preferences for guiding the EBM.
The data obtained by clinical observation were considered because there is no consensus in literature regarding the optimal medical treatment currently available (11), and the therapies are mainly related to “off-label” drugs anecdotally adapted to children (17).
With regard to the pediatric population, some authors, already many years ago, used a higher initial drug schedule: for age 3–10 years, the final dose was 25 mg twice a day, and for age >10 years the final dose was 50 mg twice a day, but due to the occurrence of drowsiness, the drug regimen was reduced to half dose (18). Other studies (5, 7, 19–21) on the use of TBZ treatment in the hyperkinetic movements, but not related to DCP or children, introduce a wide range of doses of TBZ which vary from 12.5 to 350 mg/day based on the positive drug response.
These findings were confirmed in the current study: in common clinical practice, the optimal dose of TBZ in the treatment of DCP in a pediatric population is individualized and not related to any specific dose per body weight but according to the clinical improvement.
This study, differently from those undertaken previously, also evaluated the efficacy of TBZ in children with DCP by using MD-CRS 4–18 R, a standardized and suitable tool to detect changes during pharmacological treatment.
Indeed, a significant clinical reduction of movement disorder after 6 months was detected, subsequently followed by a “plateau state.” A significant improvement in the general assessment (including Motor function, Oral/verbal function, Self-care and Attention/Alertness) and in the severity of movement disorders (including grading and spread of movement disorders for different body regions) was found after 6 and 12 months of TBZ treatment. No relevant differences were obtained during TBZ administration between 6 and 12 months. These results are crucial from a clinical point of view because they show how the children and parents can be assured that the use of TBZ impacts not only the reduction of movement disorder but also the clinical general functioning such as language and the self-care activities.
No relevant differences were observed in the type and frequency of adverse events reported in scientific literature and this study. The main side effect, in fact, was sedation, followed by dystonia-parkinsonism, depression, and akathisia.
In the long-term subgroup of the sample, a stable improvement was reached after a treatment period of more than 2 years and no important side effects were detected.
Although no side effects relating to heart rhythm abnormalities were detected, according to our experience, EKG evaluations, including QTc measurement, are advisable before starting TBZ, during up-titration (10 days after each dose increasing) and subsequently an annual follow-up.
The main limitations of this study are related to the small size of the sample and the low dosage of TBZ prescribed, compared to the previous reports. A retrospective design based on the review of each Center database and the inclusion criteria (i.e., polytherapy with stable dosage for at least 12 months during TBZ treatment) were probably responsible for the small size of the cohort and the concomitant use of other medications, which could have interfered with the obtained benefits. In addition, the lack of further clinical improvement after the initial reduction of hyperkinetic movements and the absence of severe side effects could be justified by the low dose used in the study cohort.
However, the present study reflects the common clinical practice in the management of an “off-label” drug in children while at the same time embedding valid and agreed-upon age-specific outcome measures.
In conclusion, this study shows that (a) the efficacy of TBZ in children with DCP through a gradual titration has been demonstrated when a standardized outcome measure is used; (b) an optimal TBZ dose should be individualized according to the clinical improvement, such as the reduction of movement disorders; (c) a standardized outcome measure, such as MD-CRS 4–18 R, is also essential during the clinical observational trial and not only in the randomized trial, since it is important to detect changes in an objective way; and (d) good safety and tolerability of TBZ in children has been proved while the occurrence of the side effects should be evaluated through a clinical neurological and psychiatric follow-up and periodic EKG monitoring.
Further studies, however, are needed in children with DCP by randomized clinical trials including parallel groups with different doses of the drug to determine the standardized dosage to be shared in clinical and research settings.
Data Availability Statement
The datasets presented in this article are not readily available because the they contain information that could compromise the privacy of the participants. Requests to access the datasets should be directed to rbattini@fsm.unipi.it.
Ethics Statement
The research was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and local laws. The study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for the treatment “off label” with tetrabenazine.
Author Contributions
RS contributed to the study concept and design and to the execution of the research project and wrote and edited the first draft of the manuscript. GS contributed to the study concept and design, execution and review of the statistical analysis, and manuscript revision. VM organized the database for data collection, generated the tables, and edited the manuscript. NC proofread the data and wrote a part of the manuscript. DR, FS, RD, EP, and MF contributed to the execution of the research project and data collection. GC read, critically revised, and approved the final manuscript. RB conceived the study concept and design, the execution of the research project, interpretation of results, and critical revision of the submitted version. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We wish to thank Miningful Studio for carrying out the statistical analysis and revising the manuscript; and Prof. Ailish Lynam for reviewing the English in the manuscript.
Funding. The authors have not received specific funding sources for this study. The study was partially supported by the Italian Ministry of Health (Grant No. RC2019) and taxpayers' contributions (5 × 1,000) to 2018 IRCCS Stella Maris Foundation. | TETRABENAZINE | DrugsGivenReaction | CC BY | 33716922 | 19,975,767 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Parkinsonism'. | A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine.
Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders-Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4-18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4-18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.
Introduction
Tetrabenazine (TBZ; Xenazine®) is a selective and reversible depletor of monoamines from synaptic terminals, preferentially dopamine but also norepinephrine, serotonin, histamine (1). TBZ has a short half-life, which lasts for about 16–24 h, and a rapid onset of action, which is useful in clinical applications (2). The antichorea efficacy of TBZ is related to dopamine depletion, whereas the risk of depression may be mediated by serotonin and norepinephrine depletion, and sedation may be explained by histamine depletion (1).
TBZ could determine a mild increase in the corrected QT (QTc) interval and should be used properly and carefully when combined with other drugs that also increase the interval of QTc or in patients with congenital long QT syndrome and a history of cardiac arrhythmias (3).
The dose of TBZ should be personalized for each patient (3), with significantly interindividual differences in reaching the “optimal dose,” which is the dose that provides the main clinical response with minimal or tolerable adverse events (1).
The principal most common and dose-limiting side effects of TBZ are known. These include sedation (28%), akathisia (13%), parkinsonism (7%), depression (5.5%), anxiety (4%), fatigue (2%), and diarrhea (2%), all of which are usually rapidly reversible upon dosage reduction (1, 2, 4).
To date, there is no consensus regarding the best clinical practice in the pediatric population; in this instance, the administration of TBZ to the adult population is empirically adapted to children and it is “off-label” (5) for a wide variety of hyperkinetic movement disorders (6–10), including dyskinetic cerebral palsy (DCP) (11).
DCP, the second most common type of cerebral palsy (CP) (almost 15%), typically caused by non-progressive basal ganglia and/or thalamus lesions, is characterized by abnormal postures or movements associated with compromised tone regulation and coordination. In DCP, the two typical movement disorders are dystonia and choreoathetosis, which are often co-occurring; dystonia is usually more severe than choreoathetosis, affecting daily activity, quality of life, and social participation (12).
A recent review has highlighted the inadequate evidence for pharmacological interventions in DCP due to the absence of any therapeutic algorithm and the lack of reliable, valid, and agreed-upon age-specific outcome measures (11). To fill this gap, in 2008, the Childhood Movement Disorders Rating Scale (MD-CRS) was proposed and has been recently updated in a revised form (MD-CRS 4-18 R). The scale aimed to define the functional impairment and the severity produced by movement disorder (e.g., dystonia and choreoathetosis) in the pediatric population (11, 13–15). The psychometric properties in DCP of MD-CRS 4–18 R have been recently published (15).
In this study, we have hypothesized that (i) the use of standardized outcome measures, such as MD-CRS, could provide useful data for a retrospective analysis of “off-label” treatment with TBZ obtained from routine clinical practice in the pediatric population affected by DCP; (ii) clinical data could provide a preliminary insight for evaluating the safety and effectiveness of TBZ treatment.
The primary purpose of this study was to retrospectively evaluate a sample of children with DCP who had been treated with TBZ in order to collect data on its efficacy using the MD-CRS 4–18 R as a standardized tool to assess movement disorders in childhood and to detect changes during treatment.
The secondary aims of the study were (1) to determine the impact of TBZ-associated side effects in children with DCP and (2) to analyze the long-term effectiveness and tolerability of TBZ in clinical practice, by evaluating the outcome on a sub-group with a follow-up >2 years.
Materials and Methods
Study Design
A multicenter retrospective longitudinal study was designed involving three Italian Research and Clinical Scientific Institutes: The Department of Developmental Neuroscience of Stella Maris Foundation (Pisa), The Developmental Neurology Unit Institute “C. Besta” (Milano), and The Pediatric Neurology Unit of Fondazione Policlinico “A. Gemelli” (Rome).
These scientific institutes cooperate in the research on movement disorders, sharing agreed clinical and pharmacological protocols, including outcome measures, as MD-CRS. Each Center has its own database for CP data collection, which accounts for at least 600 subjects. From these data sets, cases were selected according to the following inclusion criteria: (a) DCP diagnosis according to the Surveillance of Cerebral Palsy in Europe criteria (16); (b) age ≥4 years; (c) use of TBZ, in mono- or polytherapy—in the presence of polytherapy a stable dosage of other drugs was maintained during the 12 months of follow up, after starting TBZ; (d) videos of Movement Disorder-Childhood Rating Scale which had been collected between July 2007 and December 2019, at the following timing: baseline, i.e., before starting TBZ (T0), after 6 (T1), and 12 (T2) months of treatment. When available, a MD-CRS video after ≥2 years of treatment (long term—LT), was also included (Figure 1).
Figure 1 Design and management of the study with subjects selection.
Procedures
The clinical, demographic, and pharmacological data of each selected subject were extracted from medical records to fulfill the aims of the study.
All participants were classified according to the Gross Motor Function Classification System (GMFCS) for cerebral palsy which is based on self-initiated movement, with emphasis on sitting, transfers, and mobility. A five-level classification system is used to define the subject (from I to V increasing severity) and the distinctions are based on functional limitations, the need for hand-held mobility devices or wheeled mobility, and to a much lesser extent, quality of movement.
A neurological and psychiatric history assessment was carried out on all the subjects.
The psychiatric evaluation was carried out by anamnestic interview and, when available for subjects >6 years, with some items from a semi-structured interview, the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL).
These evaluations were checked before and during the follow up visit.
TBZ treatment indications for all the included subjects were based on multidisciplinary assessments made by child neurologists, an expert in movement disorders, and a pediatric physical therapist.
TBZ administration usually started with a low fixed dose of 6.25 mg (1/4 oral tablet of 25 mg) at least during the first week and was gradually and variably increased according to weight or the clinical neuromotor picture with an aim of reaching a “possible optimal dose,” as in previous reports (1, 4). The dosage was subdivided into 2 or 3 times daily.
Data collection of corrected QT (QTc) was considered if the subjects had performed an EKG before the study, during up-titration, and subsequently annually during follow-up to monitor the risk of a potential increase in the QTc interval or cardiac arrhythmias.
Outcome Measure
All the videos included were recorded according to a standardized videoprotocol and blind scored according to MD-CRS 4–18 R (15).
MD-CRS 4–18 R is a feasible tool to verify the natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP.
The MD-CRS 4–18 R was developed for the assessment of function and disability in various types of movement disorders. This scale requires that the evaluation be recorded according to a specific videoprotocol, and subsequently a score is assigned. The MD-CRS 4–18 R scale is divided into two parts: General Assessment (Part I) and Movement-Disorder Severity (Part II). In Part I, four areas are included: motor function, oral/verbal function, self-care, and attention/alertness, for a total of 15 items. In Part II, the intensity of the prevalent movement abnormality in seven body parts (eye and periorbital region, face, tongue and perioral region, neck, trunk, upper limb, lower limb) in two conditions, at rest and during the execution of specific tasks, is assessed. All items are scored on a 5-point ordinal scale (0–4): zero corresponds to no signs, and 4 corresponds to the most severe findings. The scores for part I and part II and the total score are calculated by statistical analysis obtaining Index I, Index II, and Global Index, respectively. Indexes range come from 0 (severe impairment) to 1 (normal).
The Stella Maris Foundation holds the copyright for the MD-CRS 4–18 R (MD-CRS copyright owner) which is distributed, worldwide, by Mapi Research Trust, a nonprofit organization. For further information and conditions of use of the MD-CRS 4–18 R, consult the online platform Mapi Research Trust, ePROVIDE (https://eprovide.mapi-trust.org).
Ethics Approval
The multicenter study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for treatment “off label” at baseline.
Statistical Analyses
A linear mixed model was used to evaluate the effects of the different timings (T0, T1, and T2 as fixed factors) on each Index (Index I, Index II, and Global Index) adding age and type of MD as random effect. Further analysis with the same approach was also carried out for the subgroup of subjects with the long-term follow-up to evaluate the effects of T0, T1, T2, and LT on each index. For both models, a post hoc analysis between different time points was performed.
Results
Participants
The study included 23 children and adolescents (19 male and 4 female) affected by DCP, age range 4.02–16.30 years at baseline observation (mean age 8.28 years, SD 3.59).
Clinical and demographic data are reported in Table 1.
Table 1 Clinical and demographic data of the sample.
Demographic Participants N = 23
Sex: n (%) Male: 19 (83%)
Female 4 (17%)
Mean age ± SD (range) at T0 (years) 8.28 ± 3.59 (4.02–16.30)
Mean weight ± SD (range) at T0 (kg) 25.13 ± 11.94 (12.00–62.00)
Type of MD: n (%) Dystonia and choreoathetosis: 19 (83%)
Choreoathetosis: 4 (17%)
Etiology: n (%) Hypoxic-ischemic encephalopathy: 17 (74%)
Kernicterus: 4 (17%) Cytomegalovirus infection: 2 (9%)
GMFCS level: n (%) I: 1 (4%)
II: 1 (4%)
III: 2 (9%)
IV: 5 (22%)
V: 14 (61%)
None of the participants presented clinically relevant psychiatric diseases (e.g., significant depression or history of suicidal intent) at baseline (T0).
At the beginning of TBZ treatment, seven subjects with DCP started TBZ in monotherapy, while the others were in polytherapy (e.g., oral baclofen, trihexyphenidyl, benzodiazepines).
A mean dosage of TBZ close to 1 mg/kg was reached (Table 2).
Table 2 Mean and range TBZ dosage at the different time points.
Timing Mean (mg/kg) ± SD Min (mg/kg) Max (mg/kg)
T1 (T0 +6 months) 0.70 ± 0.41 0.30 2.08
T2 (T0 +12 months) 0.84 ± 0.44 0.20 2.08
Long Term 0.97 ± 0.58 0.20 2.08
T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, > 2 year of therapy.
The reduction of the minimum dosage after 12 months and at long term after treatment was related to the maintenance of a stable oral dose between T1 and T2 (5 subjects) without considering the weight increase of the subjects. 4 of the other children reduced their dosage, 2 after 6 months, and 2 after 12 months respectively, due to the occurrence of adverse events (see specific section).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) of TBZ Treatment
A relevant effect of timing was found with a significant reduction of each index between T0 and T1 and between T0 and T2, but not between T1 and T2. Specifically, the mean value of Index I (General Assessment) at T0 0.60 ± 0.06, at T1 0.57 ± 0.06, and at T2 0.57 ± 0.06; the mean value for Index II (MD severity) at T0 was 0.63 ± 0.03, at T1 0.53 ± 0.03, and at T2 0.48 ± 0.03; finally, the mean value of for Global Index at T0 was 0.61 ± 0.05, at T1 0.56 ± 0.05, and at T2 0.54 ± 0.05.
The results of the analysis at T0, T1, and T2 are reported in Table 3.
Table 3 Linear mixed model results during 12 months of follow up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.60 (0.06) >0.05 0.98
T1 −0.03 (0.01) <0.01
T2 −0.03 (0.01) <0.01
Index II Intercept 0.63 (0.03) <0.01 0.73
T1 −0.10 (0.03) <0.01
T2 −0.15 (0.03) <0.01
Global index Intercept 0.61 (0.05) >0.05 0.95
T1 −0.05 (0.01) <0.01
T2 −0.07 (0.01) <0.01
MD-CRS R, movement disorders—childhood rating scale revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
As shown, a significant effect of timing was found at T1 and T2 (Table 3).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) and TBZ Long-Term (LT) Treatment
A small group, 10 subjects, had a long-term follow-up >2 years, and the efficacy of TBZ was still present and stable without important side effects.
In this long-term group (LT), a significant reduction of each Index was found between T0 and T2 but not between T2 and LT. Specifically, the MD-CRS R Index I (General Assessment) mean value was 0.52 ± 0.08 at T0, 0.48 ± 0.08 at T1, 0.49 ± 0.08 at T2, and 0.46 ± 0.08 at long term; the Index II (MD Severity) mean value was 0.62 ± 0.06 at T0, 0.52 ± 0.06 at T1, 0.49 ± 0.06 at T2, and 0.52 ± 0.06 at long term; the Global Index mean value was 0.55 ± 0.07 at T0, 0.49 ± 0.07 at T1, 0.48 ± 0.07 at T2, and 0.48 at long term.
The post hoc analysis between the different time points during 12 months follow up are reported in Table 4. The results of the analysis on the T0, T1, T2, and long-term subgroup are reported in Table 5. As shown, all-time points are significant (Table 5).
Table 4 Post-hoc analysis between the different time points during 12 months follow up.
Timing MD-CRS 4-18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
T0–T1 Index I 0.03 (0.01) 42 2.92 <0.05
Index II 0.10 (0.02) 42 3.81 <0.01
Global index 0.05 (0.01) 42 4.15 <0.01
T0–T2 Index I 0.03 (0.01) 42 3.06 <0.05
Index II 0.15 (0.03) 42.3 5.38 <0.01
Global index 0.07 (0.01) 42 5.40 <0.01
T1–T2 Index I 0.01 (0.01) 42 0.24 > 0.05
Index II 0.05 (0.02) 42.3 1.69 > 0.05
Global index 0.02 (0.01) 42 1.39 > 0.05
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
Table 5 Linear mixed model results during the long-term follow-up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.52 (0.08) <0.01 0.98
T1 −0.05 (0.01) <0.01
T2 −0.03 (0.01) <0.05
LT −0.07 (0.02) <0.01
Index II Intercept 0.62 (0.06) <0.01 0.75
T1 −0.10 (0.04) <0.05
T2 −0.13 (0.04) <0.05
LT −0.09 (0.04) <0.05
Global index Intercept 0.55 (0.07) <0.01 0.96
T1 −0.06 (0.02) <0.01
T2 −0.07 (0.02) <0.01
LT −0.08 (0.02) <0.01
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, >2 year of therapy.
In the following table, the result of the post-hoc analysis of long-term vs. baseline (T0) and T2 are represented (Table 6).
Table 6 Post-hoc analysis between the different time points during the long-term follow-up.
Timing MD-CRS 4–18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
LT–T0 Index I −0.07 (0.02) 28 −4.44 <0.01
Index II −0.09 (0.04) 28.2 −2.13 <0.05
Global index −0.08 (0.02) 28 −3.78 <0.01
LT–T2 Index I −0.03 (0.01) 28 −2.22 <0.05
Index II 0.04 (0.04) 28 0.79 > 0.05
Global index −0.01 (0.02) 28 −0.22 > 0.05
MD-CRS 4–18 R: movement disorders—childhood rating scale 4–18 revised; t0, baseline; t2, 12 months of therapy; lt, long term, >2 year of therapy.
TBZ-Associated Side Effects
TBZ was associated with side effects in 6/23 (26%) subjects: drowsiness in 3/23 (13.04%); dystonia in 2/23 (8.69%); parkinsonism/rigidity in 2/23 (8.69%), anxiety and depressive problems in 1 (4.35%), and akathisia in 1 (4.35%).
Three of these children showed two side effects: one child showed drowsiness after 6 months of treatment and parkinsonism/rigidity after 12 months; another showed dystonia after 6 months of therapy and anxious-depressive problems in the long-term follow-up while the third child presented dystonia and akathisia after 12 months of therapy. Of these subjects, 2 dropped out after T1, one due to dystonia and the other to parkinsonism/rigidity which was treated subsequently with the implantation of Intrathecal Baclofen Pump.
An ECG (included QTc) was performed on all individuals with QTc at baseline (T0) and during up-titration, T1, and T2. The QTc value remained in a normal range in all subjects. Two children reported no clinically significant tachycardia.
Discussion
To our knowledge, this is the first study dedicated to a homogeneous cohort of children with DCP treated with TBZ who were subsequently followed up for at least 1 year and evaluated with a standardized clinical outcome (MD-CRS). Specifically, it represents the results of a routine medical practice by monitoring, by a standardized outcome measure, the use of TBZ when prescribed to children with DCP.
In this study, the use of TBZ was determined by the ineffectiveness of other dystonia and chorea drugs or it was prescribed as an add-on to hyperkinetic movement disorder treatment specifically. The effects of TBZ in children with DCP, either in a dystonic or choreic form, were evaluated, and a clinical improvement was reported regarding both the severity and quantity of the movement disorder in different parts of the body. Improvement in general clinical functioning, such as the motor and self-care abilities and activities, was also detected.
During the titration period, the dose of TBZ was adjusted empirically according to the clinical benefit: the starting dose of 6.25 mg (1/4 oral tablet of 25 mg) was prescribed once daily, and it was titrated gradually increasing it to 6.25 mg weekly or bi-weekly until a maximum of 50 mg/day (2 mg/kg, twice or three times daily).
In order to identify a dose level that clinically reduced movement disorders and was well tolerated, a customized TBZ dose regimen was considered for each subject. This step is a very crucial achievement because it shows the common behavior of clinicians to customize the TBZ dose on the basis of the clinical improvement and functioning. In general, research impacts the clinical behavior, but in this case, as is important in evidence-based medicine (EBM), clinical expertise is essential and works in parallel with research evidence and patient preferences for guiding the EBM.
The data obtained by clinical observation were considered because there is no consensus in literature regarding the optimal medical treatment currently available (11), and the therapies are mainly related to “off-label” drugs anecdotally adapted to children (17).
With regard to the pediatric population, some authors, already many years ago, used a higher initial drug schedule: for age 3–10 years, the final dose was 25 mg twice a day, and for age >10 years the final dose was 50 mg twice a day, but due to the occurrence of drowsiness, the drug regimen was reduced to half dose (18). Other studies (5, 7, 19–21) on the use of TBZ treatment in the hyperkinetic movements, but not related to DCP or children, introduce a wide range of doses of TBZ which vary from 12.5 to 350 mg/day based on the positive drug response.
These findings were confirmed in the current study: in common clinical practice, the optimal dose of TBZ in the treatment of DCP in a pediatric population is individualized and not related to any specific dose per body weight but according to the clinical improvement.
This study, differently from those undertaken previously, also evaluated the efficacy of TBZ in children with DCP by using MD-CRS 4–18 R, a standardized and suitable tool to detect changes during pharmacological treatment.
Indeed, a significant clinical reduction of movement disorder after 6 months was detected, subsequently followed by a “plateau state.” A significant improvement in the general assessment (including Motor function, Oral/verbal function, Self-care and Attention/Alertness) and in the severity of movement disorders (including grading and spread of movement disorders for different body regions) was found after 6 and 12 months of TBZ treatment. No relevant differences were obtained during TBZ administration between 6 and 12 months. These results are crucial from a clinical point of view because they show how the children and parents can be assured that the use of TBZ impacts not only the reduction of movement disorder but also the clinical general functioning such as language and the self-care activities.
No relevant differences were observed in the type and frequency of adverse events reported in scientific literature and this study. The main side effect, in fact, was sedation, followed by dystonia-parkinsonism, depression, and akathisia.
In the long-term subgroup of the sample, a stable improvement was reached after a treatment period of more than 2 years and no important side effects were detected.
Although no side effects relating to heart rhythm abnormalities were detected, according to our experience, EKG evaluations, including QTc measurement, are advisable before starting TBZ, during up-titration (10 days after each dose increasing) and subsequently an annual follow-up.
The main limitations of this study are related to the small size of the sample and the low dosage of TBZ prescribed, compared to the previous reports. A retrospective design based on the review of each Center database and the inclusion criteria (i.e., polytherapy with stable dosage for at least 12 months during TBZ treatment) were probably responsible for the small size of the cohort and the concomitant use of other medications, which could have interfered with the obtained benefits. In addition, the lack of further clinical improvement after the initial reduction of hyperkinetic movements and the absence of severe side effects could be justified by the low dose used in the study cohort.
However, the present study reflects the common clinical practice in the management of an “off-label” drug in children while at the same time embedding valid and agreed-upon age-specific outcome measures.
In conclusion, this study shows that (a) the efficacy of TBZ in children with DCP through a gradual titration has been demonstrated when a standardized outcome measure is used; (b) an optimal TBZ dose should be individualized according to the clinical improvement, such as the reduction of movement disorders; (c) a standardized outcome measure, such as MD-CRS 4–18 R, is also essential during the clinical observational trial and not only in the randomized trial, since it is important to detect changes in an objective way; and (d) good safety and tolerability of TBZ in children has been proved while the occurrence of the side effects should be evaluated through a clinical neurological and psychiatric follow-up and periodic EKG monitoring.
Further studies, however, are needed in children with DCP by randomized clinical trials including parallel groups with different doses of the drug to determine the standardized dosage to be shared in clinical and research settings.
Data Availability Statement
The datasets presented in this article are not readily available because the they contain information that could compromise the privacy of the participants. Requests to access the datasets should be directed to rbattini@fsm.unipi.it.
Ethics Statement
The research was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and local laws. The study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for the treatment “off label” with tetrabenazine.
Author Contributions
RS contributed to the study concept and design and to the execution of the research project and wrote and edited the first draft of the manuscript. GS contributed to the study concept and design, execution and review of the statistical analysis, and manuscript revision. VM organized the database for data collection, generated the tables, and edited the manuscript. NC proofread the data and wrote a part of the manuscript. DR, FS, RD, EP, and MF contributed to the execution of the research project and data collection. GC read, critically revised, and approved the final manuscript. RB conceived the study concept and design, the execution of the research project, interpretation of results, and critical revision of the submitted version. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We wish to thank Miningful Studio for carrying out the statistical analysis and revising the manuscript; and Prof. Ailish Lynam for reviewing the English in the manuscript.
Funding. The authors have not received specific funding sources for this study. The study was partially supported by the Italian Ministry of Health (Grant No. RC2019) and taxpayers' contributions (5 × 1,000) to 2018 IRCCS Stella Maris Foundation. | TETRABENAZINE | DrugsGivenReaction | CC BY | 33716922 | 19,975,767 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somnolence'. | A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine.
Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders-Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4-18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4-18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.
Introduction
Tetrabenazine (TBZ; Xenazine®) is a selective and reversible depletor of monoamines from synaptic terminals, preferentially dopamine but also norepinephrine, serotonin, histamine (1). TBZ has a short half-life, which lasts for about 16–24 h, and a rapid onset of action, which is useful in clinical applications (2). The antichorea efficacy of TBZ is related to dopamine depletion, whereas the risk of depression may be mediated by serotonin and norepinephrine depletion, and sedation may be explained by histamine depletion (1).
TBZ could determine a mild increase in the corrected QT (QTc) interval and should be used properly and carefully when combined with other drugs that also increase the interval of QTc or in patients with congenital long QT syndrome and a history of cardiac arrhythmias (3).
The dose of TBZ should be personalized for each patient (3), with significantly interindividual differences in reaching the “optimal dose,” which is the dose that provides the main clinical response with minimal or tolerable adverse events (1).
The principal most common and dose-limiting side effects of TBZ are known. These include sedation (28%), akathisia (13%), parkinsonism (7%), depression (5.5%), anxiety (4%), fatigue (2%), and diarrhea (2%), all of which are usually rapidly reversible upon dosage reduction (1, 2, 4).
To date, there is no consensus regarding the best clinical practice in the pediatric population; in this instance, the administration of TBZ to the adult population is empirically adapted to children and it is “off-label” (5) for a wide variety of hyperkinetic movement disorders (6–10), including dyskinetic cerebral palsy (DCP) (11).
DCP, the second most common type of cerebral palsy (CP) (almost 15%), typically caused by non-progressive basal ganglia and/or thalamus lesions, is characterized by abnormal postures or movements associated with compromised tone regulation and coordination. In DCP, the two typical movement disorders are dystonia and choreoathetosis, which are often co-occurring; dystonia is usually more severe than choreoathetosis, affecting daily activity, quality of life, and social participation (12).
A recent review has highlighted the inadequate evidence for pharmacological interventions in DCP due to the absence of any therapeutic algorithm and the lack of reliable, valid, and agreed-upon age-specific outcome measures (11). To fill this gap, in 2008, the Childhood Movement Disorders Rating Scale (MD-CRS) was proposed and has been recently updated in a revised form (MD-CRS 4-18 R). The scale aimed to define the functional impairment and the severity produced by movement disorder (e.g., dystonia and choreoathetosis) in the pediatric population (11, 13–15). The psychometric properties in DCP of MD-CRS 4–18 R have been recently published (15).
In this study, we have hypothesized that (i) the use of standardized outcome measures, such as MD-CRS, could provide useful data for a retrospective analysis of “off-label” treatment with TBZ obtained from routine clinical practice in the pediatric population affected by DCP; (ii) clinical data could provide a preliminary insight for evaluating the safety and effectiveness of TBZ treatment.
The primary purpose of this study was to retrospectively evaluate a sample of children with DCP who had been treated with TBZ in order to collect data on its efficacy using the MD-CRS 4–18 R as a standardized tool to assess movement disorders in childhood and to detect changes during treatment.
The secondary aims of the study were (1) to determine the impact of TBZ-associated side effects in children with DCP and (2) to analyze the long-term effectiveness and tolerability of TBZ in clinical practice, by evaluating the outcome on a sub-group with a follow-up >2 years.
Materials and Methods
Study Design
A multicenter retrospective longitudinal study was designed involving three Italian Research and Clinical Scientific Institutes: The Department of Developmental Neuroscience of Stella Maris Foundation (Pisa), The Developmental Neurology Unit Institute “C. Besta” (Milano), and The Pediatric Neurology Unit of Fondazione Policlinico “A. Gemelli” (Rome).
These scientific institutes cooperate in the research on movement disorders, sharing agreed clinical and pharmacological protocols, including outcome measures, as MD-CRS. Each Center has its own database for CP data collection, which accounts for at least 600 subjects. From these data sets, cases were selected according to the following inclusion criteria: (a) DCP diagnosis according to the Surveillance of Cerebral Palsy in Europe criteria (16); (b) age ≥4 years; (c) use of TBZ, in mono- or polytherapy—in the presence of polytherapy a stable dosage of other drugs was maintained during the 12 months of follow up, after starting TBZ; (d) videos of Movement Disorder-Childhood Rating Scale which had been collected between July 2007 and December 2019, at the following timing: baseline, i.e., before starting TBZ (T0), after 6 (T1), and 12 (T2) months of treatment. When available, a MD-CRS video after ≥2 years of treatment (long term—LT), was also included (Figure 1).
Figure 1 Design and management of the study with subjects selection.
Procedures
The clinical, demographic, and pharmacological data of each selected subject were extracted from medical records to fulfill the aims of the study.
All participants were classified according to the Gross Motor Function Classification System (GMFCS) for cerebral palsy which is based on self-initiated movement, with emphasis on sitting, transfers, and mobility. A five-level classification system is used to define the subject (from I to V increasing severity) and the distinctions are based on functional limitations, the need for hand-held mobility devices or wheeled mobility, and to a much lesser extent, quality of movement.
A neurological and psychiatric history assessment was carried out on all the subjects.
The psychiatric evaluation was carried out by anamnestic interview and, when available for subjects >6 years, with some items from a semi-structured interview, the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL).
These evaluations were checked before and during the follow up visit.
TBZ treatment indications for all the included subjects were based on multidisciplinary assessments made by child neurologists, an expert in movement disorders, and a pediatric physical therapist.
TBZ administration usually started with a low fixed dose of 6.25 mg (1/4 oral tablet of 25 mg) at least during the first week and was gradually and variably increased according to weight or the clinical neuromotor picture with an aim of reaching a “possible optimal dose,” as in previous reports (1, 4). The dosage was subdivided into 2 or 3 times daily.
Data collection of corrected QT (QTc) was considered if the subjects had performed an EKG before the study, during up-titration, and subsequently annually during follow-up to monitor the risk of a potential increase in the QTc interval or cardiac arrhythmias.
Outcome Measure
All the videos included were recorded according to a standardized videoprotocol and blind scored according to MD-CRS 4–18 R (15).
MD-CRS 4–18 R is a feasible tool to verify the natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP.
The MD-CRS 4–18 R was developed for the assessment of function and disability in various types of movement disorders. This scale requires that the evaluation be recorded according to a specific videoprotocol, and subsequently a score is assigned. The MD-CRS 4–18 R scale is divided into two parts: General Assessment (Part I) and Movement-Disorder Severity (Part II). In Part I, four areas are included: motor function, oral/verbal function, self-care, and attention/alertness, for a total of 15 items. In Part II, the intensity of the prevalent movement abnormality in seven body parts (eye and periorbital region, face, tongue and perioral region, neck, trunk, upper limb, lower limb) in two conditions, at rest and during the execution of specific tasks, is assessed. All items are scored on a 5-point ordinal scale (0–4): zero corresponds to no signs, and 4 corresponds to the most severe findings. The scores for part I and part II and the total score are calculated by statistical analysis obtaining Index I, Index II, and Global Index, respectively. Indexes range come from 0 (severe impairment) to 1 (normal).
The Stella Maris Foundation holds the copyright for the MD-CRS 4–18 R (MD-CRS copyright owner) which is distributed, worldwide, by Mapi Research Trust, a nonprofit organization. For further information and conditions of use of the MD-CRS 4–18 R, consult the online platform Mapi Research Trust, ePROVIDE (https://eprovide.mapi-trust.org).
Ethics Approval
The multicenter study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for treatment “off label” at baseline.
Statistical Analyses
A linear mixed model was used to evaluate the effects of the different timings (T0, T1, and T2 as fixed factors) on each Index (Index I, Index II, and Global Index) adding age and type of MD as random effect. Further analysis with the same approach was also carried out for the subgroup of subjects with the long-term follow-up to evaluate the effects of T0, T1, T2, and LT on each index. For both models, a post hoc analysis between different time points was performed.
Results
Participants
The study included 23 children and adolescents (19 male and 4 female) affected by DCP, age range 4.02–16.30 years at baseline observation (mean age 8.28 years, SD 3.59).
Clinical and demographic data are reported in Table 1.
Table 1 Clinical and demographic data of the sample.
Demographic Participants N = 23
Sex: n (%) Male: 19 (83%)
Female 4 (17%)
Mean age ± SD (range) at T0 (years) 8.28 ± 3.59 (4.02–16.30)
Mean weight ± SD (range) at T0 (kg) 25.13 ± 11.94 (12.00–62.00)
Type of MD: n (%) Dystonia and choreoathetosis: 19 (83%)
Choreoathetosis: 4 (17%)
Etiology: n (%) Hypoxic-ischemic encephalopathy: 17 (74%)
Kernicterus: 4 (17%) Cytomegalovirus infection: 2 (9%)
GMFCS level: n (%) I: 1 (4%)
II: 1 (4%)
III: 2 (9%)
IV: 5 (22%)
V: 14 (61%)
None of the participants presented clinically relevant psychiatric diseases (e.g., significant depression or history of suicidal intent) at baseline (T0).
At the beginning of TBZ treatment, seven subjects with DCP started TBZ in monotherapy, while the others were in polytherapy (e.g., oral baclofen, trihexyphenidyl, benzodiazepines).
A mean dosage of TBZ close to 1 mg/kg was reached (Table 2).
Table 2 Mean and range TBZ dosage at the different time points.
Timing Mean (mg/kg) ± SD Min (mg/kg) Max (mg/kg)
T1 (T0 +6 months) 0.70 ± 0.41 0.30 2.08
T2 (T0 +12 months) 0.84 ± 0.44 0.20 2.08
Long Term 0.97 ± 0.58 0.20 2.08
T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, > 2 year of therapy.
The reduction of the minimum dosage after 12 months and at long term after treatment was related to the maintenance of a stable oral dose between T1 and T2 (5 subjects) without considering the weight increase of the subjects. 4 of the other children reduced their dosage, 2 after 6 months, and 2 after 12 months respectively, due to the occurrence of adverse events (see specific section).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) of TBZ Treatment
A relevant effect of timing was found with a significant reduction of each index between T0 and T1 and between T0 and T2, but not between T1 and T2. Specifically, the mean value of Index I (General Assessment) at T0 0.60 ± 0.06, at T1 0.57 ± 0.06, and at T2 0.57 ± 0.06; the mean value for Index II (MD severity) at T0 was 0.63 ± 0.03, at T1 0.53 ± 0.03, and at T2 0.48 ± 0.03; finally, the mean value of for Global Index at T0 was 0.61 ± 0.05, at T1 0.56 ± 0.05, and at T2 0.54 ± 0.05.
The results of the analysis at T0, T1, and T2 are reported in Table 3.
Table 3 Linear mixed model results during 12 months of follow up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.60 (0.06) >0.05 0.98
T1 −0.03 (0.01) <0.01
T2 −0.03 (0.01) <0.01
Index II Intercept 0.63 (0.03) <0.01 0.73
T1 −0.10 (0.03) <0.01
T2 −0.15 (0.03) <0.01
Global index Intercept 0.61 (0.05) >0.05 0.95
T1 −0.05 (0.01) <0.01
T2 −0.07 (0.01) <0.01
MD-CRS R, movement disorders—childhood rating scale revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
As shown, a significant effect of timing was found at T1 and T2 (Table 3).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) and TBZ Long-Term (LT) Treatment
A small group, 10 subjects, had a long-term follow-up >2 years, and the efficacy of TBZ was still present and stable without important side effects.
In this long-term group (LT), a significant reduction of each Index was found between T0 and T2 but not between T2 and LT. Specifically, the MD-CRS R Index I (General Assessment) mean value was 0.52 ± 0.08 at T0, 0.48 ± 0.08 at T1, 0.49 ± 0.08 at T2, and 0.46 ± 0.08 at long term; the Index II (MD Severity) mean value was 0.62 ± 0.06 at T0, 0.52 ± 0.06 at T1, 0.49 ± 0.06 at T2, and 0.52 ± 0.06 at long term; the Global Index mean value was 0.55 ± 0.07 at T0, 0.49 ± 0.07 at T1, 0.48 ± 0.07 at T2, and 0.48 at long term.
The post hoc analysis between the different time points during 12 months follow up are reported in Table 4. The results of the analysis on the T0, T1, T2, and long-term subgroup are reported in Table 5. As shown, all-time points are significant (Table 5).
Table 4 Post-hoc analysis between the different time points during 12 months follow up.
Timing MD-CRS 4-18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
T0–T1 Index I 0.03 (0.01) 42 2.92 <0.05
Index II 0.10 (0.02) 42 3.81 <0.01
Global index 0.05 (0.01) 42 4.15 <0.01
T0–T2 Index I 0.03 (0.01) 42 3.06 <0.05
Index II 0.15 (0.03) 42.3 5.38 <0.01
Global index 0.07 (0.01) 42 5.40 <0.01
T1–T2 Index I 0.01 (0.01) 42 0.24 > 0.05
Index II 0.05 (0.02) 42.3 1.69 > 0.05
Global index 0.02 (0.01) 42 1.39 > 0.05
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
Table 5 Linear mixed model results during the long-term follow-up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.52 (0.08) <0.01 0.98
T1 −0.05 (0.01) <0.01
T2 −0.03 (0.01) <0.05
LT −0.07 (0.02) <0.01
Index II Intercept 0.62 (0.06) <0.01 0.75
T1 −0.10 (0.04) <0.05
T2 −0.13 (0.04) <0.05
LT −0.09 (0.04) <0.05
Global index Intercept 0.55 (0.07) <0.01 0.96
T1 −0.06 (0.02) <0.01
T2 −0.07 (0.02) <0.01
LT −0.08 (0.02) <0.01
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, >2 year of therapy.
In the following table, the result of the post-hoc analysis of long-term vs. baseline (T0) and T2 are represented (Table 6).
Table 6 Post-hoc analysis between the different time points during the long-term follow-up.
Timing MD-CRS 4–18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
LT–T0 Index I −0.07 (0.02) 28 −4.44 <0.01
Index II −0.09 (0.04) 28.2 −2.13 <0.05
Global index −0.08 (0.02) 28 −3.78 <0.01
LT–T2 Index I −0.03 (0.01) 28 −2.22 <0.05
Index II 0.04 (0.04) 28 0.79 > 0.05
Global index −0.01 (0.02) 28 −0.22 > 0.05
MD-CRS 4–18 R: movement disorders—childhood rating scale 4–18 revised; t0, baseline; t2, 12 months of therapy; lt, long term, >2 year of therapy.
TBZ-Associated Side Effects
TBZ was associated with side effects in 6/23 (26%) subjects: drowsiness in 3/23 (13.04%); dystonia in 2/23 (8.69%); parkinsonism/rigidity in 2/23 (8.69%), anxiety and depressive problems in 1 (4.35%), and akathisia in 1 (4.35%).
Three of these children showed two side effects: one child showed drowsiness after 6 months of treatment and parkinsonism/rigidity after 12 months; another showed dystonia after 6 months of therapy and anxious-depressive problems in the long-term follow-up while the third child presented dystonia and akathisia after 12 months of therapy. Of these subjects, 2 dropped out after T1, one due to dystonia and the other to parkinsonism/rigidity which was treated subsequently with the implantation of Intrathecal Baclofen Pump.
An ECG (included QTc) was performed on all individuals with QTc at baseline (T0) and during up-titration, T1, and T2. The QTc value remained in a normal range in all subjects. Two children reported no clinically significant tachycardia.
Discussion
To our knowledge, this is the first study dedicated to a homogeneous cohort of children with DCP treated with TBZ who were subsequently followed up for at least 1 year and evaluated with a standardized clinical outcome (MD-CRS). Specifically, it represents the results of a routine medical practice by monitoring, by a standardized outcome measure, the use of TBZ when prescribed to children with DCP.
In this study, the use of TBZ was determined by the ineffectiveness of other dystonia and chorea drugs or it was prescribed as an add-on to hyperkinetic movement disorder treatment specifically. The effects of TBZ in children with DCP, either in a dystonic or choreic form, were evaluated, and a clinical improvement was reported regarding both the severity and quantity of the movement disorder in different parts of the body. Improvement in general clinical functioning, such as the motor and self-care abilities and activities, was also detected.
During the titration period, the dose of TBZ was adjusted empirically according to the clinical benefit: the starting dose of 6.25 mg (1/4 oral tablet of 25 mg) was prescribed once daily, and it was titrated gradually increasing it to 6.25 mg weekly or bi-weekly until a maximum of 50 mg/day (2 mg/kg, twice or three times daily).
In order to identify a dose level that clinically reduced movement disorders and was well tolerated, a customized TBZ dose regimen was considered for each subject. This step is a very crucial achievement because it shows the common behavior of clinicians to customize the TBZ dose on the basis of the clinical improvement and functioning. In general, research impacts the clinical behavior, but in this case, as is important in evidence-based medicine (EBM), clinical expertise is essential and works in parallel with research evidence and patient preferences for guiding the EBM.
The data obtained by clinical observation were considered because there is no consensus in literature regarding the optimal medical treatment currently available (11), and the therapies are mainly related to “off-label” drugs anecdotally adapted to children (17).
With regard to the pediatric population, some authors, already many years ago, used a higher initial drug schedule: for age 3–10 years, the final dose was 25 mg twice a day, and for age >10 years the final dose was 50 mg twice a day, but due to the occurrence of drowsiness, the drug regimen was reduced to half dose (18). Other studies (5, 7, 19–21) on the use of TBZ treatment in the hyperkinetic movements, but not related to DCP or children, introduce a wide range of doses of TBZ which vary from 12.5 to 350 mg/day based on the positive drug response.
These findings were confirmed in the current study: in common clinical practice, the optimal dose of TBZ in the treatment of DCP in a pediatric population is individualized and not related to any specific dose per body weight but according to the clinical improvement.
This study, differently from those undertaken previously, also evaluated the efficacy of TBZ in children with DCP by using MD-CRS 4–18 R, a standardized and suitable tool to detect changes during pharmacological treatment.
Indeed, a significant clinical reduction of movement disorder after 6 months was detected, subsequently followed by a “plateau state.” A significant improvement in the general assessment (including Motor function, Oral/verbal function, Self-care and Attention/Alertness) and in the severity of movement disorders (including grading and spread of movement disorders for different body regions) was found after 6 and 12 months of TBZ treatment. No relevant differences were obtained during TBZ administration between 6 and 12 months. These results are crucial from a clinical point of view because they show how the children and parents can be assured that the use of TBZ impacts not only the reduction of movement disorder but also the clinical general functioning such as language and the self-care activities.
No relevant differences were observed in the type and frequency of adverse events reported in scientific literature and this study. The main side effect, in fact, was sedation, followed by dystonia-parkinsonism, depression, and akathisia.
In the long-term subgroup of the sample, a stable improvement was reached after a treatment period of more than 2 years and no important side effects were detected.
Although no side effects relating to heart rhythm abnormalities were detected, according to our experience, EKG evaluations, including QTc measurement, are advisable before starting TBZ, during up-titration (10 days after each dose increasing) and subsequently an annual follow-up.
The main limitations of this study are related to the small size of the sample and the low dosage of TBZ prescribed, compared to the previous reports. A retrospective design based on the review of each Center database and the inclusion criteria (i.e., polytherapy with stable dosage for at least 12 months during TBZ treatment) were probably responsible for the small size of the cohort and the concomitant use of other medications, which could have interfered with the obtained benefits. In addition, the lack of further clinical improvement after the initial reduction of hyperkinetic movements and the absence of severe side effects could be justified by the low dose used in the study cohort.
However, the present study reflects the common clinical practice in the management of an “off-label” drug in children while at the same time embedding valid and agreed-upon age-specific outcome measures.
In conclusion, this study shows that (a) the efficacy of TBZ in children with DCP through a gradual titration has been demonstrated when a standardized outcome measure is used; (b) an optimal TBZ dose should be individualized according to the clinical improvement, such as the reduction of movement disorders; (c) a standardized outcome measure, such as MD-CRS 4–18 R, is also essential during the clinical observational trial and not only in the randomized trial, since it is important to detect changes in an objective way; and (d) good safety and tolerability of TBZ in children has been proved while the occurrence of the side effects should be evaluated through a clinical neurological and psychiatric follow-up and periodic EKG monitoring.
Further studies, however, are needed in children with DCP by randomized clinical trials including parallel groups with different doses of the drug to determine the standardized dosage to be shared in clinical and research settings.
Data Availability Statement
The datasets presented in this article are not readily available because the they contain information that could compromise the privacy of the participants. Requests to access the datasets should be directed to rbattini@fsm.unipi.it.
Ethics Statement
The research was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and local laws. The study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for the treatment “off label” with tetrabenazine.
Author Contributions
RS contributed to the study concept and design and to the execution of the research project and wrote and edited the first draft of the manuscript. GS contributed to the study concept and design, execution and review of the statistical analysis, and manuscript revision. VM organized the database for data collection, generated the tables, and edited the manuscript. NC proofread the data and wrote a part of the manuscript. DR, FS, RD, EP, and MF contributed to the execution of the research project and data collection. GC read, critically revised, and approved the final manuscript. RB conceived the study concept and design, the execution of the research project, interpretation of results, and critical revision of the submitted version. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We wish to thank Miningful Studio for carrying out the statistical analysis and revising the manuscript; and Prof. Ailish Lynam for reviewing the English in the manuscript.
Funding. The authors have not received specific funding sources for this study. The study was partially supported by the Italian Ministry of Health (Grant No. RC2019) and taxpayers' contributions (5 × 1,000) to 2018 IRCCS Stella Maris Foundation. | TETRABENAZINE | DrugsGivenReaction | CC BY | 33716922 | 19,975,767 | 2021 |
What was the administration route of drug 'TETRABENAZINE'? | A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine.
Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders-Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4-18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4-18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.
Introduction
Tetrabenazine (TBZ; Xenazine®) is a selective and reversible depletor of monoamines from synaptic terminals, preferentially dopamine but also norepinephrine, serotonin, histamine (1). TBZ has a short half-life, which lasts for about 16–24 h, and a rapid onset of action, which is useful in clinical applications (2). The antichorea efficacy of TBZ is related to dopamine depletion, whereas the risk of depression may be mediated by serotonin and norepinephrine depletion, and sedation may be explained by histamine depletion (1).
TBZ could determine a mild increase in the corrected QT (QTc) interval and should be used properly and carefully when combined with other drugs that also increase the interval of QTc or in patients with congenital long QT syndrome and a history of cardiac arrhythmias (3).
The dose of TBZ should be personalized for each patient (3), with significantly interindividual differences in reaching the “optimal dose,” which is the dose that provides the main clinical response with minimal or tolerable adverse events (1).
The principal most common and dose-limiting side effects of TBZ are known. These include sedation (28%), akathisia (13%), parkinsonism (7%), depression (5.5%), anxiety (4%), fatigue (2%), and diarrhea (2%), all of which are usually rapidly reversible upon dosage reduction (1, 2, 4).
To date, there is no consensus regarding the best clinical practice in the pediatric population; in this instance, the administration of TBZ to the adult population is empirically adapted to children and it is “off-label” (5) for a wide variety of hyperkinetic movement disorders (6–10), including dyskinetic cerebral palsy (DCP) (11).
DCP, the second most common type of cerebral palsy (CP) (almost 15%), typically caused by non-progressive basal ganglia and/or thalamus lesions, is characterized by abnormal postures or movements associated with compromised tone regulation and coordination. In DCP, the two typical movement disorders are dystonia and choreoathetosis, which are often co-occurring; dystonia is usually more severe than choreoathetosis, affecting daily activity, quality of life, and social participation (12).
A recent review has highlighted the inadequate evidence for pharmacological interventions in DCP due to the absence of any therapeutic algorithm and the lack of reliable, valid, and agreed-upon age-specific outcome measures (11). To fill this gap, in 2008, the Childhood Movement Disorders Rating Scale (MD-CRS) was proposed and has been recently updated in a revised form (MD-CRS 4-18 R). The scale aimed to define the functional impairment and the severity produced by movement disorder (e.g., dystonia and choreoathetosis) in the pediatric population (11, 13–15). The psychometric properties in DCP of MD-CRS 4–18 R have been recently published (15).
In this study, we have hypothesized that (i) the use of standardized outcome measures, such as MD-CRS, could provide useful data for a retrospective analysis of “off-label” treatment with TBZ obtained from routine clinical practice in the pediatric population affected by DCP; (ii) clinical data could provide a preliminary insight for evaluating the safety and effectiveness of TBZ treatment.
The primary purpose of this study was to retrospectively evaluate a sample of children with DCP who had been treated with TBZ in order to collect data on its efficacy using the MD-CRS 4–18 R as a standardized tool to assess movement disorders in childhood and to detect changes during treatment.
The secondary aims of the study were (1) to determine the impact of TBZ-associated side effects in children with DCP and (2) to analyze the long-term effectiveness and tolerability of TBZ in clinical practice, by evaluating the outcome on a sub-group with a follow-up >2 years.
Materials and Methods
Study Design
A multicenter retrospective longitudinal study was designed involving three Italian Research and Clinical Scientific Institutes: The Department of Developmental Neuroscience of Stella Maris Foundation (Pisa), The Developmental Neurology Unit Institute “C. Besta” (Milano), and The Pediatric Neurology Unit of Fondazione Policlinico “A. Gemelli” (Rome).
These scientific institutes cooperate in the research on movement disorders, sharing agreed clinical and pharmacological protocols, including outcome measures, as MD-CRS. Each Center has its own database for CP data collection, which accounts for at least 600 subjects. From these data sets, cases were selected according to the following inclusion criteria: (a) DCP diagnosis according to the Surveillance of Cerebral Palsy in Europe criteria (16); (b) age ≥4 years; (c) use of TBZ, in mono- or polytherapy—in the presence of polytherapy a stable dosage of other drugs was maintained during the 12 months of follow up, after starting TBZ; (d) videos of Movement Disorder-Childhood Rating Scale which had been collected between July 2007 and December 2019, at the following timing: baseline, i.e., before starting TBZ (T0), after 6 (T1), and 12 (T2) months of treatment. When available, a MD-CRS video after ≥2 years of treatment (long term—LT), was also included (Figure 1).
Figure 1 Design and management of the study with subjects selection.
Procedures
The clinical, demographic, and pharmacological data of each selected subject were extracted from medical records to fulfill the aims of the study.
All participants were classified according to the Gross Motor Function Classification System (GMFCS) for cerebral palsy which is based on self-initiated movement, with emphasis on sitting, transfers, and mobility. A five-level classification system is used to define the subject (from I to V increasing severity) and the distinctions are based on functional limitations, the need for hand-held mobility devices or wheeled mobility, and to a much lesser extent, quality of movement.
A neurological and psychiatric history assessment was carried out on all the subjects.
The psychiatric evaluation was carried out by anamnestic interview and, when available for subjects >6 years, with some items from a semi-structured interview, the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL).
These evaluations were checked before and during the follow up visit.
TBZ treatment indications for all the included subjects were based on multidisciplinary assessments made by child neurologists, an expert in movement disorders, and a pediatric physical therapist.
TBZ administration usually started with a low fixed dose of 6.25 mg (1/4 oral tablet of 25 mg) at least during the first week and was gradually and variably increased according to weight or the clinical neuromotor picture with an aim of reaching a “possible optimal dose,” as in previous reports (1, 4). The dosage was subdivided into 2 or 3 times daily.
Data collection of corrected QT (QTc) was considered if the subjects had performed an EKG before the study, during up-titration, and subsequently annually during follow-up to monitor the risk of a potential increase in the QTc interval or cardiac arrhythmias.
Outcome Measure
All the videos included were recorded according to a standardized videoprotocol and blind scored according to MD-CRS 4–18 R (15).
MD-CRS 4–18 R is a feasible tool to verify the natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP.
The MD-CRS 4–18 R was developed for the assessment of function and disability in various types of movement disorders. This scale requires that the evaluation be recorded according to a specific videoprotocol, and subsequently a score is assigned. The MD-CRS 4–18 R scale is divided into two parts: General Assessment (Part I) and Movement-Disorder Severity (Part II). In Part I, four areas are included: motor function, oral/verbal function, self-care, and attention/alertness, for a total of 15 items. In Part II, the intensity of the prevalent movement abnormality in seven body parts (eye and periorbital region, face, tongue and perioral region, neck, trunk, upper limb, lower limb) in two conditions, at rest and during the execution of specific tasks, is assessed. All items are scored on a 5-point ordinal scale (0–4): zero corresponds to no signs, and 4 corresponds to the most severe findings. The scores for part I and part II and the total score are calculated by statistical analysis obtaining Index I, Index II, and Global Index, respectively. Indexes range come from 0 (severe impairment) to 1 (normal).
The Stella Maris Foundation holds the copyright for the MD-CRS 4–18 R (MD-CRS copyright owner) which is distributed, worldwide, by Mapi Research Trust, a nonprofit organization. For further information and conditions of use of the MD-CRS 4–18 R, consult the online platform Mapi Research Trust, ePROVIDE (https://eprovide.mapi-trust.org).
Ethics Approval
The multicenter study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for treatment “off label” at baseline.
Statistical Analyses
A linear mixed model was used to evaluate the effects of the different timings (T0, T1, and T2 as fixed factors) on each Index (Index I, Index II, and Global Index) adding age and type of MD as random effect. Further analysis with the same approach was also carried out for the subgroup of subjects with the long-term follow-up to evaluate the effects of T0, T1, T2, and LT on each index. For both models, a post hoc analysis between different time points was performed.
Results
Participants
The study included 23 children and adolescents (19 male and 4 female) affected by DCP, age range 4.02–16.30 years at baseline observation (mean age 8.28 years, SD 3.59).
Clinical and demographic data are reported in Table 1.
Table 1 Clinical and demographic data of the sample.
Demographic Participants N = 23
Sex: n (%) Male: 19 (83%)
Female 4 (17%)
Mean age ± SD (range) at T0 (years) 8.28 ± 3.59 (4.02–16.30)
Mean weight ± SD (range) at T0 (kg) 25.13 ± 11.94 (12.00–62.00)
Type of MD: n (%) Dystonia and choreoathetosis: 19 (83%)
Choreoathetosis: 4 (17%)
Etiology: n (%) Hypoxic-ischemic encephalopathy: 17 (74%)
Kernicterus: 4 (17%) Cytomegalovirus infection: 2 (9%)
GMFCS level: n (%) I: 1 (4%)
II: 1 (4%)
III: 2 (9%)
IV: 5 (22%)
V: 14 (61%)
None of the participants presented clinically relevant psychiatric diseases (e.g., significant depression or history of suicidal intent) at baseline (T0).
At the beginning of TBZ treatment, seven subjects with DCP started TBZ in monotherapy, while the others were in polytherapy (e.g., oral baclofen, trihexyphenidyl, benzodiazepines).
A mean dosage of TBZ close to 1 mg/kg was reached (Table 2).
Table 2 Mean and range TBZ dosage at the different time points.
Timing Mean (mg/kg) ± SD Min (mg/kg) Max (mg/kg)
T1 (T0 +6 months) 0.70 ± 0.41 0.30 2.08
T2 (T0 +12 months) 0.84 ± 0.44 0.20 2.08
Long Term 0.97 ± 0.58 0.20 2.08
T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, > 2 year of therapy.
The reduction of the minimum dosage after 12 months and at long term after treatment was related to the maintenance of a stable oral dose between T1 and T2 (5 subjects) without considering the weight increase of the subjects. 4 of the other children reduced their dosage, 2 after 6 months, and 2 after 12 months respectively, due to the occurrence of adverse events (see specific section).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) of TBZ Treatment
A relevant effect of timing was found with a significant reduction of each index between T0 and T1 and between T0 and T2, but not between T1 and T2. Specifically, the mean value of Index I (General Assessment) at T0 0.60 ± 0.06, at T1 0.57 ± 0.06, and at T2 0.57 ± 0.06; the mean value for Index II (MD severity) at T0 was 0.63 ± 0.03, at T1 0.53 ± 0.03, and at T2 0.48 ± 0.03; finally, the mean value of for Global Index at T0 was 0.61 ± 0.05, at T1 0.56 ± 0.05, and at T2 0.54 ± 0.05.
The results of the analysis at T0, T1, and T2 are reported in Table 3.
Table 3 Linear mixed model results during 12 months of follow up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.60 (0.06) >0.05 0.98
T1 −0.03 (0.01) <0.01
T2 −0.03 (0.01) <0.01
Index II Intercept 0.63 (0.03) <0.01 0.73
T1 −0.10 (0.03) <0.01
T2 −0.15 (0.03) <0.01
Global index Intercept 0.61 (0.05) >0.05 0.95
T1 −0.05 (0.01) <0.01
T2 −0.07 (0.01) <0.01
MD-CRS R, movement disorders—childhood rating scale revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
As shown, a significant effect of timing was found at T1 and T2 (Table 3).
Clinical Outcomes at Baseline (T0), After 6 (T1), and 12 Months (T2) and TBZ Long-Term (LT) Treatment
A small group, 10 subjects, had a long-term follow-up >2 years, and the efficacy of TBZ was still present and stable without important side effects.
In this long-term group (LT), a significant reduction of each Index was found between T0 and T2 but not between T2 and LT. Specifically, the MD-CRS R Index I (General Assessment) mean value was 0.52 ± 0.08 at T0, 0.48 ± 0.08 at T1, 0.49 ± 0.08 at T2, and 0.46 ± 0.08 at long term; the Index II (MD Severity) mean value was 0.62 ± 0.06 at T0, 0.52 ± 0.06 at T1, 0.49 ± 0.06 at T2, and 0.52 ± 0.06 at long term; the Global Index mean value was 0.55 ± 0.07 at T0, 0.49 ± 0.07 at T1, 0.48 ± 0.07 at T2, and 0.48 at long term.
The post hoc analysis between the different time points during 12 months follow up are reported in Table 4. The results of the analysis on the T0, T1, T2, and long-term subgroup are reported in Table 5. As shown, all-time points are significant (Table 5).
Table 4 Post-hoc analysis between the different time points during 12 months follow up.
Timing MD-CRS 4-18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
T0–T1 Index I 0.03 (0.01) 42 2.92 <0.05
Index II 0.10 (0.02) 42 3.81 <0.01
Global index 0.05 (0.01) 42 4.15 <0.01
T0–T2 Index I 0.03 (0.01) 42 3.06 <0.05
Index II 0.15 (0.03) 42.3 5.38 <0.01
Global index 0.07 (0.01) 42 5.40 <0.01
T1–T2 Index I 0.01 (0.01) 42 0.24 > 0.05
Index II 0.05 (0.02) 42.3 1.69 > 0.05
Global index 0.02 (0.01) 42 1.39 > 0.05
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy.
Table 5 Linear mixed model results during the long-term follow-up.
MD-CRS 4–18 R indexes Timing Coefficient estimate (SD) p-value R2
Index I Intercept 0.52 (0.08) <0.01 0.98
T1 −0.05 (0.01) <0.01
T2 −0.03 (0.01) <0.05
LT −0.07 (0.02) <0.01
Index II Intercept 0.62 (0.06) <0.01 0.75
T1 −0.10 (0.04) <0.05
T2 −0.13 (0.04) <0.05
LT −0.09 (0.04) <0.05
Global index Intercept 0.55 (0.07) <0.01 0.96
T1 −0.06 (0.02) <0.01
T2 −0.07 (0.02) <0.01
LT −0.08 (0.02) <0.01
MD-CRS 4–18 R, movement disorders—childhood rating scale 4–18 revised; T0, baseline; T1, 6 months of therapy; T2, 12 months of therapy; LT, long term, >2 year of therapy.
In the following table, the result of the post-hoc analysis of long-term vs. baseline (T0) and T2 are represented (Table 6).
Table 6 Post-hoc analysis between the different time points during the long-term follow-up.
Timing MD-CRS 4–18 R indexes Estimate (SE) Degrees of freedom t ratio p-value
LT–T0 Index I −0.07 (0.02) 28 −4.44 <0.01
Index II −0.09 (0.04) 28.2 −2.13 <0.05
Global index −0.08 (0.02) 28 −3.78 <0.01
LT–T2 Index I −0.03 (0.01) 28 −2.22 <0.05
Index II 0.04 (0.04) 28 0.79 > 0.05
Global index −0.01 (0.02) 28 −0.22 > 0.05
MD-CRS 4–18 R: movement disorders—childhood rating scale 4–18 revised; t0, baseline; t2, 12 months of therapy; lt, long term, >2 year of therapy.
TBZ-Associated Side Effects
TBZ was associated with side effects in 6/23 (26%) subjects: drowsiness in 3/23 (13.04%); dystonia in 2/23 (8.69%); parkinsonism/rigidity in 2/23 (8.69%), anxiety and depressive problems in 1 (4.35%), and akathisia in 1 (4.35%).
Three of these children showed two side effects: one child showed drowsiness after 6 months of treatment and parkinsonism/rigidity after 12 months; another showed dystonia after 6 months of therapy and anxious-depressive problems in the long-term follow-up while the third child presented dystonia and akathisia after 12 months of therapy. Of these subjects, 2 dropped out after T1, one due to dystonia and the other to parkinsonism/rigidity which was treated subsequently with the implantation of Intrathecal Baclofen Pump.
An ECG (included QTc) was performed on all individuals with QTc at baseline (T0) and during up-titration, T1, and T2. The QTc value remained in a normal range in all subjects. Two children reported no clinically significant tachycardia.
Discussion
To our knowledge, this is the first study dedicated to a homogeneous cohort of children with DCP treated with TBZ who were subsequently followed up for at least 1 year and evaluated with a standardized clinical outcome (MD-CRS). Specifically, it represents the results of a routine medical practice by monitoring, by a standardized outcome measure, the use of TBZ when prescribed to children with DCP.
In this study, the use of TBZ was determined by the ineffectiveness of other dystonia and chorea drugs or it was prescribed as an add-on to hyperkinetic movement disorder treatment specifically. The effects of TBZ in children with DCP, either in a dystonic or choreic form, were evaluated, and a clinical improvement was reported regarding both the severity and quantity of the movement disorder in different parts of the body. Improvement in general clinical functioning, such as the motor and self-care abilities and activities, was also detected.
During the titration period, the dose of TBZ was adjusted empirically according to the clinical benefit: the starting dose of 6.25 mg (1/4 oral tablet of 25 mg) was prescribed once daily, and it was titrated gradually increasing it to 6.25 mg weekly or bi-weekly until a maximum of 50 mg/day (2 mg/kg, twice or three times daily).
In order to identify a dose level that clinically reduced movement disorders and was well tolerated, a customized TBZ dose regimen was considered for each subject. This step is a very crucial achievement because it shows the common behavior of clinicians to customize the TBZ dose on the basis of the clinical improvement and functioning. In general, research impacts the clinical behavior, but in this case, as is important in evidence-based medicine (EBM), clinical expertise is essential and works in parallel with research evidence and patient preferences for guiding the EBM.
The data obtained by clinical observation were considered because there is no consensus in literature regarding the optimal medical treatment currently available (11), and the therapies are mainly related to “off-label” drugs anecdotally adapted to children (17).
With regard to the pediatric population, some authors, already many years ago, used a higher initial drug schedule: for age 3–10 years, the final dose was 25 mg twice a day, and for age >10 years the final dose was 50 mg twice a day, but due to the occurrence of drowsiness, the drug regimen was reduced to half dose (18). Other studies (5, 7, 19–21) on the use of TBZ treatment in the hyperkinetic movements, but not related to DCP or children, introduce a wide range of doses of TBZ which vary from 12.5 to 350 mg/day based on the positive drug response.
These findings were confirmed in the current study: in common clinical practice, the optimal dose of TBZ in the treatment of DCP in a pediatric population is individualized and not related to any specific dose per body weight but according to the clinical improvement.
This study, differently from those undertaken previously, also evaluated the efficacy of TBZ in children with DCP by using MD-CRS 4–18 R, a standardized and suitable tool to detect changes during pharmacological treatment.
Indeed, a significant clinical reduction of movement disorder after 6 months was detected, subsequently followed by a “plateau state.” A significant improvement in the general assessment (including Motor function, Oral/verbal function, Self-care and Attention/Alertness) and in the severity of movement disorders (including grading and spread of movement disorders for different body regions) was found after 6 and 12 months of TBZ treatment. No relevant differences were obtained during TBZ administration between 6 and 12 months. These results are crucial from a clinical point of view because they show how the children and parents can be assured that the use of TBZ impacts not only the reduction of movement disorder but also the clinical general functioning such as language and the self-care activities.
No relevant differences were observed in the type and frequency of adverse events reported in scientific literature and this study. The main side effect, in fact, was sedation, followed by dystonia-parkinsonism, depression, and akathisia.
In the long-term subgroup of the sample, a stable improvement was reached after a treatment period of more than 2 years and no important side effects were detected.
Although no side effects relating to heart rhythm abnormalities were detected, according to our experience, EKG evaluations, including QTc measurement, are advisable before starting TBZ, during up-titration (10 days after each dose increasing) and subsequently an annual follow-up.
The main limitations of this study are related to the small size of the sample and the low dosage of TBZ prescribed, compared to the previous reports. A retrospective design based on the review of each Center database and the inclusion criteria (i.e., polytherapy with stable dosage for at least 12 months during TBZ treatment) were probably responsible for the small size of the cohort and the concomitant use of other medications, which could have interfered with the obtained benefits. In addition, the lack of further clinical improvement after the initial reduction of hyperkinetic movements and the absence of severe side effects could be justified by the low dose used in the study cohort.
However, the present study reflects the common clinical practice in the management of an “off-label” drug in children while at the same time embedding valid and agreed-upon age-specific outcome measures.
In conclusion, this study shows that (a) the efficacy of TBZ in children with DCP through a gradual titration has been demonstrated when a standardized outcome measure is used; (b) an optimal TBZ dose should be individualized according to the clinical improvement, such as the reduction of movement disorders; (c) a standardized outcome measure, such as MD-CRS 4–18 R, is also essential during the clinical observational trial and not only in the randomized trial, since it is important to detect changes in an objective way; and (d) good safety and tolerability of TBZ in children has been proved while the occurrence of the side effects should be evaluated through a clinical neurological and psychiatric follow-up and periodic EKG monitoring.
Further studies, however, are needed in children with DCP by randomized clinical trials including parallel groups with different doses of the drug to determine the standardized dosage to be shared in clinical and research settings.
Data Availability Statement
The datasets presented in this article are not readily available because the they contain information that could compromise the privacy of the participants. Requests to access the datasets should be directed to rbattini@fsm.unipi.it.
Ethics Statement
The research was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and local laws. The study was approved by the Tuscany Pediatric Ethics Committee (94/2019). All the parents were asked to sign an informed written consent form for the treatment “off label” with tetrabenazine.
Author Contributions
RS contributed to the study concept and design and to the execution of the research project and wrote and edited the first draft of the manuscript. GS contributed to the study concept and design, execution and review of the statistical analysis, and manuscript revision. VM organized the database for data collection, generated the tables, and edited the manuscript. NC proofread the data and wrote a part of the manuscript. DR, FS, RD, EP, and MF contributed to the execution of the research project and data collection. GC read, critically revised, and approved the final manuscript. RB conceived the study concept and design, the execution of the research project, interpretation of results, and critical revision of the submitted version. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We wish to thank Miningful Studio for carrying out the statistical analysis and revising the manuscript; and Prof. Ailish Lynam for reviewing the English in the manuscript.
Funding. The authors have not received specific funding sources for this study. The study was partially supported by the Italian Ministry of Health (Grant No. RC2019) and taxpayers' contributions (5 × 1,000) to 2018 IRCCS Stella Maris Foundation. | Oral | DrugAdministrationRoute | CC BY | 33716922 | 19,975,767 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abortion induced'. | Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.
Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors' knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.
Introduction
Dermatomyositis (DM) is a spectrum of muscle myalgia and weakness, with typical skin manifestations, including heliotrope rash and Gottron’s sign. Clinically amyopathic dermatomyositis (CADM) is an independent spectrum of classic DM with typical skin lesions and minimal or absent muscle disease (1). It has been reported that the prevalence of CADM in all patients with dermatomyositis is 5%–20% (2). Rapidly progressive interstitial lung disease (RP-ILD) is common in CADM patients with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody (3), which tends to be treatment-refractory with a poor prognosis (4). The onset of CADM during pregnancy is extremely rare and the outcome of pregnancy in these patients is poor for both mother and fetus, including maternal and fetal death, as well as prematurity (5, 6). The present case study reports on a pregnant woman with CADM with the positive anti-MDA5 antibody, who developed RP-ILD during her first 7 weeks of gestation. She was successfully treated with combined immunosuppressive therapy without residual pulmonary interstitial changes.
Case Presentation
A 38-year-old woman with a 7-week pregnancy was admitted to our hospital with complaints of dry cough, dyspnea on exertion, and a rash over the face, neck, and dorsum of the hands for 23 days and polyarthritis for 2 days ( Figure 1A ). Prior to admission, she was treated with loratadine without resolution, and her symptoms gradually worsened. Her past medical history was unremarkable.
Figure 1 Clinical presentation of the patient (A) on admission and (B) after recovery.
Physical examination on admission revealed a high body mass index of 33.1, heliotrope rash, Gottron’s papules and fine crackles audible bilaterally in the lower lung fields. No signs of muscle weakness or pain were present. The patient had tachycardia (113 beats/min) with normal oxygen saturation. Laboratory findings revealed the levels of creatine phosphokinase (CK; reference range, 25–192) to be 171 U/l, lactate dehydrogenase (LDH; reference range, 110–240) to be 441 U/l, alanine transaminase (AST; reference range, 0–40) to be 50 U/l, C-reactive protein (CRP; reference range, <5) to be 30.94 mg/l, erythrocyte sedimentation rate (ESR, reference range, 0–20) to be 53 mm/h, and ferritin (reference range, 11.0–306.8) to be 167.3 ng/ml. The main laboratory results are shown in Table 1 . No evidence was identified that may have suggested infection or malignancy, and therefore CADM was suspected in this patient. She was treated with 24 mg/day of oral methylprednisolone for 3 days, along with 400 mg/day of hydroxychloroquine in her first week of admission. However, the patient’s respiratory condition continued to worsen with percutaneous blood oxygen saturation decreasing to 88% under use of low- flow nasal cannula oxygen and therefore she was given oxygen by way of medium-flow mask oxygen. Moreover, she was unable to complete the pulmonary function test due to the rapid deterioration of the respiratory status.
Table 1 Laboratory findings on admission.
Parameter Value Reference range
Leukocytes (109/L) 3.6 4–10
Erythrocytes (1012/L) 4.76 3.5–5
Hemoglobin (g/L) 129 110–150
Platelets (109/L) 251 100–300
Glucose (mmol/L) 4.89 3.9–6.1
Cholesterol (mmol/L) 3.46 3.4–6.5
HDL (mmol/L) 0.94 0.9–1.91
LDL (mmol/L) 1.69 2.08–4.14
AST (U/L) 50 0–40
ALT (U/L) 48 0–45
ALP (U/L) 61 15–121
CK (U/L) 171 25–192
LDH (U/L) 441 110–240
Urea nitrogen (mmol/L) 2.79 2.5–7.5
Creatinie (µmol/L) 64 44–133
IgG (g/L) 10.21 8–18
Ferritin level (µg/L) 167.3 11.0–306.8
24-h urine protein (g/24 h) 0.216 0.028–0.141
ESR (mm/h) 53 0–20
CRP (mg/L) 30.94 <5
PCT (ng/ml) <0.05 <0.05
C3 (g/L) 1.28 0.80–1.81
C4 (g/L) 0.32 0.15–0.57
Coombs’ test Negative Negative
RF (IU/mL) 7.3 <25
Anti-CCP Negative Negative
cANCA Negative Negative
anti-PR3 Negative Negative
pANCA Negative Negative
anti-MPO Negative Negative
ANA Negative Negative
Anti-centromere Negative Negative
Anti-dsDNA Negative Negative
Anti-SS-A Negative Negative
Anti-SS-B Negative Negative
Anti-MDA5 Strongly positive Negative
Anti-tRNA synthase autoantibody panel Negative Negative
HDL, high-density lipoprotein; LDL, low density lipoprotein; AST, alanine transaminase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CK, creatine phosphokinase; LDH, lactic dehydrogenase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PCT, procalcitonin; RF, rheumatoid factor; C3, complement C3; C4, complement C4; Anti-MDA5, anti-melanoma differentiation-associated gene 5. Anti-CCP, anti-cyclic citrullinated peptide antibody; cANCA, cytoplasmic-staining anti-neutrophil cytoplasm antibody; pANCA, perinuclear-staining anti-neutrophil cytoplasm antibody; Anti-MPO, anti-myeloperoxidase antibody; Anti-PR3, anti-proteinase 3 antibody; ANA, anti-nuclear antibodies; Anti-dsDNA, anti-double-stranded (ds) DNA antibody; Anti-SS-A, anti-Sjögren's syndrome antigen A antibody; Anti-SS-B, anti-Sjögren's syndrome antigen B antibody.
Further tests revealed that her anti-MDA5 antibody was positive. The high-resolution computed tomography (HRCT) scan on day 7 revealed reticular shadows, patchy ground glass opacities and inflammation in both lungs ( Figure 2A ). On the basis of these findings, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made. According to the results of a multi-disciplinary discussion, on day 10, the patient was treated with combination therapy including methylprednisolone (1.0 mg/kg/day, that is, 80 mg/day) accompanied by oral cyclosporine (100 mg twice a day) and intravenous cyclophosphamide (IVCY, 400 mg/week) following high dose pulsed methylprednisolone at 500 mg/day for 3 days and intravenous immunoglobulin (IVIG, 20 g/day for 3 days). Considering her worsening condition, artificial abortion was conducted on day 10 with her permission. The respiratory condition of the patient improved gradually. A chest CT scan performed on day 21 of hospitalization revealed a patchy density shadow that had significantly decreased compared with its appearance previously ( Figure 2B ). The patient was discharged while being treated with methylprednisolone at 80 mg/day, cyclosporine at 200 mg/day, IVCY at 400 mg/2 weeks.
Figure 2 Changes in chest computed tomography scan findings (A) on admission, (B) before discharge and (C) after recovery.
Because of the significant improvement in her respiratory condition, we decided to taper the methylprednisolone and IVCY dose gradually. During the follow up, the patient achieved complete remission, her rash disappeared ( Figure 1B ) and the chest CT scan revealed that the patient had returned to the normal state after treatment for 10 months ( Figure 2C ). IVCY treatment was discontinued after treatment for 14 months, and anti-MDA5 antibody was negative after treatment for 24 months. At the time of writing this report, the patient was being treated with 4 mg/day methylprednisolone and 75 mg/day cyclosporine. The clinical course of the patient is shown in Figure 3 .
Figure 3 Clinical course of the patient. mPSL, methylprednisolone; Pulse: intravenous methylprednisolone pulse therapy (500 mg/d×3 days); IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; CyA, cyclosporine A; IVCY, intravenous cyclophosphamide; O2, oxygen; Anti-MDA5, anti-melanoma differentiation-associated gene 5 antibody; ++, strongly positive; +, positive; −, negative.
Discussion
Inflammatory myopathies are a spectrum of systemic immune-mediated disorders characterized by muscle inflammation, and affecting extramuscular organs, including skin, joints, and lungs. It is widely recognized that there are five main types of inflammatory myopathies: DM, polymyositis (PM), overlap myositis (including anti-synthetase syndrome (ASS)), inclusion-body myositis, and immune-mediated necrotizing myopathy (7, 8). RP-ILD was mainly defined as progressive dyspnea, or according to HRCT findings secondary to ILD within 3 months after the onset of respiratory symptoms (9, 10). RP-ILD often occurs as a complication of CADM, which usually portends poor prognosis with reported mortality rates in the first year as high as 60% (11). Anti-MDA5 antibodies were first identified by Sato et al. in 2005 in Japanese patients with CADM (12). Since that discovery, anti-MDA5 antibodies have predominantly been found in cases of CADM (13). Mortality rates ranged from 36%–46% in anti-MDA5 positive patients with CADM or DM (14). Anti-MDA5 antibodies have also been associated with RP-ILD, as identified in 39%–100% of patients with RP-ILD in Asian cohorts (15). The cumulative 6-month survival rate was reported to be about 50% for RP-ILD patients with the anti-MDA5 antibody (16). Hence, anti-MDA5 antibodies can be a useful predictor for the complication of RP-ILD in patients with CADM. In the present case study, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made as the patient experienced respiratory symptoms from the beginning, and her respiratory status deteriorated rapidly within one month. It has been suggested that immunosuppressants should be used early in patients with RP-ILD, since the damage caused to the pulmonary tissue may be irreversible once CADM is complicated by RP-ILD, which may result in the patient being irresponsive to combination immunosuppressive therapy, leading to death after only a few months (17). However, the use of immunosuppressants may not ensure rapid remission of the patient’s condition (18). It was reported that combination immunosuppressive therapy consisting of high-dose corticosteroids, cyclosporine and intravenous immunoglobulin might be effective for CADM patients with RP-ILD (16). Moreover, previous studies have also shown that patients with RP-ILD or respiratory failure may benefit from the use of basiliximab, mycophenolate mofetil or cyclophosphamide (19, 20).
The onset of DM during pregnancy is a rare event. It has been reported that one in 173 female patients with DM/PM experienced disease onset during pregnancy (21). Pregnancy outcomes are closely associated with the disease activity during pregnancy. Patients with quiescent disease before pregnancy have good pregnancy outcomes. By contrast, a pre-existing active condition or onset of DM during pregnancy leads to a high frequency of premature delivery and fetal death (21).
There are several factors that may explain the trigger for development of DM during pregnancy, such as changes in maternal hormonal status, exposure of the mother to fetal antigens, and the reactivation of certain viruses due to pregnancy (6). In addition, a high body mass index was noticed in the patient. Previous studies have revealed that obesity is a metabolic disease which may lead to the activation of the immune system and a consequently worse prognosis (22). Moreover, the obese are prone to respiratory failure even with mild pulmonary challenge (23). Hence, the rapid deterioration of the respiratory status in this patient may be partially explained by her high body mass index.
In view of these considerations, the onset of CADM during pregnancy is a problematic issue to be resolved for both physicians and patients. Treatment regimen should consider the safety of both the mother and the fetus, which requires individualized therapy. Glucocorticoids are the first line treatment in pregnant patients with DM (24). In certain rare cases, the use of glucocorticoids has been demonstrated to lead to a good outcome (6). However, certain patients have been shown to be non-responsive or intolerant to glucocorticoids (24). A previous study illustrated that gestational exposure to glucocorticoids led to a slight increase in the risk of premature birth and fetal oral cleft (25). Efficacy and safety of IVIG during pregnancy has been well documented in DM, especially for refractory cases (24, 25). In a previously published case report, short term remission was achieved following treatment with IVIG (4.5 g for 3 consecutive days) (25).
Examples of clinical case studies for treating pregnant patients with DM or PM, especially CADM, are relatively rare, and case studies of a similar nature that we were able to identify are shown in supplementary material (18, 26–28). Tomohiro et al (18). described the case of a 33-year-old pregnant woman who developed progressive interstitial pneumonia (IP) complicated by anti Jo-1 positive ASS at 28 weeks of gestation. At 30 weeks of her gestation, since the neonate could be treated at the neonatal intensive care unit after delivery, an emergency cesarean section was performed. The patient was eventually successfully treated with a combination of immunosuppressive therapy including intravenous methylprednisolone pulse therapy (1 g/day) and IVCY and the use of high flow nasal cannula oxygen therapy without intubation. In another case report, a pregnant woman at 16 weeks of gestation had developed IP preceding anti Jo-1 positive ASS, and was treated with a combination of steroid pulse therapy and tacrolimus. The fetus did not survive since it was too small, and the maternal condition deteriorated (26). To the best of our knowledge, the present case study is the first reported case of a patient having been diagnosed with anti-MDA5-positive RP-ILD complicated with CADM. In our case, artificial abortion was conducted because the maternal condition was unstable. The influences of high dose steroids and the CT scan were also taken into consideration. After combining steroid pulse and immunosuppressive therapy, the maternal condition gradually improved and our patient had complete remission without residual pulmonary interstitial changes. In anti-MDA5-positive patients with CADM, the CT scans usually show ground-glass opacities and bilateral subpleural reticular opacities, predominantly in the lower lungs, which would improve substantially or become stable after combination immunosuppressive therapy (29, 30). The present report describes a pregnant woman with CADM with positive anti-MDA5 antibody, who developed RP-ILD and subsequently achieved complete remission without residual pulmonary interstitial changes after treatment, which has been rarely reported in the previous literature. It is difficult to save the fetal lives in CADM patients with anti-MDA5 antibody. Because it was dispensable to use combination of high dose corticosteroids and immunosuppressive agents including IVCY in CADM patients even if they were in pregnancy.
Certain biological parameters have been evaluated for their ability to predict the disease activity, occurrence, and outcomes of patients with CADM. As mentioned above, both anti-MDA5 antibodies and RP-ILD are crucial predictors. Furthermore, LDH, Krebs von den Lungen 6 (KL-6), serum surfactant protein D (SP-D), ferritin level, and the HRCT imaging score are also associated with prognosis of the disease (14, 31). In this case, the patient’s ferritin level was elevated when her respiratory condition continued to worsen, which also suggested a poor prognosis in our patient. Recently, Lian et al. established a simple and practical score model to predict the prognosis of patients with ADM-ILD (31). According to this model, our patient was at least in the medium risk group, with a score of 5 (three points for anti-MDA5 antibodies, and two points for RP-ILD). Despite the fact that not all patients with this antibody develop lethal ILD, one possible explanation may be that all of the patients who have this particular antibody may undergo an early stage of disease, with only a skin rash or skin rash accompanied by arthralgia. They subsequently develop asymptomatic ILD, which progresses to RP-ILD if left untreated (32). The main limitation of the current study is that this is a case report, and several cases of CADM and DM developing during pregnancy have been previously described. However, we have made a comprehensive review, and to be best of our knowledge, this is the first case study depicting a pregnant patient with anti-MDA5-positive RP-ILD complicated with CADM. Notably, the patient finally achieved complete remission without residual pulmonary interstitial changes, indicating the importance of early intervention with combined immunosuppressive therapy in such patients.
Concluding Remarks
The present case study has reported on a case of a 38-year-old pregnant woman at 7 weeks of gestation who developed RP-ILD due to CADM with positive anti-MDA5 antibody. She achieved complete remission following early intervention of combination immunosuppressive therapy without residual pulmonary interstitial changes.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
CC and YC summarized the case, reviewed the literature, and drafted the manuscript. QinH and QiuH drafted the manuscript. XH reviewed and summarized the case. All authors contributed to the article and approved the submitted version.
Funding
The research is supported by Shenzhen Key Medical Discipline Construction Fund (no. SZXK011), Shenzhen Health Plan Committee Research Foundation (no. SZXJ2018021), Shenzhen Science and Technology Plan Program (no. JCYJ20190807144418845), and Sanming Project of Medicine in Shenzhen (no. SYJY201901).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors wish to thank the patient in this study.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.625495/full#supplementary-material
Click here for additional data file. | CYCLOPHOSPHAMIDE, CYCLOSPORINE, HYDROXYCHLOROQUINE, IMMUNE GLOBULIN NOS, LORATADINE, METHYLPREDNISOLONE, OXYGEN | DrugsGivenReaction | CC BY | 33717138 | 19,108,899 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.
Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors' knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.
Introduction
Dermatomyositis (DM) is a spectrum of muscle myalgia and weakness, with typical skin manifestations, including heliotrope rash and Gottron’s sign. Clinically amyopathic dermatomyositis (CADM) is an independent spectrum of classic DM with typical skin lesions and minimal or absent muscle disease (1). It has been reported that the prevalence of CADM in all patients with dermatomyositis is 5%–20% (2). Rapidly progressive interstitial lung disease (RP-ILD) is common in CADM patients with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody (3), which tends to be treatment-refractory with a poor prognosis (4). The onset of CADM during pregnancy is extremely rare and the outcome of pregnancy in these patients is poor for both mother and fetus, including maternal and fetal death, as well as prematurity (5, 6). The present case study reports on a pregnant woman with CADM with the positive anti-MDA5 antibody, who developed RP-ILD during her first 7 weeks of gestation. She was successfully treated with combined immunosuppressive therapy without residual pulmonary interstitial changes.
Case Presentation
A 38-year-old woman with a 7-week pregnancy was admitted to our hospital with complaints of dry cough, dyspnea on exertion, and a rash over the face, neck, and dorsum of the hands for 23 days and polyarthritis for 2 days ( Figure 1A ). Prior to admission, she was treated with loratadine without resolution, and her symptoms gradually worsened. Her past medical history was unremarkable.
Figure 1 Clinical presentation of the patient (A) on admission and (B) after recovery.
Physical examination on admission revealed a high body mass index of 33.1, heliotrope rash, Gottron’s papules and fine crackles audible bilaterally in the lower lung fields. No signs of muscle weakness or pain were present. The patient had tachycardia (113 beats/min) with normal oxygen saturation. Laboratory findings revealed the levels of creatine phosphokinase (CK; reference range, 25–192) to be 171 U/l, lactate dehydrogenase (LDH; reference range, 110–240) to be 441 U/l, alanine transaminase (AST; reference range, 0–40) to be 50 U/l, C-reactive protein (CRP; reference range, <5) to be 30.94 mg/l, erythrocyte sedimentation rate (ESR, reference range, 0–20) to be 53 mm/h, and ferritin (reference range, 11.0–306.8) to be 167.3 ng/ml. The main laboratory results are shown in Table 1 . No evidence was identified that may have suggested infection or malignancy, and therefore CADM was suspected in this patient. She was treated with 24 mg/day of oral methylprednisolone for 3 days, along with 400 mg/day of hydroxychloroquine in her first week of admission. However, the patient’s respiratory condition continued to worsen with percutaneous blood oxygen saturation decreasing to 88% under use of low- flow nasal cannula oxygen and therefore she was given oxygen by way of medium-flow mask oxygen. Moreover, she was unable to complete the pulmonary function test due to the rapid deterioration of the respiratory status.
Table 1 Laboratory findings on admission.
Parameter Value Reference range
Leukocytes (109/L) 3.6 4–10
Erythrocytes (1012/L) 4.76 3.5–5
Hemoglobin (g/L) 129 110–150
Platelets (109/L) 251 100–300
Glucose (mmol/L) 4.89 3.9–6.1
Cholesterol (mmol/L) 3.46 3.4–6.5
HDL (mmol/L) 0.94 0.9–1.91
LDL (mmol/L) 1.69 2.08–4.14
AST (U/L) 50 0–40
ALT (U/L) 48 0–45
ALP (U/L) 61 15–121
CK (U/L) 171 25–192
LDH (U/L) 441 110–240
Urea nitrogen (mmol/L) 2.79 2.5–7.5
Creatinie (µmol/L) 64 44–133
IgG (g/L) 10.21 8–18
Ferritin level (µg/L) 167.3 11.0–306.8
24-h urine protein (g/24 h) 0.216 0.028–0.141
ESR (mm/h) 53 0–20
CRP (mg/L) 30.94 <5
PCT (ng/ml) <0.05 <0.05
C3 (g/L) 1.28 0.80–1.81
C4 (g/L) 0.32 0.15–0.57
Coombs’ test Negative Negative
RF (IU/mL) 7.3 <25
Anti-CCP Negative Negative
cANCA Negative Negative
anti-PR3 Negative Negative
pANCA Negative Negative
anti-MPO Negative Negative
ANA Negative Negative
Anti-centromere Negative Negative
Anti-dsDNA Negative Negative
Anti-SS-A Negative Negative
Anti-SS-B Negative Negative
Anti-MDA5 Strongly positive Negative
Anti-tRNA synthase autoantibody panel Negative Negative
HDL, high-density lipoprotein; LDL, low density lipoprotein; AST, alanine transaminase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CK, creatine phosphokinase; LDH, lactic dehydrogenase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PCT, procalcitonin; RF, rheumatoid factor; C3, complement C3; C4, complement C4; Anti-MDA5, anti-melanoma differentiation-associated gene 5. Anti-CCP, anti-cyclic citrullinated peptide antibody; cANCA, cytoplasmic-staining anti-neutrophil cytoplasm antibody; pANCA, perinuclear-staining anti-neutrophil cytoplasm antibody; Anti-MPO, anti-myeloperoxidase antibody; Anti-PR3, anti-proteinase 3 antibody; ANA, anti-nuclear antibodies; Anti-dsDNA, anti-double-stranded (ds) DNA antibody; Anti-SS-A, anti-Sjögren's syndrome antigen A antibody; Anti-SS-B, anti-Sjögren's syndrome antigen B antibody.
Further tests revealed that her anti-MDA5 antibody was positive. The high-resolution computed tomography (HRCT) scan on day 7 revealed reticular shadows, patchy ground glass opacities and inflammation in both lungs ( Figure 2A ). On the basis of these findings, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made. According to the results of a multi-disciplinary discussion, on day 10, the patient was treated with combination therapy including methylprednisolone (1.0 mg/kg/day, that is, 80 mg/day) accompanied by oral cyclosporine (100 mg twice a day) and intravenous cyclophosphamide (IVCY, 400 mg/week) following high dose pulsed methylprednisolone at 500 mg/day for 3 days and intravenous immunoglobulin (IVIG, 20 g/day for 3 days). Considering her worsening condition, artificial abortion was conducted on day 10 with her permission. The respiratory condition of the patient improved gradually. A chest CT scan performed on day 21 of hospitalization revealed a patchy density shadow that had significantly decreased compared with its appearance previously ( Figure 2B ). The patient was discharged while being treated with methylprednisolone at 80 mg/day, cyclosporine at 200 mg/day, IVCY at 400 mg/2 weeks.
Figure 2 Changes in chest computed tomography scan findings (A) on admission, (B) before discharge and (C) after recovery.
Because of the significant improvement in her respiratory condition, we decided to taper the methylprednisolone and IVCY dose gradually. During the follow up, the patient achieved complete remission, her rash disappeared ( Figure 1B ) and the chest CT scan revealed that the patient had returned to the normal state after treatment for 10 months ( Figure 2C ). IVCY treatment was discontinued after treatment for 14 months, and anti-MDA5 antibody was negative after treatment for 24 months. At the time of writing this report, the patient was being treated with 4 mg/day methylprednisolone and 75 mg/day cyclosporine. The clinical course of the patient is shown in Figure 3 .
Figure 3 Clinical course of the patient. mPSL, methylprednisolone; Pulse: intravenous methylprednisolone pulse therapy (500 mg/d×3 days); IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; CyA, cyclosporine A; IVCY, intravenous cyclophosphamide; O2, oxygen; Anti-MDA5, anti-melanoma differentiation-associated gene 5 antibody; ++, strongly positive; +, positive; −, negative.
Discussion
Inflammatory myopathies are a spectrum of systemic immune-mediated disorders characterized by muscle inflammation, and affecting extramuscular organs, including skin, joints, and lungs. It is widely recognized that there are five main types of inflammatory myopathies: DM, polymyositis (PM), overlap myositis (including anti-synthetase syndrome (ASS)), inclusion-body myositis, and immune-mediated necrotizing myopathy (7, 8). RP-ILD was mainly defined as progressive dyspnea, or according to HRCT findings secondary to ILD within 3 months after the onset of respiratory symptoms (9, 10). RP-ILD often occurs as a complication of CADM, which usually portends poor prognosis with reported mortality rates in the first year as high as 60% (11). Anti-MDA5 antibodies were first identified by Sato et al. in 2005 in Japanese patients with CADM (12). Since that discovery, anti-MDA5 antibodies have predominantly been found in cases of CADM (13). Mortality rates ranged from 36%–46% in anti-MDA5 positive patients with CADM or DM (14). Anti-MDA5 antibodies have also been associated with RP-ILD, as identified in 39%–100% of patients with RP-ILD in Asian cohorts (15). The cumulative 6-month survival rate was reported to be about 50% for RP-ILD patients with the anti-MDA5 antibody (16). Hence, anti-MDA5 antibodies can be a useful predictor for the complication of RP-ILD in patients with CADM. In the present case study, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made as the patient experienced respiratory symptoms from the beginning, and her respiratory status deteriorated rapidly within one month. It has been suggested that immunosuppressants should be used early in patients with RP-ILD, since the damage caused to the pulmonary tissue may be irreversible once CADM is complicated by RP-ILD, which may result in the patient being irresponsive to combination immunosuppressive therapy, leading to death after only a few months (17). However, the use of immunosuppressants may not ensure rapid remission of the patient’s condition (18). It was reported that combination immunosuppressive therapy consisting of high-dose corticosteroids, cyclosporine and intravenous immunoglobulin might be effective for CADM patients with RP-ILD (16). Moreover, previous studies have also shown that patients with RP-ILD or respiratory failure may benefit from the use of basiliximab, mycophenolate mofetil or cyclophosphamide (19, 20).
The onset of DM during pregnancy is a rare event. It has been reported that one in 173 female patients with DM/PM experienced disease onset during pregnancy (21). Pregnancy outcomes are closely associated with the disease activity during pregnancy. Patients with quiescent disease before pregnancy have good pregnancy outcomes. By contrast, a pre-existing active condition or onset of DM during pregnancy leads to a high frequency of premature delivery and fetal death (21).
There are several factors that may explain the trigger for development of DM during pregnancy, such as changes in maternal hormonal status, exposure of the mother to fetal antigens, and the reactivation of certain viruses due to pregnancy (6). In addition, a high body mass index was noticed in the patient. Previous studies have revealed that obesity is a metabolic disease which may lead to the activation of the immune system and a consequently worse prognosis (22). Moreover, the obese are prone to respiratory failure even with mild pulmonary challenge (23). Hence, the rapid deterioration of the respiratory status in this patient may be partially explained by her high body mass index.
In view of these considerations, the onset of CADM during pregnancy is a problematic issue to be resolved for both physicians and patients. Treatment regimen should consider the safety of both the mother and the fetus, which requires individualized therapy. Glucocorticoids are the first line treatment in pregnant patients with DM (24). In certain rare cases, the use of glucocorticoids has been demonstrated to lead to a good outcome (6). However, certain patients have been shown to be non-responsive or intolerant to glucocorticoids (24). A previous study illustrated that gestational exposure to glucocorticoids led to a slight increase in the risk of premature birth and fetal oral cleft (25). Efficacy and safety of IVIG during pregnancy has been well documented in DM, especially for refractory cases (24, 25). In a previously published case report, short term remission was achieved following treatment with IVIG (4.5 g for 3 consecutive days) (25).
Examples of clinical case studies for treating pregnant patients with DM or PM, especially CADM, are relatively rare, and case studies of a similar nature that we were able to identify are shown in supplementary material (18, 26–28). Tomohiro et al (18). described the case of a 33-year-old pregnant woman who developed progressive interstitial pneumonia (IP) complicated by anti Jo-1 positive ASS at 28 weeks of gestation. At 30 weeks of her gestation, since the neonate could be treated at the neonatal intensive care unit after delivery, an emergency cesarean section was performed. The patient was eventually successfully treated with a combination of immunosuppressive therapy including intravenous methylprednisolone pulse therapy (1 g/day) and IVCY and the use of high flow nasal cannula oxygen therapy without intubation. In another case report, a pregnant woman at 16 weeks of gestation had developed IP preceding anti Jo-1 positive ASS, and was treated with a combination of steroid pulse therapy and tacrolimus. The fetus did not survive since it was too small, and the maternal condition deteriorated (26). To the best of our knowledge, the present case study is the first reported case of a patient having been diagnosed with anti-MDA5-positive RP-ILD complicated with CADM. In our case, artificial abortion was conducted because the maternal condition was unstable. The influences of high dose steroids and the CT scan were also taken into consideration. After combining steroid pulse and immunosuppressive therapy, the maternal condition gradually improved and our patient had complete remission without residual pulmonary interstitial changes. In anti-MDA5-positive patients with CADM, the CT scans usually show ground-glass opacities and bilateral subpleural reticular opacities, predominantly in the lower lungs, which would improve substantially or become stable after combination immunosuppressive therapy (29, 30). The present report describes a pregnant woman with CADM with positive anti-MDA5 antibody, who developed RP-ILD and subsequently achieved complete remission without residual pulmonary interstitial changes after treatment, which has been rarely reported in the previous literature. It is difficult to save the fetal lives in CADM patients with anti-MDA5 antibody. Because it was dispensable to use combination of high dose corticosteroids and immunosuppressive agents including IVCY in CADM patients even if they were in pregnancy.
Certain biological parameters have been evaluated for their ability to predict the disease activity, occurrence, and outcomes of patients with CADM. As mentioned above, both anti-MDA5 antibodies and RP-ILD are crucial predictors. Furthermore, LDH, Krebs von den Lungen 6 (KL-6), serum surfactant protein D (SP-D), ferritin level, and the HRCT imaging score are also associated with prognosis of the disease (14, 31). In this case, the patient’s ferritin level was elevated when her respiratory condition continued to worsen, which also suggested a poor prognosis in our patient. Recently, Lian et al. established a simple and practical score model to predict the prognosis of patients with ADM-ILD (31). According to this model, our patient was at least in the medium risk group, with a score of 5 (three points for anti-MDA5 antibodies, and two points for RP-ILD). Despite the fact that not all patients with this antibody develop lethal ILD, one possible explanation may be that all of the patients who have this particular antibody may undergo an early stage of disease, with only a skin rash or skin rash accompanied by arthralgia. They subsequently develop asymptomatic ILD, which progresses to RP-ILD if left untreated (32). The main limitation of the current study is that this is a case report, and several cases of CADM and DM developing during pregnancy have been previously described. However, we have made a comprehensive review, and to be best of our knowledge, this is the first case study depicting a pregnant patient with anti-MDA5-positive RP-ILD complicated with CADM. Notably, the patient finally achieved complete remission without residual pulmonary interstitial changes, indicating the importance of early intervention with combined immunosuppressive therapy in such patients.
Concluding Remarks
The present case study has reported on a case of a 38-year-old pregnant woman at 7 weeks of gestation who developed RP-ILD due to CADM with positive anti-MDA5 antibody. She achieved complete remission following early intervention of combination immunosuppressive therapy without residual pulmonary interstitial changes.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
CC and YC summarized the case, reviewed the literature, and drafted the manuscript. QinH and QiuH drafted the manuscript. XH reviewed and summarized the case. All authors contributed to the article and approved the submitted version.
Funding
The research is supported by Shenzhen Key Medical Discipline Construction Fund (no. SZXK011), Shenzhen Health Plan Committee Research Foundation (no. SZXJ2018021), Shenzhen Science and Technology Plan Program (no. JCYJ20190807144418845), and Sanming Project of Medicine in Shenzhen (no. SYJY201901).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors wish to thank the patient in this study.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.625495/full#supplementary-material
Click here for additional data file. | CYCLOPHOSPHAMIDE, CYCLOSPORINE, HYDROXYCHLOROQUINE, IMMUNE GLOBULIN NOS, LORATADINE, METHYLPREDNISOLONE, OXYGEN | DrugsGivenReaction | CC BY | 33717138 | 19,108,899 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.
Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors' knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.
Introduction
Dermatomyositis (DM) is a spectrum of muscle myalgia and weakness, with typical skin manifestations, including heliotrope rash and Gottron’s sign. Clinically amyopathic dermatomyositis (CADM) is an independent spectrum of classic DM with typical skin lesions and minimal or absent muscle disease (1). It has been reported that the prevalence of CADM in all patients with dermatomyositis is 5%–20% (2). Rapidly progressive interstitial lung disease (RP-ILD) is common in CADM patients with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody (3), which tends to be treatment-refractory with a poor prognosis (4). The onset of CADM during pregnancy is extremely rare and the outcome of pregnancy in these patients is poor for both mother and fetus, including maternal and fetal death, as well as prematurity (5, 6). The present case study reports on a pregnant woman with CADM with the positive anti-MDA5 antibody, who developed RP-ILD during her first 7 weeks of gestation. She was successfully treated with combined immunosuppressive therapy without residual pulmonary interstitial changes.
Case Presentation
A 38-year-old woman with a 7-week pregnancy was admitted to our hospital with complaints of dry cough, dyspnea on exertion, and a rash over the face, neck, and dorsum of the hands for 23 days and polyarthritis for 2 days ( Figure 1A ). Prior to admission, she was treated with loratadine without resolution, and her symptoms gradually worsened. Her past medical history was unremarkable.
Figure 1 Clinical presentation of the patient (A) on admission and (B) after recovery.
Physical examination on admission revealed a high body mass index of 33.1, heliotrope rash, Gottron’s papules and fine crackles audible bilaterally in the lower lung fields. No signs of muscle weakness or pain were present. The patient had tachycardia (113 beats/min) with normal oxygen saturation. Laboratory findings revealed the levels of creatine phosphokinase (CK; reference range, 25–192) to be 171 U/l, lactate dehydrogenase (LDH; reference range, 110–240) to be 441 U/l, alanine transaminase (AST; reference range, 0–40) to be 50 U/l, C-reactive protein (CRP; reference range, <5) to be 30.94 mg/l, erythrocyte sedimentation rate (ESR, reference range, 0–20) to be 53 mm/h, and ferritin (reference range, 11.0–306.8) to be 167.3 ng/ml. The main laboratory results are shown in Table 1 . No evidence was identified that may have suggested infection or malignancy, and therefore CADM was suspected in this patient. She was treated with 24 mg/day of oral methylprednisolone for 3 days, along with 400 mg/day of hydroxychloroquine in her first week of admission. However, the patient’s respiratory condition continued to worsen with percutaneous blood oxygen saturation decreasing to 88% under use of low- flow nasal cannula oxygen and therefore she was given oxygen by way of medium-flow mask oxygen. Moreover, she was unable to complete the pulmonary function test due to the rapid deterioration of the respiratory status.
Table 1 Laboratory findings on admission.
Parameter Value Reference range
Leukocytes (109/L) 3.6 4–10
Erythrocytes (1012/L) 4.76 3.5–5
Hemoglobin (g/L) 129 110–150
Platelets (109/L) 251 100–300
Glucose (mmol/L) 4.89 3.9–6.1
Cholesterol (mmol/L) 3.46 3.4–6.5
HDL (mmol/L) 0.94 0.9–1.91
LDL (mmol/L) 1.69 2.08–4.14
AST (U/L) 50 0–40
ALT (U/L) 48 0–45
ALP (U/L) 61 15–121
CK (U/L) 171 25–192
LDH (U/L) 441 110–240
Urea nitrogen (mmol/L) 2.79 2.5–7.5
Creatinie (µmol/L) 64 44–133
IgG (g/L) 10.21 8–18
Ferritin level (µg/L) 167.3 11.0–306.8
24-h urine protein (g/24 h) 0.216 0.028–0.141
ESR (mm/h) 53 0–20
CRP (mg/L) 30.94 <5
PCT (ng/ml) <0.05 <0.05
C3 (g/L) 1.28 0.80–1.81
C4 (g/L) 0.32 0.15–0.57
Coombs’ test Negative Negative
RF (IU/mL) 7.3 <25
Anti-CCP Negative Negative
cANCA Negative Negative
anti-PR3 Negative Negative
pANCA Negative Negative
anti-MPO Negative Negative
ANA Negative Negative
Anti-centromere Negative Negative
Anti-dsDNA Negative Negative
Anti-SS-A Negative Negative
Anti-SS-B Negative Negative
Anti-MDA5 Strongly positive Negative
Anti-tRNA synthase autoantibody panel Negative Negative
HDL, high-density lipoprotein; LDL, low density lipoprotein; AST, alanine transaminase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CK, creatine phosphokinase; LDH, lactic dehydrogenase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PCT, procalcitonin; RF, rheumatoid factor; C3, complement C3; C4, complement C4; Anti-MDA5, anti-melanoma differentiation-associated gene 5. Anti-CCP, anti-cyclic citrullinated peptide antibody; cANCA, cytoplasmic-staining anti-neutrophil cytoplasm antibody; pANCA, perinuclear-staining anti-neutrophil cytoplasm antibody; Anti-MPO, anti-myeloperoxidase antibody; Anti-PR3, anti-proteinase 3 antibody; ANA, anti-nuclear antibodies; Anti-dsDNA, anti-double-stranded (ds) DNA antibody; Anti-SS-A, anti-Sjögren's syndrome antigen A antibody; Anti-SS-B, anti-Sjögren's syndrome antigen B antibody.
Further tests revealed that her anti-MDA5 antibody was positive. The high-resolution computed tomography (HRCT) scan on day 7 revealed reticular shadows, patchy ground glass opacities and inflammation in both lungs ( Figure 2A ). On the basis of these findings, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made. According to the results of a multi-disciplinary discussion, on day 10, the patient was treated with combination therapy including methylprednisolone (1.0 mg/kg/day, that is, 80 mg/day) accompanied by oral cyclosporine (100 mg twice a day) and intravenous cyclophosphamide (IVCY, 400 mg/week) following high dose pulsed methylprednisolone at 500 mg/day for 3 days and intravenous immunoglobulin (IVIG, 20 g/day for 3 days). Considering her worsening condition, artificial abortion was conducted on day 10 with her permission. The respiratory condition of the patient improved gradually. A chest CT scan performed on day 21 of hospitalization revealed a patchy density shadow that had significantly decreased compared with its appearance previously ( Figure 2B ). The patient was discharged while being treated with methylprednisolone at 80 mg/day, cyclosporine at 200 mg/day, IVCY at 400 mg/2 weeks.
Figure 2 Changes in chest computed tomography scan findings (A) on admission, (B) before discharge and (C) after recovery.
Because of the significant improvement in her respiratory condition, we decided to taper the methylprednisolone and IVCY dose gradually. During the follow up, the patient achieved complete remission, her rash disappeared ( Figure 1B ) and the chest CT scan revealed that the patient had returned to the normal state after treatment for 10 months ( Figure 2C ). IVCY treatment was discontinued after treatment for 14 months, and anti-MDA5 antibody was negative after treatment for 24 months. At the time of writing this report, the patient was being treated with 4 mg/day methylprednisolone and 75 mg/day cyclosporine. The clinical course of the patient is shown in Figure 3 .
Figure 3 Clinical course of the patient. mPSL, methylprednisolone; Pulse: intravenous methylprednisolone pulse therapy (500 mg/d×3 days); IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; CyA, cyclosporine A; IVCY, intravenous cyclophosphamide; O2, oxygen; Anti-MDA5, anti-melanoma differentiation-associated gene 5 antibody; ++, strongly positive; +, positive; −, negative.
Discussion
Inflammatory myopathies are a spectrum of systemic immune-mediated disorders characterized by muscle inflammation, and affecting extramuscular organs, including skin, joints, and lungs. It is widely recognized that there are five main types of inflammatory myopathies: DM, polymyositis (PM), overlap myositis (including anti-synthetase syndrome (ASS)), inclusion-body myositis, and immune-mediated necrotizing myopathy (7, 8). RP-ILD was mainly defined as progressive dyspnea, or according to HRCT findings secondary to ILD within 3 months after the onset of respiratory symptoms (9, 10). RP-ILD often occurs as a complication of CADM, which usually portends poor prognosis with reported mortality rates in the first year as high as 60% (11). Anti-MDA5 antibodies were first identified by Sato et al. in 2005 in Japanese patients with CADM (12). Since that discovery, anti-MDA5 antibodies have predominantly been found in cases of CADM (13). Mortality rates ranged from 36%–46% in anti-MDA5 positive patients with CADM or DM (14). Anti-MDA5 antibodies have also been associated with RP-ILD, as identified in 39%–100% of patients with RP-ILD in Asian cohorts (15). The cumulative 6-month survival rate was reported to be about 50% for RP-ILD patients with the anti-MDA5 antibody (16). Hence, anti-MDA5 antibodies can be a useful predictor for the complication of RP-ILD in patients with CADM. In the present case study, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made as the patient experienced respiratory symptoms from the beginning, and her respiratory status deteriorated rapidly within one month. It has been suggested that immunosuppressants should be used early in patients with RP-ILD, since the damage caused to the pulmonary tissue may be irreversible once CADM is complicated by RP-ILD, which may result in the patient being irresponsive to combination immunosuppressive therapy, leading to death after only a few months (17). However, the use of immunosuppressants may not ensure rapid remission of the patient’s condition (18). It was reported that combination immunosuppressive therapy consisting of high-dose corticosteroids, cyclosporine and intravenous immunoglobulin might be effective for CADM patients with RP-ILD (16). Moreover, previous studies have also shown that patients with RP-ILD or respiratory failure may benefit from the use of basiliximab, mycophenolate mofetil or cyclophosphamide (19, 20).
The onset of DM during pregnancy is a rare event. It has been reported that one in 173 female patients with DM/PM experienced disease onset during pregnancy (21). Pregnancy outcomes are closely associated with the disease activity during pregnancy. Patients with quiescent disease before pregnancy have good pregnancy outcomes. By contrast, a pre-existing active condition or onset of DM during pregnancy leads to a high frequency of premature delivery and fetal death (21).
There are several factors that may explain the trigger for development of DM during pregnancy, such as changes in maternal hormonal status, exposure of the mother to fetal antigens, and the reactivation of certain viruses due to pregnancy (6). In addition, a high body mass index was noticed in the patient. Previous studies have revealed that obesity is a metabolic disease which may lead to the activation of the immune system and a consequently worse prognosis (22). Moreover, the obese are prone to respiratory failure even with mild pulmonary challenge (23). Hence, the rapid deterioration of the respiratory status in this patient may be partially explained by her high body mass index.
In view of these considerations, the onset of CADM during pregnancy is a problematic issue to be resolved for both physicians and patients. Treatment regimen should consider the safety of both the mother and the fetus, which requires individualized therapy. Glucocorticoids are the first line treatment in pregnant patients with DM (24). In certain rare cases, the use of glucocorticoids has been demonstrated to lead to a good outcome (6). However, certain patients have been shown to be non-responsive or intolerant to glucocorticoids (24). A previous study illustrated that gestational exposure to glucocorticoids led to a slight increase in the risk of premature birth and fetal oral cleft (25). Efficacy and safety of IVIG during pregnancy has been well documented in DM, especially for refractory cases (24, 25). In a previously published case report, short term remission was achieved following treatment with IVIG (4.5 g for 3 consecutive days) (25).
Examples of clinical case studies for treating pregnant patients with DM or PM, especially CADM, are relatively rare, and case studies of a similar nature that we were able to identify are shown in supplementary material (18, 26–28). Tomohiro et al (18). described the case of a 33-year-old pregnant woman who developed progressive interstitial pneumonia (IP) complicated by anti Jo-1 positive ASS at 28 weeks of gestation. At 30 weeks of her gestation, since the neonate could be treated at the neonatal intensive care unit after delivery, an emergency cesarean section was performed. The patient was eventually successfully treated with a combination of immunosuppressive therapy including intravenous methylprednisolone pulse therapy (1 g/day) and IVCY and the use of high flow nasal cannula oxygen therapy without intubation. In another case report, a pregnant woman at 16 weeks of gestation had developed IP preceding anti Jo-1 positive ASS, and was treated with a combination of steroid pulse therapy and tacrolimus. The fetus did not survive since it was too small, and the maternal condition deteriorated (26). To the best of our knowledge, the present case study is the first reported case of a patient having been diagnosed with anti-MDA5-positive RP-ILD complicated with CADM. In our case, artificial abortion was conducted because the maternal condition was unstable. The influences of high dose steroids and the CT scan were also taken into consideration. After combining steroid pulse and immunosuppressive therapy, the maternal condition gradually improved and our patient had complete remission without residual pulmonary interstitial changes. In anti-MDA5-positive patients with CADM, the CT scans usually show ground-glass opacities and bilateral subpleural reticular opacities, predominantly in the lower lungs, which would improve substantially or become stable after combination immunosuppressive therapy (29, 30). The present report describes a pregnant woman with CADM with positive anti-MDA5 antibody, who developed RP-ILD and subsequently achieved complete remission without residual pulmonary interstitial changes after treatment, which has been rarely reported in the previous literature. It is difficult to save the fetal lives in CADM patients with anti-MDA5 antibody. Because it was dispensable to use combination of high dose corticosteroids and immunosuppressive agents including IVCY in CADM patients even if they were in pregnancy.
Certain biological parameters have been evaluated for their ability to predict the disease activity, occurrence, and outcomes of patients with CADM. As mentioned above, both anti-MDA5 antibodies and RP-ILD are crucial predictors. Furthermore, LDH, Krebs von den Lungen 6 (KL-6), serum surfactant protein D (SP-D), ferritin level, and the HRCT imaging score are also associated with prognosis of the disease (14, 31). In this case, the patient’s ferritin level was elevated when her respiratory condition continued to worsen, which also suggested a poor prognosis in our patient. Recently, Lian et al. established a simple and practical score model to predict the prognosis of patients with ADM-ILD (31). According to this model, our patient was at least in the medium risk group, with a score of 5 (three points for anti-MDA5 antibodies, and two points for RP-ILD). Despite the fact that not all patients with this antibody develop lethal ILD, one possible explanation may be that all of the patients who have this particular antibody may undergo an early stage of disease, with only a skin rash or skin rash accompanied by arthralgia. They subsequently develop asymptomatic ILD, which progresses to RP-ILD if left untreated (32). The main limitation of the current study is that this is a case report, and several cases of CADM and DM developing during pregnancy have been previously described. However, we have made a comprehensive review, and to be best of our knowledge, this is the first case study depicting a pregnant patient with anti-MDA5-positive RP-ILD complicated with CADM. Notably, the patient finally achieved complete remission without residual pulmonary interstitial changes, indicating the importance of early intervention with combined immunosuppressive therapy in such patients.
Concluding Remarks
The present case study has reported on a case of a 38-year-old pregnant woman at 7 weeks of gestation who developed RP-ILD due to CADM with positive anti-MDA5 antibody. She achieved complete remission following early intervention of combination immunosuppressive therapy without residual pulmonary interstitial changes.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
CC and YC summarized the case, reviewed the literature, and drafted the manuscript. QinH and QiuH drafted the manuscript. XH reviewed and summarized the case. All authors contributed to the article and approved the submitted version.
Funding
The research is supported by Shenzhen Key Medical Discipline Construction Fund (no. SZXK011), Shenzhen Health Plan Committee Research Foundation (no. SZXJ2018021), Shenzhen Science and Technology Plan Program (no. JCYJ20190807144418845), and Sanming Project of Medicine in Shenzhen (no. SYJY201901).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors wish to thank the patient in this study.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.625495/full#supplementary-material
Click here for additional data file. | CYCLOPHOSPHAMIDE, CYCLOSPORINE, HYDROXYCHLOROQUINE, IMMUNE GLOBULIN NOS, LORATADINE, METHYLPREDNISOLONE, OXYGEN | DrugsGivenReaction | CC BY | 33717138 | 19,108,899 | 2021 |
What was the administration route of drug 'CYCLOPHOSPHAMIDE'? | Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.
Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors' knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.
Introduction
Dermatomyositis (DM) is a spectrum of muscle myalgia and weakness, with typical skin manifestations, including heliotrope rash and Gottron’s sign. Clinically amyopathic dermatomyositis (CADM) is an independent spectrum of classic DM with typical skin lesions and minimal or absent muscle disease (1). It has been reported that the prevalence of CADM in all patients with dermatomyositis is 5%–20% (2). Rapidly progressive interstitial lung disease (RP-ILD) is common in CADM patients with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody (3), which tends to be treatment-refractory with a poor prognosis (4). The onset of CADM during pregnancy is extremely rare and the outcome of pregnancy in these patients is poor for both mother and fetus, including maternal and fetal death, as well as prematurity (5, 6). The present case study reports on a pregnant woman with CADM with the positive anti-MDA5 antibody, who developed RP-ILD during her first 7 weeks of gestation. She was successfully treated with combined immunosuppressive therapy without residual pulmonary interstitial changes.
Case Presentation
A 38-year-old woman with a 7-week pregnancy was admitted to our hospital with complaints of dry cough, dyspnea on exertion, and a rash over the face, neck, and dorsum of the hands for 23 days and polyarthritis for 2 days ( Figure 1A ). Prior to admission, she was treated with loratadine without resolution, and her symptoms gradually worsened. Her past medical history was unremarkable.
Figure 1 Clinical presentation of the patient (A) on admission and (B) after recovery.
Physical examination on admission revealed a high body mass index of 33.1, heliotrope rash, Gottron’s papules and fine crackles audible bilaterally in the lower lung fields. No signs of muscle weakness or pain were present. The patient had tachycardia (113 beats/min) with normal oxygen saturation. Laboratory findings revealed the levels of creatine phosphokinase (CK; reference range, 25–192) to be 171 U/l, lactate dehydrogenase (LDH; reference range, 110–240) to be 441 U/l, alanine transaminase (AST; reference range, 0–40) to be 50 U/l, C-reactive protein (CRP; reference range, <5) to be 30.94 mg/l, erythrocyte sedimentation rate (ESR, reference range, 0–20) to be 53 mm/h, and ferritin (reference range, 11.0–306.8) to be 167.3 ng/ml. The main laboratory results are shown in Table 1 . No evidence was identified that may have suggested infection or malignancy, and therefore CADM was suspected in this patient. She was treated with 24 mg/day of oral methylprednisolone for 3 days, along with 400 mg/day of hydroxychloroquine in her first week of admission. However, the patient’s respiratory condition continued to worsen with percutaneous blood oxygen saturation decreasing to 88% under use of low- flow nasal cannula oxygen and therefore she was given oxygen by way of medium-flow mask oxygen. Moreover, she was unable to complete the pulmonary function test due to the rapid deterioration of the respiratory status.
Table 1 Laboratory findings on admission.
Parameter Value Reference range
Leukocytes (109/L) 3.6 4–10
Erythrocytes (1012/L) 4.76 3.5–5
Hemoglobin (g/L) 129 110–150
Platelets (109/L) 251 100–300
Glucose (mmol/L) 4.89 3.9–6.1
Cholesterol (mmol/L) 3.46 3.4–6.5
HDL (mmol/L) 0.94 0.9–1.91
LDL (mmol/L) 1.69 2.08–4.14
AST (U/L) 50 0–40
ALT (U/L) 48 0–45
ALP (U/L) 61 15–121
CK (U/L) 171 25–192
LDH (U/L) 441 110–240
Urea nitrogen (mmol/L) 2.79 2.5–7.5
Creatinie (µmol/L) 64 44–133
IgG (g/L) 10.21 8–18
Ferritin level (µg/L) 167.3 11.0–306.8
24-h urine protein (g/24 h) 0.216 0.028–0.141
ESR (mm/h) 53 0–20
CRP (mg/L) 30.94 <5
PCT (ng/ml) <0.05 <0.05
C3 (g/L) 1.28 0.80–1.81
C4 (g/L) 0.32 0.15–0.57
Coombs’ test Negative Negative
RF (IU/mL) 7.3 <25
Anti-CCP Negative Negative
cANCA Negative Negative
anti-PR3 Negative Negative
pANCA Negative Negative
anti-MPO Negative Negative
ANA Negative Negative
Anti-centromere Negative Negative
Anti-dsDNA Negative Negative
Anti-SS-A Negative Negative
Anti-SS-B Negative Negative
Anti-MDA5 Strongly positive Negative
Anti-tRNA synthase autoantibody panel Negative Negative
HDL, high-density lipoprotein; LDL, low density lipoprotein; AST, alanine transaminase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CK, creatine phosphokinase; LDH, lactic dehydrogenase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PCT, procalcitonin; RF, rheumatoid factor; C3, complement C3; C4, complement C4; Anti-MDA5, anti-melanoma differentiation-associated gene 5. Anti-CCP, anti-cyclic citrullinated peptide antibody; cANCA, cytoplasmic-staining anti-neutrophil cytoplasm antibody; pANCA, perinuclear-staining anti-neutrophil cytoplasm antibody; Anti-MPO, anti-myeloperoxidase antibody; Anti-PR3, anti-proteinase 3 antibody; ANA, anti-nuclear antibodies; Anti-dsDNA, anti-double-stranded (ds) DNA antibody; Anti-SS-A, anti-Sjögren's syndrome antigen A antibody; Anti-SS-B, anti-Sjögren's syndrome antigen B antibody.
Further tests revealed that her anti-MDA5 antibody was positive. The high-resolution computed tomography (HRCT) scan on day 7 revealed reticular shadows, patchy ground glass opacities and inflammation in both lungs ( Figure 2A ). On the basis of these findings, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made. According to the results of a multi-disciplinary discussion, on day 10, the patient was treated with combination therapy including methylprednisolone (1.0 mg/kg/day, that is, 80 mg/day) accompanied by oral cyclosporine (100 mg twice a day) and intravenous cyclophosphamide (IVCY, 400 mg/week) following high dose pulsed methylprednisolone at 500 mg/day for 3 days and intravenous immunoglobulin (IVIG, 20 g/day for 3 days). Considering her worsening condition, artificial abortion was conducted on day 10 with her permission. The respiratory condition of the patient improved gradually. A chest CT scan performed on day 21 of hospitalization revealed a patchy density shadow that had significantly decreased compared with its appearance previously ( Figure 2B ). The patient was discharged while being treated with methylprednisolone at 80 mg/day, cyclosporine at 200 mg/day, IVCY at 400 mg/2 weeks.
Figure 2 Changes in chest computed tomography scan findings (A) on admission, (B) before discharge and (C) after recovery.
Because of the significant improvement in her respiratory condition, we decided to taper the methylprednisolone and IVCY dose gradually. During the follow up, the patient achieved complete remission, her rash disappeared ( Figure 1B ) and the chest CT scan revealed that the patient had returned to the normal state after treatment for 10 months ( Figure 2C ). IVCY treatment was discontinued after treatment for 14 months, and anti-MDA5 antibody was negative after treatment for 24 months. At the time of writing this report, the patient was being treated with 4 mg/day methylprednisolone and 75 mg/day cyclosporine. The clinical course of the patient is shown in Figure 3 .
Figure 3 Clinical course of the patient. mPSL, methylprednisolone; Pulse: intravenous methylprednisolone pulse therapy (500 mg/d×3 days); IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; CyA, cyclosporine A; IVCY, intravenous cyclophosphamide; O2, oxygen; Anti-MDA5, anti-melanoma differentiation-associated gene 5 antibody; ++, strongly positive; +, positive; −, negative.
Discussion
Inflammatory myopathies are a spectrum of systemic immune-mediated disorders characterized by muscle inflammation, and affecting extramuscular organs, including skin, joints, and lungs. It is widely recognized that there are five main types of inflammatory myopathies: DM, polymyositis (PM), overlap myositis (including anti-synthetase syndrome (ASS)), inclusion-body myositis, and immune-mediated necrotizing myopathy (7, 8). RP-ILD was mainly defined as progressive dyspnea, or according to HRCT findings secondary to ILD within 3 months after the onset of respiratory symptoms (9, 10). RP-ILD often occurs as a complication of CADM, which usually portends poor prognosis with reported mortality rates in the first year as high as 60% (11). Anti-MDA5 antibodies were first identified by Sato et al. in 2005 in Japanese patients with CADM (12). Since that discovery, anti-MDA5 antibodies have predominantly been found in cases of CADM (13). Mortality rates ranged from 36%–46% in anti-MDA5 positive patients with CADM or DM (14). Anti-MDA5 antibodies have also been associated with RP-ILD, as identified in 39%–100% of patients with RP-ILD in Asian cohorts (15). The cumulative 6-month survival rate was reported to be about 50% for RP-ILD patients with the anti-MDA5 antibody (16). Hence, anti-MDA5 antibodies can be a useful predictor for the complication of RP-ILD in patients with CADM. In the present case study, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made as the patient experienced respiratory symptoms from the beginning, and her respiratory status deteriorated rapidly within one month. It has been suggested that immunosuppressants should be used early in patients with RP-ILD, since the damage caused to the pulmonary tissue may be irreversible once CADM is complicated by RP-ILD, which may result in the patient being irresponsive to combination immunosuppressive therapy, leading to death after only a few months (17). However, the use of immunosuppressants may not ensure rapid remission of the patient’s condition (18). It was reported that combination immunosuppressive therapy consisting of high-dose corticosteroids, cyclosporine and intravenous immunoglobulin might be effective for CADM patients with RP-ILD (16). Moreover, previous studies have also shown that patients with RP-ILD or respiratory failure may benefit from the use of basiliximab, mycophenolate mofetil or cyclophosphamide (19, 20).
The onset of DM during pregnancy is a rare event. It has been reported that one in 173 female patients with DM/PM experienced disease onset during pregnancy (21). Pregnancy outcomes are closely associated with the disease activity during pregnancy. Patients with quiescent disease before pregnancy have good pregnancy outcomes. By contrast, a pre-existing active condition or onset of DM during pregnancy leads to a high frequency of premature delivery and fetal death (21).
There are several factors that may explain the trigger for development of DM during pregnancy, such as changes in maternal hormonal status, exposure of the mother to fetal antigens, and the reactivation of certain viruses due to pregnancy (6). In addition, a high body mass index was noticed in the patient. Previous studies have revealed that obesity is a metabolic disease which may lead to the activation of the immune system and a consequently worse prognosis (22). Moreover, the obese are prone to respiratory failure even with mild pulmonary challenge (23). Hence, the rapid deterioration of the respiratory status in this patient may be partially explained by her high body mass index.
In view of these considerations, the onset of CADM during pregnancy is a problematic issue to be resolved for both physicians and patients. Treatment regimen should consider the safety of both the mother and the fetus, which requires individualized therapy. Glucocorticoids are the first line treatment in pregnant patients with DM (24). In certain rare cases, the use of glucocorticoids has been demonstrated to lead to a good outcome (6). However, certain patients have been shown to be non-responsive or intolerant to glucocorticoids (24). A previous study illustrated that gestational exposure to glucocorticoids led to a slight increase in the risk of premature birth and fetal oral cleft (25). Efficacy and safety of IVIG during pregnancy has been well documented in DM, especially for refractory cases (24, 25). In a previously published case report, short term remission was achieved following treatment with IVIG (4.5 g for 3 consecutive days) (25).
Examples of clinical case studies for treating pregnant patients with DM or PM, especially CADM, are relatively rare, and case studies of a similar nature that we were able to identify are shown in supplementary material (18, 26–28). Tomohiro et al (18). described the case of a 33-year-old pregnant woman who developed progressive interstitial pneumonia (IP) complicated by anti Jo-1 positive ASS at 28 weeks of gestation. At 30 weeks of her gestation, since the neonate could be treated at the neonatal intensive care unit after delivery, an emergency cesarean section was performed. The patient was eventually successfully treated with a combination of immunosuppressive therapy including intravenous methylprednisolone pulse therapy (1 g/day) and IVCY and the use of high flow nasal cannula oxygen therapy without intubation. In another case report, a pregnant woman at 16 weeks of gestation had developed IP preceding anti Jo-1 positive ASS, and was treated with a combination of steroid pulse therapy and tacrolimus. The fetus did not survive since it was too small, and the maternal condition deteriorated (26). To the best of our knowledge, the present case study is the first reported case of a patient having been diagnosed with anti-MDA5-positive RP-ILD complicated with CADM. In our case, artificial abortion was conducted because the maternal condition was unstable. The influences of high dose steroids and the CT scan were also taken into consideration. After combining steroid pulse and immunosuppressive therapy, the maternal condition gradually improved and our patient had complete remission without residual pulmonary interstitial changes. In anti-MDA5-positive patients with CADM, the CT scans usually show ground-glass opacities and bilateral subpleural reticular opacities, predominantly in the lower lungs, which would improve substantially or become stable after combination immunosuppressive therapy (29, 30). The present report describes a pregnant woman with CADM with positive anti-MDA5 antibody, who developed RP-ILD and subsequently achieved complete remission without residual pulmonary interstitial changes after treatment, which has been rarely reported in the previous literature. It is difficult to save the fetal lives in CADM patients with anti-MDA5 antibody. Because it was dispensable to use combination of high dose corticosteroids and immunosuppressive agents including IVCY in CADM patients even if they were in pregnancy.
Certain biological parameters have been evaluated for their ability to predict the disease activity, occurrence, and outcomes of patients with CADM. As mentioned above, both anti-MDA5 antibodies and RP-ILD are crucial predictors. Furthermore, LDH, Krebs von den Lungen 6 (KL-6), serum surfactant protein D (SP-D), ferritin level, and the HRCT imaging score are also associated with prognosis of the disease (14, 31). In this case, the patient’s ferritin level was elevated when her respiratory condition continued to worsen, which also suggested a poor prognosis in our patient. Recently, Lian et al. established a simple and practical score model to predict the prognosis of patients with ADM-ILD (31). According to this model, our patient was at least in the medium risk group, with a score of 5 (three points for anti-MDA5 antibodies, and two points for RP-ILD). Despite the fact that not all patients with this antibody develop lethal ILD, one possible explanation may be that all of the patients who have this particular antibody may undergo an early stage of disease, with only a skin rash or skin rash accompanied by arthralgia. They subsequently develop asymptomatic ILD, which progresses to RP-ILD if left untreated (32). The main limitation of the current study is that this is a case report, and several cases of CADM and DM developing during pregnancy have been previously described. However, we have made a comprehensive review, and to be best of our knowledge, this is the first case study depicting a pregnant patient with anti-MDA5-positive RP-ILD complicated with CADM. Notably, the patient finally achieved complete remission without residual pulmonary interstitial changes, indicating the importance of early intervention with combined immunosuppressive therapy in such patients.
Concluding Remarks
The present case study has reported on a case of a 38-year-old pregnant woman at 7 weeks of gestation who developed RP-ILD due to CADM with positive anti-MDA5 antibody. She achieved complete remission following early intervention of combination immunosuppressive therapy without residual pulmonary interstitial changes.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
CC and YC summarized the case, reviewed the literature, and drafted the manuscript. QinH and QiuH drafted the manuscript. XH reviewed and summarized the case. All authors contributed to the article and approved the submitted version.
Funding
The research is supported by Shenzhen Key Medical Discipline Construction Fund (no. SZXK011), Shenzhen Health Plan Committee Research Foundation (no. SZXJ2018021), Shenzhen Science and Technology Plan Program (no. JCYJ20190807144418845), and Sanming Project of Medicine in Shenzhen (no. SYJY201901).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors wish to thank the patient in this study.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.625495/full#supplementary-material
Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33717138 | 19,108,899 | 2021 |
What was the administration route of drug 'CYCLOSPORINE'? | Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.
Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors' knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.
Introduction
Dermatomyositis (DM) is a spectrum of muscle myalgia and weakness, with typical skin manifestations, including heliotrope rash and Gottron’s sign. Clinically amyopathic dermatomyositis (CADM) is an independent spectrum of classic DM with typical skin lesions and minimal or absent muscle disease (1). It has been reported that the prevalence of CADM in all patients with dermatomyositis is 5%–20% (2). Rapidly progressive interstitial lung disease (RP-ILD) is common in CADM patients with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody (3), which tends to be treatment-refractory with a poor prognosis (4). The onset of CADM during pregnancy is extremely rare and the outcome of pregnancy in these patients is poor for both mother and fetus, including maternal and fetal death, as well as prematurity (5, 6). The present case study reports on a pregnant woman with CADM with the positive anti-MDA5 antibody, who developed RP-ILD during her first 7 weeks of gestation. She was successfully treated with combined immunosuppressive therapy without residual pulmonary interstitial changes.
Case Presentation
A 38-year-old woman with a 7-week pregnancy was admitted to our hospital with complaints of dry cough, dyspnea on exertion, and a rash over the face, neck, and dorsum of the hands for 23 days and polyarthritis for 2 days ( Figure 1A ). Prior to admission, she was treated with loratadine without resolution, and her symptoms gradually worsened. Her past medical history was unremarkable.
Figure 1 Clinical presentation of the patient (A) on admission and (B) after recovery.
Physical examination on admission revealed a high body mass index of 33.1, heliotrope rash, Gottron’s papules and fine crackles audible bilaterally in the lower lung fields. No signs of muscle weakness or pain were present. The patient had tachycardia (113 beats/min) with normal oxygen saturation. Laboratory findings revealed the levels of creatine phosphokinase (CK; reference range, 25–192) to be 171 U/l, lactate dehydrogenase (LDH; reference range, 110–240) to be 441 U/l, alanine transaminase (AST; reference range, 0–40) to be 50 U/l, C-reactive protein (CRP; reference range, <5) to be 30.94 mg/l, erythrocyte sedimentation rate (ESR, reference range, 0–20) to be 53 mm/h, and ferritin (reference range, 11.0–306.8) to be 167.3 ng/ml. The main laboratory results are shown in Table 1 . No evidence was identified that may have suggested infection or malignancy, and therefore CADM was suspected in this patient. She was treated with 24 mg/day of oral methylprednisolone for 3 days, along with 400 mg/day of hydroxychloroquine in her first week of admission. However, the patient’s respiratory condition continued to worsen with percutaneous blood oxygen saturation decreasing to 88% under use of low- flow nasal cannula oxygen and therefore she was given oxygen by way of medium-flow mask oxygen. Moreover, she was unable to complete the pulmonary function test due to the rapid deterioration of the respiratory status.
Table 1 Laboratory findings on admission.
Parameter Value Reference range
Leukocytes (109/L) 3.6 4–10
Erythrocytes (1012/L) 4.76 3.5–5
Hemoglobin (g/L) 129 110–150
Platelets (109/L) 251 100–300
Glucose (mmol/L) 4.89 3.9–6.1
Cholesterol (mmol/L) 3.46 3.4–6.5
HDL (mmol/L) 0.94 0.9–1.91
LDL (mmol/L) 1.69 2.08–4.14
AST (U/L) 50 0–40
ALT (U/L) 48 0–45
ALP (U/L) 61 15–121
CK (U/L) 171 25–192
LDH (U/L) 441 110–240
Urea nitrogen (mmol/L) 2.79 2.5–7.5
Creatinie (µmol/L) 64 44–133
IgG (g/L) 10.21 8–18
Ferritin level (µg/L) 167.3 11.0–306.8
24-h urine protein (g/24 h) 0.216 0.028–0.141
ESR (mm/h) 53 0–20
CRP (mg/L) 30.94 <5
PCT (ng/ml) <0.05 <0.05
C3 (g/L) 1.28 0.80–1.81
C4 (g/L) 0.32 0.15–0.57
Coombs’ test Negative Negative
RF (IU/mL) 7.3 <25
Anti-CCP Negative Negative
cANCA Negative Negative
anti-PR3 Negative Negative
pANCA Negative Negative
anti-MPO Negative Negative
ANA Negative Negative
Anti-centromere Negative Negative
Anti-dsDNA Negative Negative
Anti-SS-A Negative Negative
Anti-SS-B Negative Negative
Anti-MDA5 Strongly positive Negative
Anti-tRNA synthase autoantibody panel Negative Negative
HDL, high-density lipoprotein; LDL, low density lipoprotein; AST, alanine transaminase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CK, creatine phosphokinase; LDH, lactic dehydrogenase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PCT, procalcitonin; RF, rheumatoid factor; C3, complement C3; C4, complement C4; Anti-MDA5, anti-melanoma differentiation-associated gene 5. Anti-CCP, anti-cyclic citrullinated peptide antibody; cANCA, cytoplasmic-staining anti-neutrophil cytoplasm antibody; pANCA, perinuclear-staining anti-neutrophil cytoplasm antibody; Anti-MPO, anti-myeloperoxidase antibody; Anti-PR3, anti-proteinase 3 antibody; ANA, anti-nuclear antibodies; Anti-dsDNA, anti-double-stranded (ds) DNA antibody; Anti-SS-A, anti-Sjögren's syndrome antigen A antibody; Anti-SS-B, anti-Sjögren's syndrome antigen B antibody.
Further tests revealed that her anti-MDA5 antibody was positive. The high-resolution computed tomography (HRCT) scan on day 7 revealed reticular shadows, patchy ground glass opacities and inflammation in both lungs ( Figure 2A ). On the basis of these findings, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made. According to the results of a multi-disciplinary discussion, on day 10, the patient was treated with combination therapy including methylprednisolone (1.0 mg/kg/day, that is, 80 mg/day) accompanied by oral cyclosporine (100 mg twice a day) and intravenous cyclophosphamide (IVCY, 400 mg/week) following high dose pulsed methylprednisolone at 500 mg/day for 3 days and intravenous immunoglobulin (IVIG, 20 g/day for 3 days). Considering her worsening condition, artificial abortion was conducted on day 10 with her permission. The respiratory condition of the patient improved gradually. A chest CT scan performed on day 21 of hospitalization revealed a patchy density shadow that had significantly decreased compared with its appearance previously ( Figure 2B ). The patient was discharged while being treated with methylprednisolone at 80 mg/day, cyclosporine at 200 mg/day, IVCY at 400 mg/2 weeks.
Figure 2 Changes in chest computed tomography scan findings (A) on admission, (B) before discharge and (C) after recovery.
Because of the significant improvement in her respiratory condition, we decided to taper the methylprednisolone and IVCY dose gradually. During the follow up, the patient achieved complete remission, her rash disappeared ( Figure 1B ) and the chest CT scan revealed that the patient had returned to the normal state after treatment for 10 months ( Figure 2C ). IVCY treatment was discontinued after treatment for 14 months, and anti-MDA5 antibody was negative after treatment for 24 months. At the time of writing this report, the patient was being treated with 4 mg/day methylprednisolone and 75 mg/day cyclosporine. The clinical course of the patient is shown in Figure 3 .
Figure 3 Clinical course of the patient. mPSL, methylprednisolone; Pulse: intravenous methylprednisolone pulse therapy (500 mg/d×3 days); IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; CyA, cyclosporine A; IVCY, intravenous cyclophosphamide; O2, oxygen; Anti-MDA5, anti-melanoma differentiation-associated gene 5 antibody; ++, strongly positive; +, positive; −, negative.
Discussion
Inflammatory myopathies are a spectrum of systemic immune-mediated disorders characterized by muscle inflammation, and affecting extramuscular organs, including skin, joints, and lungs. It is widely recognized that there are five main types of inflammatory myopathies: DM, polymyositis (PM), overlap myositis (including anti-synthetase syndrome (ASS)), inclusion-body myositis, and immune-mediated necrotizing myopathy (7, 8). RP-ILD was mainly defined as progressive dyspnea, or according to HRCT findings secondary to ILD within 3 months after the onset of respiratory symptoms (9, 10). RP-ILD often occurs as a complication of CADM, which usually portends poor prognosis with reported mortality rates in the first year as high as 60% (11). Anti-MDA5 antibodies were first identified by Sato et al. in 2005 in Japanese patients with CADM (12). Since that discovery, anti-MDA5 antibodies have predominantly been found in cases of CADM (13). Mortality rates ranged from 36%–46% in anti-MDA5 positive patients with CADM or DM (14). Anti-MDA5 antibodies have also been associated with RP-ILD, as identified in 39%–100% of patients with RP-ILD in Asian cohorts (15). The cumulative 6-month survival rate was reported to be about 50% for RP-ILD patients with the anti-MDA5 antibody (16). Hence, anti-MDA5 antibodies can be a useful predictor for the complication of RP-ILD in patients with CADM. In the present case study, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made as the patient experienced respiratory symptoms from the beginning, and her respiratory status deteriorated rapidly within one month. It has been suggested that immunosuppressants should be used early in patients with RP-ILD, since the damage caused to the pulmonary tissue may be irreversible once CADM is complicated by RP-ILD, which may result in the patient being irresponsive to combination immunosuppressive therapy, leading to death after only a few months (17). However, the use of immunosuppressants may not ensure rapid remission of the patient’s condition (18). It was reported that combination immunosuppressive therapy consisting of high-dose corticosteroids, cyclosporine and intravenous immunoglobulin might be effective for CADM patients with RP-ILD (16). Moreover, previous studies have also shown that patients with RP-ILD or respiratory failure may benefit from the use of basiliximab, mycophenolate mofetil or cyclophosphamide (19, 20).
The onset of DM during pregnancy is a rare event. It has been reported that one in 173 female patients with DM/PM experienced disease onset during pregnancy (21). Pregnancy outcomes are closely associated with the disease activity during pregnancy. Patients with quiescent disease before pregnancy have good pregnancy outcomes. By contrast, a pre-existing active condition or onset of DM during pregnancy leads to a high frequency of premature delivery and fetal death (21).
There are several factors that may explain the trigger for development of DM during pregnancy, such as changes in maternal hormonal status, exposure of the mother to fetal antigens, and the reactivation of certain viruses due to pregnancy (6). In addition, a high body mass index was noticed in the patient. Previous studies have revealed that obesity is a metabolic disease which may lead to the activation of the immune system and a consequently worse prognosis (22). Moreover, the obese are prone to respiratory failure even with mild pulmonary challenge (23). Hence, the rapid deterioration of the respiratory status in this patient may be partially explained by her high body mass index.
In view of these considerations, the onset of CADM during pregnancy is a problematic issue to be resolved for both physicians and patients. Treatment regimen should consider the safety of both the mother and the fetus, which requires individualized therapy. Glucocorticoids are the first line treatment in pregnant patients with DM (24). In certain rare cases, the use of glucocorticoids has been demonstrated to lead to a good outcome (6). However, certain patients have been shown to be non-responsive or intolerant to glucocorticoids (24). A previous study illustrated that gestational exposure to glucocorticoids led to a slight increase in the risk of premature birth and fetal oral cleft (25). Efficacy and safety of IVIG during pregnancy has been well documented in DM, especially for refractory cases (24, 25). In a previously published case report, short term remission was achieved following treatment with IVIG (4.5 g for 3 consecutive days) (25).
Examples of clinical case studies for treating pregnant patients with DM or PM, especially CADM, are relatively rare, and case studies of a similar nature that we were able to identify are shown in supplementary material (18, 26–28). Tomohiro et al (18). described the case of a 33-year-old pregnant woman who developed progressive interstitial pneumonia (IP) complicated by anti Jo-1 positive ASS at 28 weeks of gestation. At 30 weeks of her gestation, since the neonate could be treated at the neonatal intensive care unit after delivery, an emergency cesarean section was performed. The patient was eventually successfully treated with a combination of immunosuppressive therapy including intravenous methylprednisolone pulse therapy (1 g/day) and IVCY and the use of high flow nasal cannula oxygen therapy without intubation. In another case report, a pregnant woman at 16 weeks of gestation had developed IP preceding anti Jo-1 positive ASS, and was treated with a combination of steroid pulse therapy and tacrolimus. The fetus did not survive since it was too small, and the maternal condition deteriorated (26). To the best of our knowledge, the present case study is the first reported case of a patient having been diagnosed with anti-MDA5-positive RP-ILD complicated with CADM. In our case, artificial abortion was conducted because the maternal condition was unstable. The influences of high dose steroids and the CT scan were also taken into consideration. After combining steroid pulse and immunosuppressive therapy, the maternal condition gradually improved and our patient had complete remission without residual pulmonary interstitial changes. In anti-MDA5-positive patients with CADM, the CT scans usually show ground-glass opacities and bilateral subpleural reticular opacities, predominantly in the lower lungs, which would improve substantially or become stable after combination immunosuppressive therapy (29, 30). The present report describes a pregnant woman with CADM with positive anti-MDA5 antibody, who developed RP-ILD and subsequently achieved complete remission without residual pulmonary interstitial changes after treatment, which has been rarely reported in the previous literature. It is difficult to save the fetal lives in CADM patients with anti-MDA5 antibody. Because it was dispensable to use combination of high dose corticosteroids and immunosuppressive agents including IVCY in CADM patients even if they were in pregnancy.
Certain biological parameters have been evaluated for their ability to predict the disease activity, occurrence, and outcomes of patients with CADM. As mentioned above, both anti-MDA5 antibodies and RP-ILD are crucial predictors. Furthermore, LDH, Krebs von den Lungen 6 (KL-6), serum surfactant protein D (SP-D), ferritin level, and the HRCT imaging score are also associated with prognosis of the disease (14, 31). In this case, the patient’s ferritin level was elevated when her respiratory condition continued to worsen, which also suggested a poor prognosis in our patient. Recently, Lian et al. established a simple and practical score model to predict the prognosis of patients with ADM-ILD (31). According to this model, our patient was at least in the medium risk group, with a score of 5 (three points for anti-MDA5 antibodies, and two points for RP-ILD). Despite the fact that not all patients with this antibody develop lethal ILD, one possible explanation may be that all of the patients who have this particular antibody may undergo an early stage of disease, with only a skin rash or skin rash accompanied by arthralgia. They subsequently develop asymptomatic ILD, which progresses to RP-ILD if left untreated (32). The main limitation of the current study is that this is a case report, and several cases of CADM and DM developing during pregnancy have been previously described. However, we have made a comprehensive review, and to be best of our knowledge, this is the first case study depicting a pregnant patient with anti-MDA5-positive RP-ILD complicated with CADM. Notably, the patient finally achieved complete remission without residual pulmonary interstitial changes, indicating the importance of early intervention with combined immunosuppressive therapy in such patients.
Concluding Remarks
The present case study has reported on a case of a 38-year-old pregnant woman at 7 weeks of gestation who developed RP-ILD due to CADM with positive anti-MDA5 antibody. She achieved complete remission following early intervention of combination immunosuppressive therapy without residual pulmonary interstitial changes.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
CC and YC summarized the case, reviewed the literature, and drafted the manuscript. QinH and QiuH drafted the manuscript. XH reviewed and summarized the case. All authors contributed to the article and approved the submitted version.
Funding
The research is supported by Shenzhen Key Medical Discipline Construction Fund (no. SZXK011), Shenzhen Health Plan Committee Research Foundation (no. SZXJ2018021), Shenzhen Science and Technology Plan Program (no. JCYJ20190807144418845), and Sanming Project of Medicine in Shenzhen (no. SYJY201901).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors wish to thank the patient in this study.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.625495/full#supplementary-material
Click here for additional data file. | Oral | DrugAdministrationRoute | CC BY | 33717138 | 19,108,899 | 2021 |
What was the administration route of drug 'IMMUNE GLOBULIN NOS'? | Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.
Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors' knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.
Introduction
Dermatomyositis (DM) is a spectrum of muscle myalgia and weakness, with typical skin manifestations, including heliotrope rash and Gottron’s sign. Clinically amyopathic dermatomyositis (CADM) is an independent spectrum of classic DM with typical skin lesions and minimal or absent muscle disease (1). It has been reported that the prevalence of CADM in all patients with dermatomyositis is 5%–20% (2). Rapidly progressive interstitial lung disease (RP-ILD) is common in CADM patients with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody (3), which tends to be treatment-refractory with a poor prognosis (4). The onset of CADM during pregnancy is extremely rare and the outcome of pregnancy in these patients is poor for both mother and fetus, including maternal and fetal death, as well as prematurity (5, 6). The present case study reports on a pregnant woman with CADM with the positive anti-MDA5 antibody, who developed RP-ILD during her first 7 weeks of gestation. She was successfully treated with combined immunosuppressive therapy without residual pulmonary interstitial changes.
Case Presentation
A 38-year-old woman with a 7-week pregnancy was admitted to our hospital with complaints of dry cough, dyspnea on exertion, and a rash over the face, neck, and dorsum of the hands for 23 days and polyarthritis for 2 days ( Figure 1A ). Prior to admission, she was treated with loratadine without resolution, and her symptoms gradually worsened. Her past medical history was unremarkable.
Figure 1 Clinical presentation of the patient (A) on admission and (B) after recovery.
Physical examination on admission revealed a high body mass index of 33.1, heliotrope rash, Gottron’s papules and fine crackles audible bilaterally in the lower lung fields. No signs of muscle weakness or pain were present. The patient had tachycardia (113 beats/min) with normal oxygen saturation. Laboratory findings revealed the levels of creatine phosphokinase (CK; reference range, 25–192) to be 171 U/l, lactate dehydrogenase (LDH; reference range, 110–240) to be 441 U/l, alanine transaminase (AST; reference range, 0–40) to be 50 U/l, C-reactive protein (CRP; reference range, <5) to be 30.94 mg/l, erythrocyte sedimentation rate (ESR, reference range, 0–20) to be 53 mm/h, and ferritin (reference range, 11.0–306.8) to be 167.3 ng/ml. The main laboratory results are shown in Table 1 . No evidence was identified that may have suggested infection or malignancy, and therefore CADM was suspected in this patient. She was treated with 24 mg/day of oral methylprednisolone for 3 days, along with 400 mg/day of hydroxychloroquine in her first week of admission. However, the patient’s respiratory condition continued to worsen with percutaneous blood oxygen saturation decreasing to 88% under use of low- flow nasal cannula oxygen and therefore she was given oxygen by way of medium-flow mask oxygen. Moreover, she was unable to complete the pulmonary function test due to the rapid deterioration of the respiratory status.
Table 1 Laboratory findings on admission.
Parameter Value Reference range
Leukocytes (109/L) 3.6 4–10
Erythrocytes (1012/L) 4.76 3.5–5
Hemoglobin (g/L) 129 110–150
Platelets (109/L) 251 100–300
Glucose (mmol/L) 4.89 3.9–6.1
Cholesterol (mmol/L) 3.46 3.4–6.5
HDL (mmol/L) 0.94 0.9–1.91
LDL (mmol/L) 1.69 2.08–4.14
AST (U/L) 50 0–40
ALT (U/L) 48 0–45
ALP (U/L) 61 15–121
CK (U/L) 171 25–192
LDH (U/L) 441 110–240
Urea nitrogen (mmol/L) 2.79 2.5–7.5
Creatinie (µmol/L) 64 44–133
IgG (g/L) 10.21 8–18
Ferritin level (µg/L) 167.3 11.0–306.8
24-h urine protein (g/24 h) 0.216 0.028–0.141
ESR (mm/h) 53 0–20
CRP (mg/L) 30.94 <5
PCT (ng/ml) <0.05 <0.05
C3 (g/L) 1.28 0.80–1.81
C4 (g/L) 0.32 0.15–0.57
Coombs’ test Negative Negative
RF (IU/mL) 7.3 <25
Anti-CCP Negative Negative
cANCA Negative Negative
anti-PR3 Negative Negative
pANCA Negative Negative
anti-MPO Negative Negative
ANA Negative Negative
Anti-centromere Negative Negative
Anti-dsDNA Negative Negative
Anti-SS-A Negative Negative
Anti-SS-B Negative Negative
Anti-MDA5 Strongly positive Negative
Anti-tRNA synthase autoantibody panel Negative Negative
HDL, high-density lipoprotein; LDL, low density lipoprotein; AST, alanine transaminase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CK, creatine phosphokinase; LDH, lactic dehydrogenase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PCT, procalcitonin; RF, rheumatoid factor; C3, complement C3; C4, complement C4; Anti-MDA5, anti-melanoma differentiation-associated gene 5. Anti-CCP, anti-cyclic citrullinated peptide antibody; cANCA, cytoplasmic-staining anti-neutrophil cytoplasm antibody; pANCA, perinuclear-staining anti-neutrophil cytoplasm antibody; Anti-MPO, anti-myeloperoxidase antibody; Anti-PR3, anti-proteinase 3 antibody; ANA, anti-nuclear antibodies; Anti-dsDNA, anti-double-stranded (ds) DNA antibody; Anti-SS-A, anti-Sjögren's syndrome antigen A antibody; Anti-SS-B, anti-Sjögren's syndrome antigen B antibody.
Further tests revealed that her anti-MDA5 antibody was positive. The high-resolution computed tomography (HRCT) scan on day 7 revealed reticular shadows, patchy ground glass opacities and inflammation in both lungs ( Figure 2A ). On the basis of these findings, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made. According to the results of a multi-disciplinary discussion, on day 10, the patient was treated with combination therapy including methylprednisolone (1.0 mg/kg/day, that is, 80 mg/day) accompanied by oral cyclosporine (100 mg twice a day) and intravenous cyclophosphamide (IVCY, 400 mg/week) following high dose pulsed methylprednisolone at 500 mg/day for 3 days and intravenous immunoglobulin (IVIG, 20 g/day for 3 days). Considering her worsening condition, artificial abortion was conducted on day 10 with her permission. The respiratory condition of the patient improved gradually. A chest CT scan performed on day 21 of hospitalization revealed a patchy density shadow that had significantly decreased compared with its appearance previously ( Figure 2B ). The patient was discharged while being treated with methylprednisolone at 80 mg/day, cyclosporine at 200 mg/day, IVCY at 400 mg/2 weeks.
Figure 2 Changes in chest computed tomography scan findings (A) on admission, (B) before discharge and (C) after recovery.
Because of the significant improvement in her respiratory condition, we decided to taper the methylprednisolone and IVCY dose gradually. During the follow up, the patient achieved complete remission, her rash disappeared ( Figure 1B ) and the chest CT scan revealed that the patient had returned to the normal state after treatment for 10 months ( Figure 2C ). IVCY treatment was discontinued after treatment for 14 months, and anti-MDA5 antibody was negative after treatment for 24 months. At the time of writing this report, the patient was being treated with 4 mg/day methylprednisolone and 75 mg/day cyclosporine. The clinical course of the patient is shown in Figure 3 .
Figure 3 Clinical course of the patient. mPSL, methylprednisolone; Pulse: intravenous methylprednisolone pulse therapy (500 mg/d×3 days); IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; CyA, cyclosporine A; IVCY, intravenous cyclophosphamide; O2, oxygen; Anti-MDA5, anti-melanoma differentiation-associated gene 5 antibody; ++, strongly positive; +, positive; −, negative.
Discussion
Inflammatory myopathies are a spectrum of systemic immune-mediated disorders characterized by muscle inflammation, and affecting extramuscular organs, including skin, joints, and lungs. It is widely recognized that there are five main types of inflammatory myopathies: DM, polymyositis (PM), overlap myositis (including anti-synthetase syndrome (ASS)), inclusion-body myositis, and immune-mediated necrotizing myopathy (7, 8). RP-ILD was mainly defined as progressive dyspnea, or according to HRCT findings secondary to ILD within 3 months after the onset of respiratory symptoms (9, 10). RP-ILD often occurs as a complication of CADM, which usually portends poor prognosis with reported mortality rates in the first year as high as 60% (11). Anti-MDA5 antibodies were first identified by Sato et al. in 2005 in Japanese patients with CADM (12). Since that discovery, anti-MDA5 antibodies have predominantly been found in cases of CADM (13). Mortality rates ranged from 36%–46% in anti-MDA5 positive patients with CADM or DM (14). Anti-MDA5 antibodies have also been associated with RP-ILD, as identified in 39%–100% of patients with RP-ILD in Asian cohorts (15). The cumulative 6-month survival rate was reported to be about 50% for RP-ILD patients with the anti-MDA5 antibody (16). Hence, anti-MDA5 antibodies can be a useful predictor for the complication of RP-ILD in patients with CADM. In the present case study, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made as the patient experienced respiratory symptoms from the beginning, and her respiratory status deteriorated rapidly within one month. It has been suggested that immunosuppressants should be used early in patients with RP-ILD, since the damage caused to the pulmonary tissue may be irreversible once CADM is complicated by RP-ILD, which may result in the patient being irresponsive to combination immunosuppressive therapy, leading to death after only a few months (17). However, the use of immunosuppressants may not ensure rapid remission of the patient’s condition (18). It was reported that combination immunosuppressive therapy consisting of high-dose corticosteroids, cyclosporine and intravenous immunoglobulin might be effective for CADM patients with RP-ILD (16). Moreover, previous studies have also shown that patients with RP-ILD or respiratory failure may benefit from the use of basiliximab, mycophenolate mofetil or cyclophosphamide (19, 20).
The onset of DM during pregnancy is a rare event. It has been reported that one in 173 female patients with DM/PM experienced disease onset during pregnancy (21). Pregnancy outcomes are closely associated with the disease activity during pregnancy. Patients with quiescent disease before pregnancy have good pregnancy outcomes. By contrast, a pre-existing active condition or onset of DM during pregnancy leads to a high frequency of premature delivery and fetal death (21).
There are several factors that may explain the trigger for development of DM during pregnancy, such as changes in maternal hormonal status, exposure of the mother to fetal antigens, and the reactivation of certain viruses due to pregnancy (6). In addition, a high body mass index was noticed in the patient. Previous studies have revealed that obesity is a metabolic disease which may lead to the activation of the immune system and a consequently worse prognosis (22). Moreover, the obese are prone to respiratory failure even with mild pulmonary challenge (23). Hence, the rapid deterioration of the respiratory status in this patient may be partially explained by her high body mass index.
In view of these considerations, the onset of CADM during pregnancy is a problematic issue to be resolved for both physicians and patients. Treatment regimen should consider the safety of both the mother and the fetus, which requires individualized therapy. Glucocorticoids are the first line treatment in pregnant patients with DM (24). In certain rare cases, the use of glucocorticoids has been demonstrated to lead to a good outcome (6). However, certain patients have been shown to be non-responsive or intolerant to glucocorticoids (24). A previous study illustrated that gestational exposure to glucocorticoids led to a slight increase in the risk of premature birth and fetal oral cleft (25). Efficacy and safety of IVIG during pregnancy has been well documented in DM, especially for refractory cases (24, 25). In a previously published case report, short term remission was achieved following treatment with IVIG (4.5 g for 3 consecutive days) (25).
Examples of clinical case studies for treating pregnant patients with DM or PM, especially CADM, are relatively rare, and case studies of a similar nature that we were able to identify are shown in supplementary material (18, 26–28). Tomohiro et al (18). described the case of a 33-year-old pregnant woman who developed progressive interstitial pneumonia (IP) complicated by anti Jo-1 positive ASS at 28 weeks of gestation. At 30 weeks of her gestation, since the neonate could be treated at the neonatal intensive care unit after delivery, an emergency cesarean section was performed. The patient was eventually successfully treated with a combination of immunosuppressive therapy including intravenous methylprednisolone pulse therapy (1 g/day) and IVCY and the use of high flow nasal cannula oxygen therapy without intubation. In another case report, a pregnant woman at 16 weeks of gestation had developed IP preceding anti Jo-1 positive ASS, and was treated with a combination of steroid pulse therapy and tacrolimus. The fetus did not survive since it was too small, and the maternal condition deteriorated (26). To the best of our knowledge, the present case study is the first reported case of a patient having been diagnosed with anti-MDA5-positive RP-ILD complicated with CADM. In our case, artificial abortion was conducted because the maternal condition was unstable. The influences of high dose steroids and the CT scan were also taken into consideration. After combining steroid pulse and immunosuppressive therapy, the maternal condition gradually improved and our patient had complete remission without residual pulmonary interstitial changes. In anti-MDA5-positive patients with CADM, the CT scans usually show ground-glass opacities and bilateral subpleural reticular opacities, predominantly in the lower lungs, which would improve substantially or become stable after combination immunosuppressive therapy (29, 30). The present report describes a pregnant woman with CADM with positive anti-MDA5 antibody, who developed RP-ILD and subsequently achieved complete remission without residual pulmonary interstitial changes after treatment, which has been rarely reported in the previous literature. It is difficult to save the fetal lives in CADM patients with anti-MDA5 antibody. Because it was dispensable to use combination of high dose corticosteroids and immunosuppressive agents including IVCY in CADM patients even if they were in pregnancy.
Certain biological parameters have been evaluated for their ability to predict the disease activity, occurrence, and outcomes of patients with CADM. As mentioned above, both anti-MDA5 antibodies and RP-ILD are crucial predictors. Furthermore, LDH, Krebs von den Lungen 6 (KL-6), serum surfactant protein D (SP-D), ferritin level, and the HRCT imaging score are also associated with prognosis of the disease (14, 31). In this case, the patient’s ferritin level was elevated when her respiratory condition continued to worsen, which also suggested a poor prognosis in our patient. Recently, Lian et al. established a simple and practical score model to predict the prognosis of patients with ADM-ILD (31). According to this model, our patient was at least in the medium risk group, with a score of 5 (three points for anti-MDA5 antibodies, and two points for RP-ILD). Despite the fact that not all patients with this antibody develop lethal ILD, one possible explanation may be that all of the patients who have this particular antibody may undergo an early stage of disease, with only a skin rash or skin rash accompanied by arthralgia. They subsequently develop asymptomatic ILD, which progresses to RP-ILD if left untreated (32). The main limitation of the current study is that this is a case report, and several cases of CADM and DM developing during pregnancy have been previously described. However, we have made a comprehensive review, and to be best of our knowledge, this is the first case study depicting a pregnant patient with anti-MDA5-positive RP-ILD complicated with CADM. Notably, the patient finally achieved complete remission without residual pulmonary interstitial changes, indicating the importance of early intervention with combined immunosuppressive therapy in such patients.
Concluding Remarks
The present case study has reported on a case of a 38-year-old pregnant woman at 7 weeks of gestation who developed RP-ILD due to CADM with positive anti-MDA5 antibody. She achieved complete remission following early intervention of combination immunosuppressive therapy without residual pulmonary interstitial changes.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
CC and YC summarized the case, reviewed the literature, and drafted the manuscript. QinH and QiuH drafted the manuscript. XH reviewed and summarized the case. All authors contributed to the article and approved the submitted version.
Funding
The research is supported by Shenzhen Key Medical Discipline Construction Fund (no. SZXK011), Shenzhen Health Plan Committee Research Foundation (no. SZXJ2018021), Shenzhen Science and Technology Plan Program (no. JCYJ20190807144418845), and Sanming Project of Medicine in Shenzhen (no. SYJY201901).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors wish to thank the patient in this study.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.625495/full#supplementary-material
Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33717138 | 19,108,899 | 2021 |
What was the administration route of drug 'LORATADINE'? | Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.
Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors' knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.
Introduction
Dermatomyositis (DM) is a spectrum of muscle myalgia and weakness, with typical skin manifestations, including heliotrope rash and Gottron’s sign. Clinically amyopathic dermatomyositis (CADM) is an independent spectrum of classic DM with typical skin lesions and minimal or absent muscle disease (1). It has been reported that the prevalence of CADM in all patients with dermatomyositis is 5%–20% (2). Rapidly progressive interstitial lung disease (RP-ILD) is common in CADM patients with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody (3), which tends to be treatment-refractory with a poor prognosis (4). The onset of CADM during pregnancy is extremely rare and the outcome of pregnancy in these patients is poor for both mother and fetus, including maternal and fetal death, as well as prematurity (5, 6). The present case study reports on a pregnant woman with CADM with the positive anti-MDA5 antibody, who developed RP-ILD during her first 7 weeks of gestation. She was successfully treated with combined immunosuppressive therapy without residual pulmonary interstitial changes.
Case Presentation
A 38-year-old woman with a 7-week pregnancy was admitted to our hospital with complaints of dry cough, dyspnea on exertion, and a rash over the face, neck, and dorsum of the hands for 23 days and polyarthritis for 2 days ( Figure 1A ). Prior to admission, she was treated with loratadine without resolution, and her symptoms gradually worsened. Her past medical history was unremarkable.
Figure 1 Clinical presentation of the patient (A) on admission and (B) after recovery.
Physical examination on admission revealed a high body mass index of 33.1, heliotrope rash, Gottron’s papules and fine crackles audible bilaterally in the lower lung fields. No signs of muscle weakness or pain were present. The patient had tachycardia (113 beats/min) with normal oxygen saturation. Laboratory findings revealed the levels of creatine phosphokinase (CK; reference range, 25–192) to be 171 U/l, lactate dehydrogenase (LDH; reference range, 110–240) to be 441 U/l, alanine transaminase (AST; reference range, 0–40) to be 50 U/l, C-reactive protein (CRP; reference range, <5) to be 30.94 mg/l, erythrocyte sedimentation rate (ESR, reference range, 0–20) to be 53 mm/h, and ferritin (reference range, 11.0–306.8) to be 167.3 ng/ml. The main laboratory results are shown in Table 1 . No evidence was identified that may have suggested infection or malignancy, and therefore CADM was suspected in this patient. She was treated with 24 mg/day of oral methylprednisolone for 3 days, along with 400 mg/day of hydroxychloroquine in her first week of admission. However, the patient’s respiratory condition continued to worsen with percutaneous blood oxygen saturation decreasing to 88% under use of low- flow nasal cannula oxygen and therefore she was given oxygen by way of medium-flow mask oxygen. Moreover, she was unable to complete the pulmonary function test due to the rapid deterioration of the respiratory status.
Table 1 Laboratory findings on admission.
Parameter Value Reference range
Leukocytes (109/L) 3.6 4–10
Erythrocytes (1012/L) 4.76 3.5–5
Hemoglobin (g/L) 129 110–150
Platelets (109/L) 251 100–300
Glucose (mmol/L) 4.89 3.9–6.1
Cholesterol (mmol/L) 3.46 3.4–6.5
HDL (mmol/L) 0.94 0.9–1.91
LDL (mmol/L) 1.69 2.08–4.14
AST (U/L) 50 0–40
ALT (U/L) 48 0–45
ALP (U/L) 61 15–121
CK (U/L) 171 25–192
LDH (U/L) 441 110–240
Urea nitrogen (mmol/L) 2.79 2.5–7.5
Creatinie (µmol/L) 64 44–133
IgG (g/L) 10.21 8–18
Ferritin level (µg/L) 167.3 11.0–306.8
24-h urine protein (g/24 h) 0.216 0.028–0.141
ESR (mm/h) 53 0–20
CRP (mg/L) 30.94 <5
PCT (ng/ml) <0.05 <0.05
C3 (g/L) 1.28 0.80–1.81
C4 (g/L) 0.32 0.15–0.57
Coombs’ test Negative Negative
RF (IU/mL) 7.3 <25
Anti-CCP Negative Negative
cANCA Negative Negative
anti-PR3 Negative Negative
pANCA Negative Negative
anti-MPO Negative Negative
ANA Negative Negative
Anti-centromere Negative Negative
Anti-dsDNA Negative Negative
Anti-SS-A Negative Negative
Anti-SS-B Negative Negative
Anti-MDA5 Strongly positive Negative
Anti-tRNA synthase autoantibody panel Negative Negative
HDL, high-density lipoprotein; LDL, low density lipoprotein; AST, alanine transaminase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CK, creatine phosphokinase; LDH, lactic dehydrogenase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PCT, procalcitonin; RF, rheumatoid factor; C3, complement C3; C4, complement C4; Anti-MDA5, anti-melanoma differentiation-associated gene 5. Anti-CCP, anti-cyclic citrullinated peptide antibody; cANCA, cytoplasmic-staining anti-neutrophil cytoplasm antibody; pANCA, perinuclear-staining anti-neutrophil cytoplasm antibody; Anti-MPO, anti-myeloperoxidase antibody; Anti-PR3, anti-proteinase 3 antibody; ANA, anti-nuclear antibodies; Anti-dsDNA, anti-double-stranded (ds) DNA antibody; Anti-SS-A, anti-Sjögren's syndrome antigen A antibody; Anti-SS-B, anti-Sjögren's syndrome antigen B antibody.
Further tests revealed that her anti-MDA5 antibody was positive. The high-resolution computed tomography (HRCT) scan on day 7 revealed reticular shadows, patchy ground glass opacities and inflammation in both lungs ( Figure 2A ). On the basis of these findings, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made. According to the results of a multi-disciplinary discussion, on day 10, the patient was treated with combination therapy including methylprednisolone (1.0 mg/kg/day, that is, 80 mg/day) accompanied by oral cyclosporine (100 mg twice a day) and intravenous cyclophosphamide (IVCY, 400 mg/week) following high dose pulsed methylprednisolone at 500 mg/day for 3 days and intravenous immunoglobulin (IVIG, 20 g/day for 3 days). Considering her worsening condition, artificial abortion was conducted on day 10 with her permission. The respiratory condition of the patient improved gradually. A chest CT scan performed on day 21 of hospitalization revealed a patchy density shadow that had significantly decreased compared with its appearance previously ( Figure 2B ). The patient was discharged while being treated with methylprednisolone at 80 mg/day, cyclosporine at 200 mg/day, IVCY at 400 mg/2 weeks.
Figure 2 Changes in chest computed tomography scan findings (A) on admission, (B) before discharge and (C) after recovery.
Because of the significant improvement in her respiratory condition, we decided to taper the methylprednisolone and IVCY dose gradually. During the follow up, the patient achieved complete remission, her rash disappeared ( Figure 1B ) and the chest CT scan revealed that the patient had returned to the normal state after treatment for 10 months ( Figure 2C ). IVCY treatment was discontinued after treatment for 14 months, and anti-MDA5 antibody was negative after treatment for 24 months. At the time of writing this report, the patient was being treated with 4 mg/day methylprednisolone and 75 mg/day cyclosporine. The clinical course of the patient is shown in Figure 3 .
Figure 3 Clinical course of the patient. mPSL, methylprednisolone; Pulse: intravenous methylprednisolone pulse therapy (500 mg/d×3 days); IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; CyA, cyclosporine A; IVCY, intravenous cyclophosphamide; O2, oxygen; Anti-MDA5, anti-melanoma differentiation-associated gene 5 antibody; ++, strongly positive; +, positive; −, negative.
Discussion
Inflammatory myopathies are a spectrum of systemic immune-mediated disorders characterized by muscle inflammation, and affecting extramuscular organs, including skin, joints, and lungs. It is widely recognized that there are five main types of inflammatory myopathies: DM, polymyositis (PM), overlap myositis (including anti-synthetase syndrome (ASS)), inclusion-body myositis, and immune-mediated necrotizing myopathy (7, 8). RP-ILD was mainly defined as progressive dyspnea, or according to HRCT findings secondary to ILD within 3 months after the onset of respiratory symptoms (9, 10). RP-ILD often occurs as a complication of CADM, which usually portends poor prognosis with reported mortality rates in the first year as high as 60% (11). Anti-MDA5 antibodies were first identified by Sato et al. in 2005 in Japanese patients with CADM (12). Since that discovery, anti-MDA5 antibodies have predominantly been found in cases of CADM (13). Mortality rates ranged from 36%–46% in anti-MDA5 positive patients with CADM or DM (14). Anti-MDA5 antibodies have also been associated with RP-ILD, as identified in 39%–100% of patients with RP-ILD in Asian cohorts (15). The cumulative 6-month survival rate was reported to be about 50% for RP-ILD patients with the anti-MDA5 antibody (16). Hence, anti-MDA5 antibodies can be a useful predictor for the complication of RP-ILD in patients with CADM. In the present case study, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made as the patient experienced respiratory symptoms from the beginning, and her respiratory status deteriorated rapidly within one month. It has been suggested that immunosuppressants should be used early in patients with RP-ILD, since the damage caused to the pulmonary tissue may be irreversible once CADM is complicated by RP-ILD, which may result in the patient being irresponsive to combination immunosuppressive therapy, leading to death after only a few months (17). However, the use of immunosuppressants may not ensure rapid remission of the patient’s condition (18). It was reported that combination immunosuppressive therapy consisting of high-dose corticosteroids, cyclosporine and intravenous immunoglobulin might be effective for CADM patients with RP-ILD (16). Moreover, previous studies have also shown that patients with RP-ILD or respiratory failure may benefit from the use of basiliximab, mycophenolate mofetil or cyclophosphamide (19, 20).
The onset of DM during pregnancy is a rare event. It has been reported that one in 173 female patients with DM/PM experienced disease onset during pregnancy (21). Pregnancy outcomes are closely associated with the disease activity during pregnancy. Patients with quiescent disease before pregnancy have good pregnancy outcomes. By contrast, a pre-existing active condition or onset of DM during pregnancy leads to a high frequency of premature delivery and fetal death (21).
There are several factors that may explain the trigger for development of DM during pregnancy, such as changes in maternal hormonal status, exposure of the mother to fetal antigens, and the reactivation of certain viruses due to pregnancy (6). In addition, a high body mass index was noticed in the patient. Previous studies have revealed that obesity is a metabolic disease which may lead to the activation of the immune system and a consequently worse prognosis (22). Moreover, the obese are prone to respiratory failure even with mild pulmonary challenge (23). Hence, the rapid deterioration of the respiratory status in this patient may be partially explained by her high body mass index.
In view of these considerations, the onset of CADM during pregnancy is a problematic issue to be resolved for both physicians and patients. Treatment regimen should consider the safety of both the mother and the fetus, which requires individualized therapy. Glucocorticoids are the first line treatment in pregnant patients with DM (24). In certain rare cases, the use of glucocorticoids has been demonstrated to lead to a good outcome (6). However, certain patients have been shown to be non-responsive or intolerant to glucocorticoids (24). A previous study illustrated that gestational exposure to glucocorticoids led to a slight increase in the risk of premature birth and fetal oral cleft (25). Efficacy and safety of IVIG during pregnancy has been well documented in DM, especially for refractory cases (24, 25). In a previously published case report, short term remission was achieved following treatment with IVIG (4.5 g for 3 consecutive days) (25).
Examples of clinical case studies for treating pregnant patients with DM or PM, especially CADM, are relatively rare, and case studies of a similar nature that we were able to identify are shown in supplementary material (18, 26–28). Tomohiro et al (18). described the case of a 33-year-old pregnant woman who developed progressive interstitial pneumonia (IP) complicated by anti Jo-1 positive ASS at 28 weeks of gestation. At 30 weeks of her gestation, since the neonate could be treated at the neonatal intensive care unit after delivery, an emergency cesarean section was performed. The patient was eventually successfully treated with a combination of immunosuppressive therapy including intravenous methylprednisolone pulse therapy (1 g/day) and IVCY and the use of high flow nasal cannula oxygen therapy without intubation. In another case report, a pregnant woman at 16 weeks of gestation had developed IP preceding anti Jo-1 positive ASS, and was treated with a combination of steroid pulse therapy and tacrolimus. The fetus did not survive since it was too small, and the maternal condition deteriorated (26). To the best of our knowledge, the present case study is the first reported case of a patient having been diagnosed with anti-MDA5-positive RP-ILD complicated with CADM. In our case, artificial abortion was conducted because the maternal condition was unstable. The influences of high dose steroids and the CT scan were also taken into consideration. After combining steroid pulse and immunosuppressive therapy, the maternal condition gradually improved and our patient had complete remission without residual pulmonary interstitial changes. In anti-MDA5-positive patients with CADM, the CT scans usually show ground-glass opacities and bilateral subpleural reticular opacities, predominantly in the lower lungs, which would improve substantially or become stable after combination immunosuppressive therapy (29, 30). The present report describes a pregnant woman with CADM with positive anti-MDA5 antibody, who developed RP-ILD and subsequently achieved complete remission without residual pulmonary interstitial changes after treatment, which has been rarely reported in the previous literature. It is difficult to save the fetal lives in CADM patients with anti-MDA5 antibody. Because it was dispensable to use combination of high dose corticosteroids and immunosuppressive agents including IVCY in CADM patients even if they were in pregnancy.
Certain biological parameters have been evaluated for their ability to predict the disease activity, occurrence, and outcomes of patients with CADM. As mentioned above, both anti-MDA5 antibodies and RP-ILD are crucial predictors. Furthermore, LDH, Krebs von den Lungen 6 (KL-6), serum surfactant protein D (SP-D), ferritin level, and the HRCT imaging score are also associated with prognosis of the disease (14, 31). In this case, the patient’s ferritin level was elevated when her respiratory condition continued to worsen, which also suggested a poor prognosis in our patient. Recently, Lian et al. established a simple and practical score model to predict the prognosis of patients with ADM-ILD (31). According to this model, our patient was at least in the medium risk group, with a score of 5 (three points for anti-MDA5 antibodies, and two points for RP-ILD). Despite the fact that not all patients with this antibody develop lethal ILD, one possible explanation may be that all of the patients who have this particular antibody may undergo an early stage of disease, with only a skin rash or skin rash accompanied by arthralgia. They subsequently develop asymptomatic ILD, which progresses to RP-ILD if left untreated (32). The main limitation of the current study is that this is a case report, and several cases of CADM and DM developing during pregnancy have been previously described. However, we have made a comprehensive review, and to be best of our knowledge, this is the first case study depicting a pregnant patient with anti-MDA5-positive RP-ILD complicated with CADM. Notably, the patient finally achieved complete remission without residual pulmonary interstitial changes, indicating the importance of early intervention with combined immunosuppressive therapy in such patients.
Concluding Remarks
The present case study has reported on a case of a 38-year-old pregnant woman at 7 weeks of gestation who developed RP-ILD due to CADM with positive anti-MDA5 antibody. She achieved complete remission following early intervention of combination immunosuppressive therapy without residual pulmonary interstitial changes.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
CC and YC summarized the case, reviewed the literature, and drafted the manuscript. QinH and QiuH drafted the manuscript. XH reviewed and summarized the case. All authors contributed to the article and approved the submitted version.
Funding
The research is supported by Shenzhen Key Medical Discipline Construction Fund (no. SZXK011), Shenzhen Health Plan Committee Research Foundation (no. SZXJ2018021), Shenzhen Science and Technology Plan Program (no. JCYJ20190807144418845), and Sanming Project of Medicine in Shenzhen (no. SYJY201901).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors wish to thank the patient in this study.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.625495/full#supplementary-material
Click here for additional data file. | Oral | DrugAdministrationRoute | CC BY | 33717138 | 19,108,899 | 2021 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.
Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors' knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.
Introduction
Dermatomyositis (DM) is a spectrum of muscle myalgia and weakness, with typical skin manifestations, including heliotrope rash and Gottron’s sign. Clinically amyopathic dermatomyositis (CADM) is an independent spectrum of classic DM with typical skin lesions and minimal or absent muscle disease (1). It has been reported that the prevalence of CADM in all patients with dermatomyositis is 5%–20% (2). Rapidly progressive interstitial lung disease (RP-ILD) is common in CADM patients with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody (3), which tends to be treatment-refractory with a poor prognosis (4). The onset of CADM during pregnancy is extremely rare and the outcome of pregnancy in these patients is poor for both mother and fetus, including maternal and fetal death, as well as prematurity (5, 6). The present case study reports on a pregnant woman with CADM with the positive anti-MDA5 antibody, who developed RP-ILD during her first 7 weeks of gestation. She was successfully treated with combined immunosuppressive therapy without residual pulmonary interstitial changes.
Case Presentation
A 38-year-old woman with a 7-week pregnancy was admitted to our hospital with complaints of dry cough, dyspnea on exertion, and a rash over the face, neck, and dorsum of the hands for 23 days and polyarthritis for 2 days ( Figure 1A ). Prior to admission, she was treated with loratadine without resolution, and her symptoms gradually worsened. Her past medical history was unremarkable.
Figure 1 Clinical presentation of the patient (A) on admission and (B) after recovery.
Physical examination on admission revealed a high body mass index of 33.1, heliotrope rash, Gottron’s papules and fine crackles audible bilaterally in the lower lung fields. No signs of muscle weakness or pain were present. The patient had tachycardia (113 beats/min) with normal oxygen saturation. Laboratory findings revealed the levels of creatine phosphokinase (CK; reference range, 25–192) to be 171 U/l, lactate dehydrogenase (LDH; reference range, 110–240) to be 441 U/l, alanine transaminase (AST; reference range, 0–40) to be 50 U/l, C-reactive protein (CRP; reference range, <5) to be 30.94 mg/l, erythrocyte sedimentation rate (ESR, reference range, 0–20) to be 53 mm/h, and ferritin (reference range, 11.0–306.8) to be 167.3 ng/ml. The main laboratory results are shown in Table 1 . No evidence was identified that may have suggested infection or malignancy, and therefore CADM was suspected in this patient. She was treated with 24 mg/day of oral methylprednisolone for 3 days, along with 400 mg/day of hydroxychloroquine in her first week of admission. However, the patient’s respiratory condition continued to worsen with percutaneous blood oxygen saturation decreasing to 88% under use of low- flow nasal cannula oxygen and therefore she was given oxygen by way of medium-flow mask oxygen. Moreover, she was unable to complete the pulmonary function test due to the rapid deterioration of the respiratory status.
Table 1 Laboratory findings on admission.
Parameter Value Reference range
Leukocytes (109/L) 3.6 4–10
Erythrocytes (1012/L) 4.76 3.5–5
Hemoglobin (g/L) 129 110–150
Platelets (109/L) 251 100–300
Glucose (mmol/L) 4.89 3.9–6.1
Cholesterol (mmol/L) 3.46 3.4–6.5
HDL (mmol/L) 0.94 0.9–1.91
LDL (mmol/L) 1.69 2.08–4.14
AST (U/L) 50 0–40
ALT (U/L) 48 0–45
ALP (U/L) 61 15–121
CK (U/L) 171 25–192
LDH (U/L) 441 110–240
Urea nitrogen (mmol/L) 2.79 2.5–7.5
Creatinie (µmol/L) 64 44–133
IgG (g/L) 10.21 8–18
Ferritin level (µg/L) 167.3 11.0–306.8
24-h urine protein (g/24 h) 0.216 0.028–0.141
ESR (mm/h) 53 0–20
CRP (mg/L) 30.94 <5
PCT (ng/ml) <0.05 <0.05
C3 (g/L) 1.28 0.80–1.81
C4 (g/L) 0.32 0.15–0.57
Coombs’ test Negative Negative
RF (IU/mL) 7.3 <25
Anti-CCP Negative Negative
cANCA Negative Negative
anti-PR3 Negative Negative
pANCA Negative Negative
anti-MPO Negative Negative
ANA Negative Negative
Anti-centromere Negative Negative
Anti-dsDNA Negative Negative
Anti-SS-A Negative Negative
Anti-SS-B Negative Negative
Anti-MDA5 Strongly positive Negative
Anti-tRNA synthase autoantibody panel Negative Negative
HDL, high-density lipoprotein; LDL, low density lipoprotein; AST, alanine transaminase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CK, creatine phosphokinase; LDH, lactic dehydrogenase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PCT, procalcitonin; RF, rheumatoid factor; C3, complement C3; C4, complement C4; Anti-MDA5, anti-melanoma differentiation-associated gene 5. Anti-CCP, anti-cyclic citrullinated peptide antibody; cANCA, cytoplasmic-staining anti-neutrophil cytoplasm antibody; pANCA, perinuclear-staining anti-neutrophil cytoplasm antibody; Anti-MPO, anti-myeloperoxidase antibody; Anti-PR3, anti-proteinase 3 antibody; ANA, anti-nuclear antibodies; Anti-dsDNA, anti-double-stranded (ds) DNA antibody; Anti-SS-A, anti-Sjögren's syndrome antigen A antibody; Anti-SS-B, anti-Sjögren's syndrome antigen B antibody.
Further tests revealed that her anti-MDA5 antibody was positive. The high-resolution computed tomography (HRCT) scan on day 7 revealed reticular shadows, patchy ground glass opacities and inflammation in both lungs ( Figure 2A ). On the basis of these findings, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made. According to the results of a multi-disciplinary discussion, on day 10, the patient was treated with combination therapy including methylprednisolone (1.0 mg/kg/day, that is, 80 mg/day) accompanied by oral cyclosporine (100 mg twice a day) and intravenous cyclophosphamide (IVCY, 400 mg/week) following high dose pulsed methylprednisolone at 500 mg/day for 3 days and intravenous immunoglobulin (IVIG, 20 g/day for 3 days). Considering her worsening condition, artificial abortion was conducted on day 10 with her permission. The respiratory condition of the patient improved gradually. A chest CT scan performed on day 21 of hospitalization revealed a patchy density shadow that had significantly decreased compared with its appearance previously ( Figure 2B ). The patient was discharged while being treated with methylprednisolone at 80 mg/day, cyclosporine at 200 mg/day, IVCY at 400 mg/2 weeks.
Figure 2 Changes in chest computed tomography scan findings (A) on admission, (B) before discharge and (C) after recovery.
Because of the significant improvement in her respiratory condition, we decided to taper the methylprednisolone and IVCY dose gradually. During the follow up, the patient achieved complete remission, her rash disappeared ( Figure 1B ) and the chest CT scan revealed that the patient had returned to the normal state after treatment for 10 months ( Figure 2C ). IVCY treatment was discontinued after treatment for 14 months, and anti-MDA5 antibody was negative after treatment for 24 months. At the time of writing this report, the patient was being treated with 4 mg/day methylprednisolone and 75 mg/day cyclosporine. The clinical course of the patient is shown in Figure 3 .
Figure 3 Clinical course of the patient. mPSL, methylprednisolone; Pulse: intravenous methylprednisolone pulse therapy (500 mg/d×3 days); IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; CyA, cyclosporine A; IVCY, intravenous cyclophosphamide; O2, oxygen; Anti-MDA5, anti-melanoma differentiation-associated gene 5 antibody; ++, strongly positive; +, positive; −, negative.
Discussion
Inflammatory myopathies are a spectrum of systemic immune-mediated disorders characterized by muscle inflammation, and affecting extramuscular organs, including skin, joints, and lungs. It is widely recognized that there are five main types of inflammatory myopathies: DM, polymyositis (PM), overlap myositis (including anti-synthetase syndrome (ASS)), inclusion-body myositis, and immune-mediated necrotizing myopathy (7, 8). RP-ILD was mainly defined as progressive dyspnea, or according to HRCT findings secondary to ILD within 3 months after the onset of respiratory symptoms (9, 10). RP-ILD often occurs as a complication of CADM, which usually portends poor prognosis with reported mortality rates in the first year as high as 60% (11). Anti-MDA5 antibodies were first identified by Sato et al. in 2005 in Japanese patients with CADM (12). Since that discovery, anti-MDA5 antibodies have predominantly been found in cases of CADM (13). Mortality rates ranged from 36%–46% in anti-MDA5 positive patients with CADM or DM (14). Anti-MDA5 antibodies have also been associated with RP-ILD, as identified in 39%–100% of patients with RP-ILD in Asian cohorts (15). The cumulative 6-month survival rate was reported to be about 50% for RP-ILD patients with the anti-MDA5 antibody (16). Hence, anti-MDA5 antibodies can be a useful predictor for the complication of RP-ILD in patients with CADM. In the present case study, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made as the patient experienced respiratory symptoms from the beginning, and her respiratory status deteriorated rapidly within one month. It has been suggested that immunosuppressants should be used early in patients with RP-ILD, since the damage caused to the pulmonary tissue may be irreversible once CADM is complicated by RP-ILD, which may result in the patient being irresponsive to combination immunosuppressive therapy, leading to death after only a few months (17). However, the use of immunosuppressants may not ensure rapid remission of the patient’s condition (18). It was reported that combination immunosuppressive therapy consisting of high-dose corticosteroids, cyclosporine and intravenous immunoglobulin might be effective for CADM patients with RP-ILD (16). Moreover, previous studies have also shown that patients with RP-ILD or respiratory failure may benefit from the use of basiliximab, mycophenolate mofetil or cyclophosphamide (19, 20).
The onset of DM during pregnancy is a rare event. It has been reported that one in 173 female patients with DM/PM experienced disease onset during pregnancy (21). Pregnancy outcomes are closely associated with the disease activity during pregnancy. Patients with quiescent disease before pregnancy have good pregnancy outcomes. By contrast, a pre-existing active condition or onset of DM during pregnancy leads to a high frequency of premature delivery and fetal death (21).
There are several factors that may explain the trigger for development of DM during pregnancy, such as changes in maternal hormonal status, exposure of the mother to fetal antigens, and the reactivation of certain viruses due to pregnancy (6). In addition, a high body mass index was noticed in the patient. Previous studies have revealed that obesity is a metabolic disease which may lead to the activation of the immune system and a consequently worse prognosis (22). Moreover, the obese are prone to respiratory failure even with mild pulmonary challenge (23). Hence, the rapid deterioration of the respiratory status in this patient may be partially explained by her high body mass index.
In view of these considerations, the onset of CADM during pregnancy is a problematic issue to be resolved for both physicians and patients. Treatment regimen should consider the safety of both the mother and the fetus, which requires individualized therapy. Glucocorticoids are the first line treatment in pregnant patients with DM (24). In certain rare cases, the use of glucocorticoids has been demonstrated to lead to a good outcome (6). However, certain patients have been shown to be non-responsive or intolerant to glucocorticoids (24). A previous study illustrated that gestational exposure to glucocorticoids led to a slight increase in the risk of premature birth and fetal oral cleft (25). Efficacy and safety of IVIG during pregnancy has been well documented in DM, especially for refractory cases (24, 25). In a previously published case report, short term remission was achieved following treatment with IVIG (4.5 g for 3 consecutive days) (25).
Examples of clinical case studies for treating pregnant patients with DM or PM, especially CADM, are relatively rare, and case studies of a similar nature that we were able to identify are shown in supplementary material (18, 26–28). Tomohiro et al (18). described the case of a 33-year-old pregnant woman who developed progressive interstitial pneumonia (IP) complicated by anti Jo-1 positive ASS at 28 weeks of gestation. At 30 weeks of her gestation, since the neonate could be treated at the neonatal intensive care unit after delivery, an emergency cesarean section was performed. The patient was eventually successfully treated with a combination of immunosuppressive therapy including intravenous methylprednisolone pulse therapy (1 g/day) and IVCY and the use of high flow nasal cannula oxygen therapy without intubation. In another case report, a pregnant woman at 16 weeks of gestation had developed IP preceding anti Jo-1 positive ASS, and was treated with a combination of steroid pulse therapy and tacrolimus. The fetus did not survive since it was too small, and the maternal condition deteriorated (26). To the best of our knowledge, the present case study is the first reported case of a patient having been diagnosed with anti-MDA5-positive RP-ILD complicated with CADM. In our case, artificial abortion was conducted because the maternal condition was unstable. The influences of high dose steroids and the CT scan were also taken into consideration. After combining steroid pulse and immunosuppressive therapy, the maternal condition gradually improved and our patient had complete remission without residual pulmonary interstitial changes. In anti-MDA5-positive patients with CADM, the CT scans usually show ground-glass opacities and bilateral subpleural reticular opacities, predominantly in the lower lungs, which would improve substantially or become stable after combination immunosuppressive therapy (29, 30). The present report describes a pregnant woman with CADM with positive anti-MDA5 antibody, who developed RP-ILD and subsequently achieved complete remission without residual pulmonary interstitial changes after treatment, which has been rarely reported in the previous literature. It is difficult to save the fetal lives in CADM patients with anti-MDA5 antibody. Because it was dispensable to use combination of high dose corticosteroids and immunosuppressive agents including IVCY in CADM patients even if they were in pregnancy.
Certain biological parameters have been evaluated for their ability to predict the disease activity, occurrence, and outcomes of patients with CADM. As mentioned above, both anti-MDA5 antibodies and RP-ILD are crucial predictors. Furthermore, LDH, Krebs von den Lungen 6 (KL-6), serum surfactant protein D (SP-D), ferritin level, and the HRCT imaging score are also associated with prognosis of the disease (14, 31). In this case, the patient’s ferritin level was elevated when her respiratory condition continued to worsen, which also suggested a poor prognosis in our patient. Recently, Lian et al. established a simple and practical score model to predict the prognosis of patients with ADM-ILD (31). According to this model, our patient was at least in the medium risk group, with a score of 5 (three points for anti-MDA5 antibodies, and two points for RP-ILD). Despite the fact that not all patients with this antibody develop lethal ILD, one possible explanation may be that all of the patients who have this particular antibody may undergo an early stage of disease, with only a skin rash or skin rash accompanied by arthralgia. They subsequently develop asymptomatic ILD, which progresses to RP-ILD if left untreated (32). The main limitation of the current study is that this is a case report, and several cases of CADM and DM developing during pregnancy have been previously described. However, we have made a comprehensive review, and to be best of our knowledge, this is the first case study depicting a pregnant patient with anti-MDA5-positive RP-ILD complicated with CADM. Notably, the patient finally achieved complete remission without residual pulmonary interstitial changes, indicating the importance of early intervention with combined immunosuppressive therapy in such patients.
Concluding Remarks
The present case study has reported on a case of a 38-year-old pregnant woman at 7 weeks of gestation who developed RP-ILD due to CADM with positive anti-MDA5 antibody. She achieved complete remission following early intervention of combination immunosuppressive therapy without residual pulmonary interstitial changes.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
CC and YC summarized the case, reviewed the literature, and drafted the manuscript. QinH and QiuH drafted the manuscript. XH reviewed and summarized the case. All authors contributed to the article and approved the submitted version.
Funding
The research is supported by Shenzhen Key Medical Discipline Construction Fund (no. SZXK011), Shenzhen Health Plan Committee Research Foundation (no. SZXJ2018021), Shenzhen Science and Technology Plan Program (no. JCYJ20190807144418845), and Sanming Project of Medicine in Shenzhen (no. SYJY201901).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors wish to thank the patient in this study.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.625495/full#supplementary-material
Click here for additional data file. | Oral | DrugAdministrationRoute | CC BY | 33717138 | 19,108,899 | 2021 |
What was the administration route of drug 'OXYGEN'? | Case Report: Rapidly Progressive Interstitial Lung Disease in A Pregnant Patient With Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis.
Dermatomyositis occurs extremely rarely during pregnancy. A number of studies in the published literature have documented how the outcome of pregnancy is poor for both mother and fetus. The present case study reports on a patient who was diagnosed with clinically amyopathic dermatomyositis complicated by interstitial lung disease during pregnancy, and was successfully treated with a combined immunosuppressant regimen. To the best of the authors' knowledge, this is the first case study detailing how a pregnant woman with clinically amyopathic dermatomyositis with positive anti-melanoma differentiation-associated gene 5 antibody achieved complete remission after early intervention of combined immunosuppressive therapy without residual pulmonary interstitial changes.
Introduction
Dermatomyositis (DM) is a spectrum of muscle myalgia and weakness, with typical skin manifestations, including heliotrope rash and Gottron’s sign. Clinically amyopathic dermatomyositis (CADM) is an independent spectrum of classic DM with typical skin lesions and minimal or absent muscle disease (1). It has been reported that the prevalence of CADM in all patients with dermatomyositis is 5%–20% (2). Rapidly progressive interstitial lung disease (RP-ILD) is common in CADM patients with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody (3), which tends to be treatment-refractory with a poor prognosis (4). The onset of CADM during pregnancy is extremely rare and the outcome of pregnancy in these patients is poor for both mother and fetus, including maternal and fetal death, as well as prematurity (5, 6). The present case study reports on a pregnant woman with CADM with the positive anti-MDA5 antibody, who developed RP-ILD during her first 7 weeks of gestation. She was successfully treated with combined immunosuppressive therapy without residual pulmonary interstitial changes.
Case Presentation
A 38-year-old woman with a 7-week pregnancy was admitted to our hospital with complaints of dry cough, dyspnea on exertion, and a rash over the face, neck, and dorsum of the hands for 23 days and polyarthritis for 2 days ( Figure 1A ). Prior to admission, she was treated with loratadine without resolution, and her symptoms gradually worsened. Her past medical history was unremarkable.
Figure 1 Clinical presentation of the patient (A) on admission and (B) after recovery.
Physical examination on admission revealed a high body mass index of 33.1, heliotrope rash, Gottron’s papules and fine crackles audible bilaterally in the lower lung fields. No signs of muscle weakness or pain were present. The patient had tachycardia (113 beats/min) with normal oxygen saturation. Laboratory findings revealed the levels of creatine phosphokinase (CK; reference range, 25–192) to be 171 U/l, lactate dehydrogenase (LDH; reference range, 110–240) to be 441 U/l, alanine transaminase (AST; reference range, 0–40) to be 50 U/l, C-reactive protein (CRP; reference range, <5) to be 30.94 mg/l, erythrocyte sedimentation rate (ESR, reference range, 0–20) to be 53 mm/h, and ferritin (reference range, 11.0–306.8) to be 167.3 ng/ml. The main laboratory results are shown in Table 1 . No evidence was identified that may have suggested infection or malignancy, and therefore CADM was suspected in this patient. She was treated with 24 mg/day of oral methylprednisolone for 3 days, along with 400 mg/day of hydroxychloroquine in her first week of admission. However, the patient’s respiratory condition continued to worsen with percutaneous blood oxygen saturation decreasing to 88% under use of low- flow nasal cannula oxygen and therefore she was given oxygen by way of medium-flow mask oxygen. Moreover, she was unable to complete the pulmonary function test due to the rapid deterioration of the respiratory status.
Table 1 Laboratory findings on admission.
Parameter Value Reference range
Leukocytes (109/L) 3.6 4–10
Erythrocytes (1012/L) 4.76 3.5–5
Hemoglobin (g/L) 129 110–150
Platelets (109/L) 251 100–300
Glucose (mmol/L) 4.89 3.9–6.1
Cholesterol (mmol/L) 3.46 3.4–6.5
HDL (mmol/L) 0.94 0.9–1.91
LDL (mmol/L) 1.69 2.08–4.14
AST (U/L) 50 0–40
ALT (U/L) 48 0–45
ALP (U/L) 61 15–121
CK (U/L) 171 25–192
LDH (U/L) 441 110–240
Urea nitrogen (mmol/L) 2.79 2.5–7.5
Creatinie (µmol/L) 64 44–133
IgG (g/L) 10.21 8–18
Ferritin level (µg/L) 167.3 11.0–306.8
24-h urine protein (g/24 h) 0.216 0.028–0.141
ESR (mm/h) 53 0–20
CRP (mg/L) 30.94 <5
PCT (ng/ml) <0.05 <0.05
C3 (g/L) 1.28 0.80–1.81
C4 (g/L) 0.32 0.15–0.57
Coombs’ test Negative Negative
RF (IU/mL) 7.3 <25
Anti-CCP Negative Negative
cANCA Negative Negative
anti-PR3 Negative Negative
pANCA Negative Negative
anti-MPO Negative Negative
ANA Negative Negative
Anti-centromere Negative Negative
Anti-dsDNA Negative Negative
Anti-SS-A Negative Negative
Anti-SS-B Negative Negative
Anti-MDA5 Strongly positive Negative
Anti-tRNA synthase autoantibody panel Negative Negative
HDL, high-density lipoprotein; LDL, low density lipoprotein; AST, alanine transaminase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CK, creatine phosphokinase; LDH, lactic dehydrogenase; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PCT, procalcitonin; RF, rheumatoid factor; C3, complement C3; C4, complement C4; Anti-MDA5, anti-melanoma differentiation-associated gene 5. Anti-CCP, anti-cyclic citrullinated peptide antibody; cANCA, cytoplasmic-staining anti-neutrophil cytoplasm antibody; pANCA, perinuclear-staining anti-neutrophil cytoplasm antibody; Anti-MPO, anti-myeloperoxidase antibody; Anti-PR3, anti-proteinase 3 antibody; ANA, anti-nuclear antibodies; Anti-dsDNA, anti-double-stranded (ds) DNA antibody; Anti-SS-A, anti-Sjögren's syndrome antigen A antibody; Anti-SS-B, anti-Sjögren's syndrome antigen B antibody.
Further tests revealed that her anti-MDA5 antibody was positive. The high-resolution computed tomography (HRCT) scan on day 7 revealed reticular shadows, patchy ground glass opacities and inflammation in both lungs ( Figure 2A ). On the basis of these findings, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made. According to the results of a multi-disciplinary discussion, on day 10, the patient was treated with combination therapy including methylprednisolone (1.0 mg/kg/day, that is, 80 mg/day) accompanied by oral cyclosporine (100 mg twice a day) and intravenous cyclophosphamide (IVCY, 400 mg/week) following high dose pulsed methylprednisolone at 500 mg/day for 3 days and intravenous immunoglobulin (IVIG, 20 g/day for 3 days). Considering her worsening condition, artificial abortion was conducted on day 10 with her permission. The respiratory condition of the patient improved gradually. A chest CT scan performed on day 21 of hospitalization revealed a patchy density shadow that had significantly decreased compared with its appearance previously ( Figure 2B ). The patient was discharged while being treated with methylprednisolone at 80 mg/day, cyclosporine at 200 mg/day, IVCY at 400 mg/2 weeks.
Figure 2 Changes in chest computed tomography scan findings (A) on admission, (B) before discharge and (C) after recovery.
Because of the significant improvement in her respiratory condition, we decided to taper the methylprednisolone and IVCY dose gradually. During the follow up, the patient achieved complete remission, her rash disappeared ( Figure 1B ) and the chest CT scan revealed that the patient had returned to the normal state after treatment for 10 months ( Figure 2C ). IVCY treatment was discontinued after treatment for 14 months, and anti-MDA5 antibody was negative after treatment for 24 months. At the time of writing this report, the patient was being treated with 4 mg/day methylprednisolone and 75 mg/day cyclosporine. The clinical course of the patient is shown in Figure 3 .
Figure 3 Clinical course of the patient. mPSL, methylprednisolone; Pulse: intravenous methylprednisolone pulse therapy (500 mg/d×3 days); IVIG, intravenous immunoglobulin; HCQ, hydroxychloroquine; CyA, cyclosporine A; IVCY, intravenous cyclophosphamide; O2, oxygen; Anti-MDA5, anti-melanoma differentiation-associated gene 5 antibody; ++, strongly positive; +, positive; −, negative.
Discussion
Inflammatory myopathies are a spectrum of systemic immune-mediated disorders characterized by muscle inflammation, and affecting extramuscular organs, including skin, joints, and lungs. It is widely recognized that there are five main types of inflammatory myopathies: DM, polymyositis (PM), overlap myositis (including anti-synthetase syndrome (ASS)), inclusion-body myositis, and immune-mediated necrotizing myopathy (7, 8). RP-ILD was mainly defined as progressive dyspnea, or according to HRCT findings secondary to ILD within 3 months after the onset of respiratory symptoms (9, 10). RP-ILD often occurs as a complication of CADM, which usually portends poor prognosis with reported mortality rates in the first year as high as 60% (11). Anti-MDA5 antibodies were first identified by Sato et al. in 2005 in Japanese patients with CADM (12). Since that discovery, anti-MDA5 antibodies have predominantly been found in cases of CADM (13). Mortality rates ranged from 36%–46% in anti-MDA5 positive patients with CADM or DM (14). Anti-MDA5 antibodies have also been associated with RP-ILD, as identified in 39%–100% of patients with RP-ILD in Asian cohorts (15). The cumulative 6-month survival rate was reported to be about 50% for RP-ILD patients with the anti-MDA5 antibody (16). Hence, anti-MDA5 antibodies can be a useful predictor for the complication of RP-ILD in patients with CADM. In the present case study, a diagnosis of anti-MDA5 positive CADM with RP-ILD was made as the patient experienced respiratory symptoms from the beginning, and her respiratory status deteriorated rapidly within one month. It has been suggested that immunosuppressants should be used early in patients with RP-ILD, since the damage caused to the pulmonary tissue may be irreversible once CADM is complicated by RP-ILD, which may result in the patient being irresponsive to combination immunosuppressive therapy, leading to death after only a few months (17). However, the use of immunosuppressants may not ensure rapid remission of the patient’s condition (18). It was reported that combination immunosuppressive therapy consisting of high-dose corticosteroids, cyclosporine and intravenous immunoglobulin might be effective for CADM patients with RP-ILD (16). Moreover, previous studies have also shown that patients with RP-ILD or respiratory failure may benefit from the use of basiliximab, mycophenolate mofetil or cyclophosphamide (19, 20).
The onset of DM during pregnancy is a rare event. It has been reported that one in 173 female patients with DM/PM experienced disease onset during pregnancy (21). Pregnancy outcomes are closely associated with the disease activity during pregnancy. Patients with quiescent disease before pregnancy have good pregnancy outcomes. By contrast, a pre-existing active condition or onset of DM during pregnancy leads to a high frequency of premature delivery and fetal death (21).
There are several factors that may explain the trigger for development of DM during pregnancy, such as changes in maternal hormonal status, exposure of the mother to fetal antigens, and the reactivation of certain viruses due to pregnancy (6). In addition, a high body mass index was noticed in the patient. Previous studies have revealed that obesity is a metabolic disease which may lead to the activation of the immune system and a consequently worse prognosis (22). Moreover, the obese are prone to respiratory failure even with mild pulmonary challenge (23). Hence, the rapid deterioration of the respiratory status in this patient may be partially explained by her high body mass index.
In view of these considerations, the onset of CADM during pregnancy is a problematic issue to be resolved for both physicians and patients. Treatment regimen should consider the safety of both the mother and the fetus, which requires individualized therapy. Glucocorticoids are the first line treatment in pregnant patients with DM (24). In certain rare cases, the use of glucocorticoids has been demonstrated to lead to a good outcome (6). However, certain patients have been shown to be non-responsive or intolerant to glucocorticoids (24). A previous study illustrated that gestational exposure to glucocorticoids led to a slight increase in the risk of premature birth and fetal oral cleft (25). Efficacy and safety of IVIG during pregnancy has been well documented in DM, especially for refractory cases (24, 25). In a previously published case report, short term remission was achieved following treatment with IVIG (4.5 g for 3 consecutive days) (25).
Examples of clinical case studies for treating pregnant patients with DM or PM, especially CADM, are relatively rare, and case studies of a similar nature that we were able to identify are shown in supplementary material (18, 26–28). Tomohiro et al (18). described the case of a 33-year-old pregnant woman who developed progressive interstitial pneumonia (IP) complicated by anti Jo-1 positive ASS at 28 weeks of gestation. At 30 weeks of her gestation, since the neonate could be treated at the neonatal intensive care unit after delivery, an emergency cesarean section was performed. The patient was eventually successfully treated with a combination of immunosuppressive therapy including intravenous methylprednisolone pulse therapy (1 g/day) and IVCY and the use of high flow nasal cannula oxygen therapy without intubation. In another case report, a pregnant woman at 16 weeks of gestation had developed IP preceding anti Jo-1 positive ASS, and was treated with a combination of steroid pulse therapy and tacrolimus. The fetus did not survive since it was too small, and the maternal condition deteriorated (26). To the best of our knowledge, the present case study is the first reported case of a patient having been diagnosed with anti-MDA5-positive RP-ILD complicated with CADM. In our case, artificial abortion was conducted because the maternal condition was unstable. The influences of high dose steroids and the CT scan were also taken into consideration. After combining steroid pulse and immunosuppressive therapy, the maternal condition gradually improved and our patient had complete remission without residual pulmonary interstitial changes. In anti-MDA5-positive patients with CADM, the CT scans usually show ground-glass opacities and bilateral subpleural reticular opacities, predominantly in the lower lungs, which would improve substantially or become stable after combination immunosuppressive therapy (29, 30). The present report describes a pregnant woman with CADM with positive anti-MDA5 antibody, who developed RP-ILD and subsequently achieved complete remission without residual pulmonary interstitial changes after treatment, which has been rarely reported in the previous literature. It is difficult to save the fetal lives in CADM patients with anti-MDA5 antibody. Because it was dispensable to use combination of high dose corticosteroids and immunosuppressive agents including IVCY in CADM patients even if they were in pregnancy.
Certain biological parameters have been evaluated for their ability to predict the disease activity, occurrence, and outcomes of patients with CADM. As mentioned above, both anti-MDA5 antibodies and RP-ILD are crucial predictors. Furthermore, LDH, Krebs von den Lungen 6 (KL-6), serum surfactant protein D (SP-D), ferritin level, and the HRCT imaging score are also associated with prognosis of the disease (14, 31). In this case, the patient’s ferritin level was elevated when her respiratory condition continued to worsen, which also suggested a poor prognosis in our patient. Recently, Lian et al. established a simple and practical score model to predict the prognosis of patients with ADM-ILD (31). According to this model, our patient was at least in the medium risk group, with a score of 5 (three points for anti-MDA5 antibodies, and two points for RP-ILD). Despite the fact that not all patients with this antibody develop lethal ILD, one possible explanation may be that all of the patients who have this particular antibody may undergo an early stage of disease, with only a skin rash or skin rash accompanied by arthralgia. They subsequently develop asymptomatic ILD, which progresses to RP-ILD if left untreated (32). The main limitation of the current study is that this is a case report, and several cases of CADM and DM developing during pregnancy have been previously described. However, we have made a comprehensive review, and to be best of our knowledge, this is the first case study depicting a pregnant patient with anti-MDA5-positive RP-ILD complicated with CADM. Notably, the patient finally achieved complete remission without residual pulmonary interstitial changes, indicating the importance of early intervention with combined immunosuppressive therapy in such patients.
Concluding Remarks
The present case study has reported on a case of a 38-year-old pregnant woman at 7 weeks of gestation who developed RP-ILD due to CADM with positive anti-MDA5 antibody. She achieved complete remission following early intervention of combination immunosuppressive therapy without residual pulmonary interstitial changes.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shenzhen People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
CC and YC summarized the case, reviewed the literature, and drafted the manuscript. QinH and QiuH drafted the manuscript. XH reviewed and summarized the case. All authors contributed to the article and approved the submitted version.
Funding
The research is supported by Shenzhen Key Medical Discipline Construction Fund (no. SZXK011), Shenzhen Health Plan Committee Research Foundation (no. SZXJ2018021), Shenzhen Science and Technology Plan Program (no. JCYJ20190807144418845), and Sanming Project of Medicine in Shenzhen (no. SYJY201901).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
The authors wish to thank the patient in this study.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.625495/full#supplementary-material
Click here for additional data file. | Respiratory (inhalation) | DrugAdministrationRoute | CC BY | 33717138 | 19,108,899 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | A case of Dressler's syndrome successfully treated with colchicine and acetaminophen.
The incidence of Dressler's syndrome after myocardial infarction (MI) has decreased in the reperfusion therapy era. Although guidelines recommend high-dose aspirin for treatment based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era, bleeding and thrombotic concerns occurred upon aspirin administration after coronary stenting. A 69-year-old man with recent MI was admitted to our hospital. The patient presented with chest pain 1 week before admission. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change. Urgent coronary angiography demonstrated a left circumflex artery occlusion. He underwent PCI, and a sirolimus-eluting stent was deployed. Aspirin, prasugrel, and apixaban were administered. However, hospital discharge was delayed because he developed heart failure during hospitalization. Twenty-three days after admission, he developed a fever of >39 °C. Electrocardiography showed anterior ST segment elevation, and echocardiography revealed a 6-mm pericardial effusion. We diagnosed the patient with Dressler's syndrome, and colchicine 0.5 mg/day + acetaminophen 2000 mg/day were administered. His condition clinically improved after treatment and he was discharged 32 days after admission. There was hesitation about administration of high-dose aspirin in a patient who has undergone recent coronary stenting. Combination therapy of colchicine and acetaminophen could be a treatment option for Dressler's syndrome. <Learning objective: Guidelines recommend high-dose aspirin for the treatment of Dressler's syndrome based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era. However, bleeding and thrombotic concerns are present upon high-dose aspirin administration in patients who have undergone PCI. Therefore, a combination therapy of low-dose colchicine and acetaminophen could be a treatment option for patients with Dressler's syndrome who have undergone recent coronary stenting.>.
Introduction
The incidence of Dressler’s syndrome has decreased owing to reperfusion therapy. It can now be experienced only in patients with recent myocardial infarction (MI) who have not undergone primary percutaneous coronary intervention (PCI). Although guidelines recommend high-dose aspirin administration for the treatment of Dressler’s syndrome [1], [2], [3], the background evidence for these recommendations was amassed in the pre-PCI era. Although coronary stenting has become a standard therapy against MI, bleeding and thrombotic concerns on high-dose aspirin administration have occurred in the modern era. Herein, we present a case of Dressler’s syndrome successfully treated with colchicine and acetaminophen.
Case report
A 69-year-old man with no prior medical history visited a clinic for persistent chest discomfort. He presented with severe chest pain 1 week before admission; he was subsequently referred to our hospital for suspected acute coronary syndrome. On physical examination, the patient was afebrile with an irregular pulse of 108 beats/min and a blood pressure of 98/69 mmHg. The oxygen saturation was 98% on room air. No heart murmurs or edema were noted. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change (Fig. 1A). Moreover, echocardiography showed inferior-lateral wall asynergy, with mild mitral valve regurgitation and no pericardial effusion (Fig. 2A). Left ventricular contraction was preserved, with an ejection fraction of 50%. Laboratory tests showed an elevation of myocardial and liver enzymes and signs of heart failure as follows: white blood cell count, 11,000 cells/μL (neutrophils, 69%; eosinophils, 0.5%); C-reactive protein, 14.3 mg/dL; creatinine kinase (CK), 197 U/L; CK-muscle/brain, 7 U/L; troponin I, 4.4 ng/mL; B-type natriuretic peptide, 357 pg/mL; aspartate transaminase, 81 U/L; alanine aminotransferase, 77 U/L; and total bilirubin level, 2.1 mg/dL. Chest radiography revealed mild left pleural effusion with no congestion. Urgent coronary angiography demonstrated a middle left circumflex artery occlusion (Online Fig. S1). The patient underwent PCI, and a sirolimus-eluting stent was successfully deployed. The levels of myocardial enzymes were monitored by laboratory tests every 4 h after admission, although no CK elevation was noted. Considering the clinical course and results from the examinations, we diagnosed the patient with recent MI, which developed 1 week before admission. We administered aspirin 100 mg/day, prasugrel 3.75 mg/day, and apixaban 10 mg/day as antithrombotic therapy. Hospital discharge was delayed because of worsening heart failure. Considering the high bleeding risk, we reduced antiplatelet drugs to clopidogrel 75 mg/day (single antiplatelet therapy) on post-admission day 14. On post-admission day 23, the patient developed a fever of 39.6 °C and experienced a left lateral chest pain. Pericardial friction rub was audible on auscultation with the forward leaning position. Widespread ST segment elevation and PR segment depression were demonstrated in the electrocardiogram (Fig. 1B). No signs of infection or acute coronary syndrome were detected after performing laboratory tests, urinary test, computed tomography, echocardiography, and coronary angiography. The eosinophil count increased to 5.1% (291 cells/μL) in the laboratory test, and echocardiography revealed a newly detected pericardial effusion of 6 mm (Fig. 2B). We diagnosed the patient as having Dressler’s syndrome and administered colchicine and acetaminophen at 0.5 and 2000 mg/day, respectively. His physical signs and laboratory data improved within several days, and he was discharged on post-admission day 32 (Online Fig. S2).Fig. 1 Electrocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge.
Fig. 1
Fig. 2 Echocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge. The yellow arrowhead indicates the pericardial effusion.
Fig. 2
Three months later, his widespread ST segment elevation had returned to normal (Fig. 1C), and his pericardial effusion had improved (Fig. 2C). Colchicine 0.5 mg/day was continued without any side effects for 6 months, with no recurrence in symptoms noted or examinations repeated (Figs. 1D, 2D).
Discussion
We report a patient with Dressler’s syndrome successfully treated with colchicine and acetaminophen. Dressler’s syndrome, which is a secondary form of pericarditis that is typically demonstrated weeks to months after MI, is presumed to be mediated by an autoimmune mechanism [2]. The incidence of this syndrome has remarkably decreased in the reperfusion therapy era and is reported as only 0.1% in patients with acute MI [4].
High-dose aspirin administration (2000–4000 mg/day) is recommended as class I therapy in guidelines [1], [2], [3], and administration of other non-steroidal anti-inflammatory drugs should be avoided because they may impair scar formation [5] or diminish coronary blood flow [6]. Corticosteroids are suggested as a second option because of the risk of favoring the chronic evolution of the disease and promoting drug dependence [1]. However, the background evidence for these recommendations was amassed in the pre-PCI era, and there is no established treatment after primary PCI has become a standard therapy. Fig. 3 shows the history of PCI and the evidence of high-dose aspirin administration against Dressler’s syndrome over time. Dressler’s syndrome was first reported in 1956. The beneficial effects of aspirin were reported around the 1970s, which was before coronary stenting became a standard therapy in the 1990s. Evidence is lacking after primary PCI has become a standard therapy in MI patients due to the decreased morbidity.Fig. 3 The history of percutaneous coronary intervention and the evidence of high-dose aspirin administration against Dressler’s syndrome over time.
Fig. 3
There are thrombotic and bleeding concerns in the administration of high-dose aspirin in patients who underwent recent coronary stenting or those who take other antithrombotic drugs. High-dose aspirin may have a different antithrombotic effect compared with the low dose, a complex mechanism known as the aspirin dilemma. Aspirin inhibits two major mechanisms to obtain antithrombotic effects: platelet thromboxane-A2 production and cyclooxygenase enzyme in the vascular endothelium [7]. The antithrombotic effect differs according to the aspirin dose. While lower doses inhibit the endothelial cyclooxygenase activity mildly, higher doses can achieve the inhibition more completely and rapidly, which may weaken the antithrombotic effect [7]. Aspirin dilemma is a mechanism that occurs with high-dose aspirin and might have thrombotic concerns compared with the low dose. Therefore, we decided to continue clopidogrel and apixaban as antithrombotic therapy instead of prescribing high-dose aspirin. As atrial fibrillation was not observed after successful reperfusion therapy, there was an option to stop anticoagulants (i.e. apixaban). However, since the patient had developed heart failure during hospitalization, his CHA2DS2-VASc score was 3 points (age ≥65 years, heart failure, and vascular disease). Considering the result from the Canadian Registry of Atrial Fibrillation study that approximately half of all newly detected atrial fibrillations would recur [8], we chose to continue anticoagulants in this patient.
Colchicine is an anti-inflammatory medication that targets the white blood cells and causes microtubule depolymerization, which in turn causes motility, phagocytosis, and degranulation. It also inhibits interleukin-1 beta and interleukin-18 by interfering with the NLRP3 inflammasome protein complex, which is increasingly recognized to have a role in acute coronary syndrome. In addition to the fact that colchicine is an inexpensive drug with only a few reports of serious side effects, it may reduce adverse cardiovascular events [9] or recurrent pericarditis [1]. Under these circumstances, we suggest that colchicine administration could be a treatment option for Dressler’s syndrome.
Although the pathogenesis of early post-infarction pericarditis (typically a few days after acute MI) is believed to be different from that of Dressler’s syndrome, combination therapy of high-dose aspirin and colchicine is recommended for treatment. Colchicine is already reported as a useful agent for acute pericarditis to improve remission rates in the acute phase and reduce recurrence rates in the chronic phase [10]. From these reports, combination therapy of colchicine and acetaminophen can be one of the treatment options for acute pericarditis in patients with an indeterminate response to high-dose aspirin administration.
In the present case, there was hesitation about high-dose aspirin administration because the patient had undergone recent coronary stenting, and clopidogrel + apixaban were already prescribed. We successfully treated the patient with low-dose colchicine and acetaminophen without any side effects. Considering the risk of aspirin dilemma and the reported beneficial effect against recent MI, combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting. The pharmacological mechanism of aspirin dilemma remains unclear and further research is necessary. As a limitation of this case report, the use of colchicine for Dressler’s syndrome is not covered by insurance in Japan, and careful informed consent is necessary upon prescription. Furthermore, although guidelines recommend continuing colchicine for 3–6 months [3], it remains unclear when to stop the therapy. In our case, we stopped prescribing colchicine after 6 months from discharge.
In conclusion, we experienced a case of Dressler’s syndrome that developed during hospitalization. There was hesitation about the administration of high-dose aspirin in a patient who has undergone recent coronary stenting due to thrombotic and bleeding concerns. Combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting.
Conflict of interest
The authors declare that there is no conflict of interest.
Appendix A Supplementary data
The following are Supplementary data to this article:Fig. S1
Coronary angiography. (A) The right coronary artery is normal (left anterior oblique 45° view). (B) A middle left circumflex artery occlusion is revealed (right anterior oblique caudal view, yellow arrowhead). (C) The patient underwent urgent percutaneous coronary intervention, and reperfusion was achieved.
Fig. S2
A chart showing the serial change of body temperature, white blood cell count (WBC), and C-reactive protein (CRP) after developing Dressler’s syndrome.
Acknowledgment
None.
Appendix A Supplementary material related to this article can be found, in the online version, at https://doi.org/10.1016/j.jccase.2020.10.019. | APIXABAN, ASPIRIN, PRASUGREL | DrugsGivenReaction | CC BY-NC-ND | 33717379 | 19,096,678 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dressler^s syndrome'. | A case of Dressler's syndrome successfully treated with colchicine and acetaminophen.
The incidence of Dressler's syndrome after myocardial infarction (MI) has decreased in the reperfusion therapy era. Although guidelines recommend high-dose aspirin for treatment based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era, bleeding and thrombotic concerns occurred upon aspirin administration after coronary stenting. A 69-year-old man with recent MI was admitted to our hospital. The patient presented with chest pain 1 week before admission. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change. Urgent coronary angiography demonstrated a left circumflex artery occlusion. He underwent PCI, and a sirolimus-eluting stent was deployed. Aspirin, prasugrel, and apixaban were administered. However, hospital discharge was delayed because he developed heart failure during hospitalization. Twenty-three days after admission, he developed a fever of >39 °C. Electrocardiography showed anterior ST segment elevation, and echocardiography revealed a 6-mm pericardial effusion. We diagnosed the patient with Dressler's syndrome, and colchicine 0.5 mg/day + acetaminophen 2000 mg/day were administered. His condition clinically improved after treatment and he was discharged 32 days after admission. There was hesitation about administration of high-dose aspirin in a patient who has undergone recent coronary stenting. Combination therapy of colchicine and acetaminophen could be a treatment option for Dressler's syndrome. <Learning objective: Guidelines recommend high-dose aspirin for the treatment of Dressler's syndrome based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era. However, bleeding and thrombotic concerns are present upon high-dose aspirin administration in patients who have undergone PCI. Therefore, a combination therapy of low-dose colchicine and acetaminophen could be a treatment option for patients with Dressler's syndrome who have undergone recent coronary stenting.>.
Introduction
The incidence of Dressler’s syndrome has decreased owing to reperfusion therapy. It can now be experienced only in patients with recent myocardial infarction (MI) who have not undergone primary percutaneous coronary intervention (PCI). Although guidelines recommend high-dose aspirin administration for the treatment of Dressler’s syndrome [1], [2], [3], the background evidence for these recommendations was amassed in the pre-PCI era. Although coronary stenting has become a standard therapy against MI, bleeding and thrombotic concerns on high-dose aspirin administration have occurred in the modern era. Herein, we present a case of Dressler’s syndrome successfully treated with colchicine and acetaminophen.
Case report
A 69-year-old man with no prior medical history visited a clinic for persistent chest discomfort. He presented with severe chest pain 1 week before admission; he was subsequently referred to our hospital for suspected acute coronary syndrome. On physical examination, the patient was afebrile with an irregular pulse of 108 beats/min and a blood pressure of 98/69 mmHg. The oxygen saturation was 98% on room air. No heart murmurs or edema were noted. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change (Fig. 1A). Moreover, echocardiography showed inferior-lateral wall asynergy, with mild mitral valve regurgitation and no pericardial effusion (Fig. 2A). Left ventricular contraction was preserved, with an ejection fraction of 50%. Laboratory tests showed an elevation of myocardial and liver enzymes and signs of heart failure as follows: white blood cell count, 11,000 cells/μL (neutrophils, 69%; eosinophils, 0.5%); C-reactive protein, 14.3 mg/dL; creatinine kinase (CK), 197 U/L; CK-muscle/brain, 7 U/L; troponin I, 4.4 ng/mL; B-type natriuretic peptide, 357 pg/mL; aspartate transaminase, 81 U/L; alanine aminotransferase, 77 U/L; and total bilirubin level, 2.1 mg/dL. Chest radiography revealed mild left pleural effusion with no congestion. Urgent coronary angiography demonstrated a middle left circumflex artery occlusion (Online Fig. S1). The patient underwent PCI, and a sirolimus-eluting stent was successfully deployed. The levels of myocardial enzymes were monitored by laboratory tests every 4 h after admission, although no CK elevation was noted. Considering the clinical course and results from the examinations, we diagnosed the patient with recent MI, which developed 1 week before admission. We administered aspirin 100 mg/day, prasugrel 3.75 mg/day, and apixaban 10 mg/day as antithrombotic therapy. Hospital discharge was delayed because of worsening heart failure. Considering the high bleeding risk, we reduced antiplatelet drugs to clopidogrel 75 mg/day (single antiplatelet therapy) on post-admission day 14. On post-admission day 23, the patient developed a fever of 39.6 °C and experienced a left lateral chest pain. Pericardial friction rub was audible on auscultation with the forward leaning position. Widespread ST segment elevation and PR segment depression were demonstrated in the electrocardiogram (Fig. 1B). No signs of infection or acute coronary syndrome were detected after performing laboratory tests, urinary test, computed tomography, echocardiography, and coronary angiography. The eosinophil count increased to 5.1% (291 cells/μL) in the laboratory test, and echocardiography revealed a newly detected pericardial effusion of 6 mm (Fig. 2B). We diagnosed the patient as having Dressler’s syndrome and administered colchicine and acetaminophen at 0.5 and 2000 mg/day, respectively. His physical signs and laboratory data improved within several days, and he was discharged on post-admission day 32 (Online Fig. S2).Fig. 1 Electrocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge.
Fig. 1
Fig. 2 Echocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge. The yellow arrowhead indicates the pericardial effusion.
Fig. 2
Three months later, his widespread ST segment elevation had returned to normal (Fig. 1C), and his pericardial effusion had improved (Fig. 2C). Colchicine 0.5 mg/day was continued without any side effects for 6 months, with no recurrence in symptoms noted or examinations repeated (Figs. 1D, 2D).
Discussion
We report a patient with Dressler’s syndrome successfully treated with colchicine and acetaminophen. Dressler’s syndrome, which is a secondary form of pericarditis that is typically demonstrated weeks to months after MI, is presumed to be mediated by an autoimmune mechanism [2]. The incidence of this syndrome has remarkably decreased in the reperfusion therapy era and is reported as only 0.1% in patients with acute MI [4].
High-dose aspirin administration (2000–4000 mg/day) is recommended as class I therapy in guidelines [1], [2], [3], and administration of other non-steroidal anti-inflammatory drugs should be avoided because they may impair scar formation [5] or diminish coronary blood flow [6]. Corticosteroids are suggested as a second option because of the risk of favoring the chronic evolution of the disease and promoting drug dependence [1]. However, the background evidence for these recommendations was amassed in the pre-PCI era, and there is no established treatment after primary PCI has become a standard therapy. Fig. 3 shows the history of PCI and the evidence of high-dose aspirin administration against Dressler’s syndrome over time. Dressler’s syndrome was first reported in 1956. The beneficial effects of aspirin were reported around the 1970s, which was before coronary stenting became a standard therapy in the 1990s. Evidence is lacking after primary PCI has become a standard therapy in MI patients due to the decreased morbidity.Fig. 3 The history of percutaneous coronary intervention and the evidence of high-dose aspirin administration against Dressler’s syndrome over time.
Fig. 3
There are thrombotic and bleeding concerns in the administration of high-dose aspirin in patients who underwent recent coronary stenting or those who take other antithrombotic drugs. High-dose aspirin may have a different antithrombotic effect compared with the low dose, a complex mechanism known as the aspirin dilemma. Aspirin inhibits two major mechanisms to obtain antithrombotic effects: platelet thromboxane-A2 production and cyclooxygenase enzyme in the vascular endothelium [7]. The antithrombotic effect differs according to the aspirin dose. While lower doses inhibit the endothelial cyclooxygenase activity mildly, higher doses can achieve the inhibition more completely and rapidly, which may weaken the antithrombotic effect [7]. Aspirin dilemma is a mechanism that occurs with high-dose aspirin and might have thrombotic concerns compared with the low dose. Therefore, we decided to continue clopidogrel and apixaban as antithrombotic therapy instead of prescribing high-dose aspirin. As atrial fibrillation was not observed after successful reperfusion therapy, there was an option to stop anticoagulants (i.e. apixaban). However, since the patient had developed heart failure during hospitalization, his CHA2DS2-VASc score was 3 points (age ≥65 years, heart failure, and vascular disease). Considering the result from the Canadian Registry of Atrial Fibrillation study that approximately half of all newly detected atrial fibrillations would recur [8], we chose to continue anticoagulants in this patient.
Colchicine is an anti-inflammatory medication that targets the white blood cells and causes microtubule depolymerization, which in turn causes motility, phagocytosis, and degranulation. It also inhibits interleukin-1 beta and interleukin-18 by interfering with the NLRP3 inflammasome protein complex, which is increasingly recognized to have a role in acute coronary syndrome. In addition to the fact that colchicine is an inexpensive drug with only a few reports of serious side effects, it may reduce adverse cardiovascular events [9] or recurrent pericarditis [1]. Under these circumstances, we suggest that colchicine administration could be a treatment option for Dressler’s syndrome.
Although the pathogenesis of early post-infarction pericarditis (typically a few days after acute MI) is believed to be different from that of Dressler’s syndrome, combination therapy of high-dose aspirin and colchicine is recommended for treatment. Colchicine is already reported as a useful agent for acute pericarditis to improve remission rates in the acute phase and reduce recurrence rates in the chronic phase [10]. From these reports, combination therapy of colchicine and acetaminophen can be one of the treatment options for acute pericarditis in patients with an indeterminate response to high-dose aspirin administration.
In the present case, there was hesitation about high-dose aspirin administration because the patient had undergone recent coronary stenting, and clopidogrel + apixaban were already prescribed. We successfully treated the patient with low-dose colchicine and acetaminophen without any side effects. Considering the risk of aspirin dilemma and the reported beneficial effect against recent MI, combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting. The pharmacological mechanism of aspirin dilemma remains unclear and further research is necessary. As a limitation of this case report, the use of colchicine for Dressler’s syndrome is not covered by insurance in Japan, and careful informed consent is necessary upon prescription. Furthermore, although guidelines recommend continuing colchicine for 3–6 months [3], it remains unclear when to stop the therapy. In our case, we stopped prescribing colchicine after 6 months from discharge.
In conclusion, we experienced a case of Dressler’s syndrome that developed during hospitalization. There was hesitation about the administration of high-dose aspirin in a patient who has undergone recent coronary stenting due to thrombotic and bleeding concerns. Combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting.
Conflict of interest
The authors declare that there is no conflict of interest.
Appendix A Supplementary data
The following are Supplementary data to this article:Fig. S1
Coronary angiography. (A) The right coronary artery is normal (left anterior oblique 45° view). (B) A middle left circumflex artery occlusion is revealed (right anterior oblique caudal view, yellow arrowhead). (C) The patient underwent urgent percutaneous coronary intervention, and reperfusion was achieved.
Fig. S2
A chart showing the serial change of body temperature, white blood cell count (WBC), and C-reactive protein (CRP) after developing Dressler’s syndrome.
Acknowledgment
None.
Appendix A Supplementary material related to this article can be found, in the online version, at https://doi.org/10.1016/j.jccase.2020.10.019. | APIXABAN, ASPIRIN, CLOPIDOGREL BISULFATE, PRASUGREL HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33717379 | 18,606,016 | 2021-03 |
What was the dosage of drug 'CLOPIDOGREL BISULFATE'? | A case of Dressler's syndrome successfully treated with colchicine and acetaminophen.
The incidence of Dressler's syndrome after myocardial infarction (MI) has decreased in the reperfusion therapy era. Although guidelines recommend high-dose aspirin for treatment based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era, bleeding and thrombotic concerns occurred upon aspirin administration after coronary stenting. A 69-year-old man with recent MI was admitted to our hospital. The patient presented with chest pain 1 week before admission. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change. Urgent coronary angiography demonstrated a left circumflex artery occlusion. He underwent PCI, and a sirolimus-eluting stent was deployed. Aspirin, prasugrel, and apixaban were administered. However, hospital discharge was delayed because he developed heart failure during hospitalization. Twenty-three days after admission, he developed a fever of >39 °C. Electrocardiography showed anterior ST segment elevation, and echocardiography revealed a 6-mm pericardial effusion. We diagnosed the patient with Dressler's syndrome, and colchicine 0.5 mg/day + acetaminophen 2000 mg/day were administered. His condition clinically improved after treatment and he was discharged 32 days after admission. There was hesitation about administration of high-dose aspirin in a patient who has undergone recent coronary stenting. Combination therapy of colchicine and acetaminophen could be a treatment option for Dressler's syndrome. <Learning objective: Guidelines recommend high-dose aspirin for the treatment of Dressler's syndrome based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era. However, bleeding and thrombotic concerns are present upon high-dose aspirin administration in patients who have undergone PCI. Therefore, a combination therapy of low-dose colchicine and acetaminophen could be a treatment option for patients with Dressler's syndrome who have undergone recent coronary stenting.>.
Introduction
The incidence of Dressler’s syndrome has decreased owing to reperfusion therapy. It can now be experienced only in patients with recent myocardial infarction (MI) who have not undergone primary percutaneous coronary intervention (PCI). Although guidelines recommend high-dose aspirin administration for the treatment of Dressler’s syndrome [1], [2], [3], the background evidence for these recommendations was amassed in the pre-PCI era. Although coronary stenting has become a standard therapy against MI, bleeding and thrombotic concerns on high-dose aspirin administration have occurred in the modern era. Herein, we present a case of Dressler’s syndrome successfully treated with colchicine and acetaminophen.
Case report
A 69-year-old man with no prior medical history visited a clinic for persistent chest discomfort. He presented with severe chest pain 1 week before admission; he was subsequently referred to our hospital for suspected acute coronary syndrome. On physical examination, the patient was afebrile with an irregular pulse of 108 beats/min and a blood pressure of 98/69 mmHg. The oxygen saturation was 98% on room air. No heart murmurs or edema were noted. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change (Fig. 1A). Moreover, echocardiography showed inferior-lateral wall asynergy, with mild mitral valve regurgitation and no pericardial effusion (Fig. 2A). Left ventricular contraction was preserved, with an ejection fraction of 50%. Laboratory tests showed an elevation of myocardial and liver enzymes and signs of heart failure as follows: white blood cell count, 11,000 cells/μL (neutrophils, 69%; eosinophils, 0.5%); C-reactive protein, 14.3 mg/dL; creatinine kinase (CK), 197 U/L; CK-muscle/brain, 7 U/L; troponin I, 4.4 ng/mL; B-type natriuretic peptide, 357 pg/mL; aspartate transaminase, 81 U/L; alanine aminotransferase, 77 U/L; and total bilirubin level, 2.1 mg/dL. Chest radiography revealed mild left pleural effusion with no congestion. Urgent coronary angiography demonstrated a middle left circumflex artery occlusion (Online Fig. S1). The patient underwent PCI, and a sirolimus-eluting stent was successfully deployed. The levels of myocardial enzymes were monitored by laboratory tests every 4 h after admission, although no CK elevation was noted. Considering the clinical course and results from the examinations, we diagnosed the patient with recent MI, which developed 1 week before admission. We administered aspirin 100 mg/day, prasugrel 3.75 mg/day, and apixaban 10 mg/day as antithrombotic therapy. Hospital discharge was delayed because of worsening heart failure. Considering the high bleeding risk, we reduced antiplatelet drugs to clopidogrel 75 mg/day (single antiplatelet therapy) on post-admission day 14. On post-admission day 23, the patient developed a fever of 39.6 °C and experienced a left lateral chest pain. Pericardial friction rub was audible on auscultation with the forward leaning position. Widespread ST segment elevation and PR segment depression were demonstrated in the electrocardiogram (Fig. 1B). No signs of infection or acute coronary syndrome were detected after performing laboratory tests, urinary test, computed tomography, echocardiography, and coronary angiography. The eosinophil count increased to 5.1% (291 cells/μL) in the laboratory test, and echocardiography revealed a newly detected pericardial effusion of 6 mm (Fig. 2B). We diagnosed the patient as having Dressler’s syndrome and administered colchicine and acetaminophen at 0.5 and 2000 mg/day, respectively. His physical signs and laboratory data improved within several days, and he was discharged on post-admission day 32 (Online Fig. S2).Fig. 1 Electrocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge.
Fig. 1
Fig. 2 Echocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge. The yellow arrowhead indicates the pericardial effusion.
Fig. 2
Three months later, his widespread ST segment elevation had returned to normal (Fig. 1C), and his pericardial effusion had improved (Fig. 2C). Colchicine 0.5 mg/day was continued without any side effects for 6 months, with no recurrence in symptoms noted or examinations repeated (Figs. 1D, 2D).
Discussion
We report a patient with Dressler’s syndrome successfully treated with colchicine and acetaminophen. Dressler’s syndrome, which is a secondary form of pericarditis that is typically demonstrated weeks to months after MI, is presumed to be mediated by an autoimmune mechanism [2]. The incidence of this syndrome has remarkably decreased in the reperfusion therapy era and is reported as only 0.1% in patients with acute MI [4].
High-dose aspirin administration (2000–4000 mg/day) is recommended as class I therapy in guidelines [1], [2], [3], and administration of other non-steroidal anti-inflammatory drugs should be avoided because they may impair scar formation [5] or diminish coronary blood flow [6]. Corticosteroids are suggested as a second option because of the risk of favoring the chronic evolution of the disease and promoting drug dependence [1]. However, the background evidence for these recommendations was amassed in the pre-PCI era, and there is no established treatment after primary PCI has become a standard therapy. Fig. 3 shows the history of PCI and the evidence of high-dose aspirin administration against Dressler’s syndrome over time. Dressler’s syndrome was first reported in 1956. The beneficial effects of aspirin were reported around the 1970s, which was before coronary stenting became a standard therapy in the 1990s. Evidence is lacking after primary PCI has become a standard therapy in MI patients due to the decreased morbidity.Fig. 3 The history of percutaneous coronary intervention and the evidence of high-dose aspirin administration against Dressler’s syndrome over time.
Fig. 3
There are thrombotic and bleeding concerns in the administration of high-dose aspirin in patients who underwent recent coronary stenting or those who take other antithrombotic drugs. High-dose aspirin may have a different antithrombotic effect compared with the low dose, a complex mechanism known as the aspirin dilemma. Aspirin inhibits two major mechanisms to obtain antithrombotic effects: platelet thromboxane-A2 production and cyclooxygenase enzyme in the vascular endothelium [7]. The antithrombotic effect differs according to the aspirin dose. While lower doses inhibit the endothelial cyclooxygenase activity mildly, higher doses can achieve the inhibition more completely and rapidly, which may weaken the antithrombotic effect [7]. Aspirin dilemma is a mechanism that occurs with high-dose aspirin and might have thrombotic concerns compared with the low dose. Therefore, we decided to continue clopidogrel and apixaban as antithrombotic therapy instead of prescribing high-dose aspirin. As atrial fibrillation was not observed after successful reperfusion therapy, there was an option to stop anticoagulants (i.e. apixaban). However, since the patient had developed heart failure during hospitalization, his CHA2DS2-VASc score was 3 points (age ≥65 years, heart failure, and vascular disease). Considering the result from the Canadian Registry of Atrial Fibrillation study that approximately half of all newly detected atrial fibrillations would recur [8], we chose to continue anticoagulants in this patient.
Colchicine is an anti-inflammatory medication that targets the white blood cells and causes microtubule depolymerization, which in turn causes motility, phagocytosis, and degranulation. It also inhibits interleukin-1 beta and interleukin-18 by interfering with the NLRP3 inflammasome protein complex, which is increasingly recognized to have a role in acute coronary syndrome. In addition to the fact that colchicine is an inexpensive drug with only a few reports of serious side effects, it may reduce adverse cardiovascular events [9] or recurrent pericarditis [1]. Under these circumstances, we suggest that colchicine administration could be a treatment option for Dressler’s syndrome.
Although the pathogenesis of early post-infarction pericarditis (typically a few days after acute MI) is believed to be different from that of Dressler’s syndrome, combination therapy of high-dose aspirin and colchicine is recommended for treatment. Colchicine is already reported as a useful agent for acute pericarditis to improve remission rates in the acute phase and reduce recurrence rates in the chronic phase [10]. From these reports, combination therapy of colchicine and acetaminophen can be one of the treatment options for acute pericarditis in patients with an indeterminate response to high-dose aspirin administration.
In the present case, there was hesitation about high-dose aspirin administration because the patient had undergone recent coronary stenting, and clopidogrel + apixaban were already prescribed. We successfully treated the patient with low-dose colchicine and acetaminophen without any side effects. Considering the risk of aspirin dilemma and the reported beneficial effect against recent MI, combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting. The pharmacological mechanism of aspirin dilemma remains unclear and further research is necessary. As a limitation of this case report, the use of colchicine for Dressler’s syndrome is not covered by insurance in Japan, and careful informed consent is necessary upon prescription. Furthermore, although guidelines recommend continuing colchicine for 3–6 months [3], it remains unclear when to stop the therapy. In our case, we stopped prescribing colchicine after 6 months from discharge.
In conclusion, we experienced a case of Dressler’s syndrome that developed during hospitalization. There was hesitation about the administration of high-dose aspirin in a patient who has undergone recent coronary stenting due to thrombotic and bleeding concerns. Combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting.
Conflict of interest
The authors declare that there is no conflict of interest.
Appendix A Supplementary data
The following are Supplementary data to this article:Fig. S1
Coronary angiography. (A) The right coronary artery is normal (left anterior oblique 45° view). (B) A middle left circumflex artery occlusion is revealed (right anterior oblique caudal view, yellow arrowhead). (C) The patient underwent urgent percutaneous coronary intervention, and reperfusion was achieved.
Fig. S2
A chart showing the serial change of body temperature, white blood cell count (WBC), and C-reactive protein (CRP) after developing Dressler’s syndrome.
Acknowledgment
None.
Appendix A Supplementary material related to this article can be found, in the online version, at https://doi.org/10.1016/j.jccase.2020.10.019. | 75MG/DAY | DrugDosageText | CC BY-NC-ND | 33717379 | 18,606,016 | 2021-03 |
What was the dosage of drug 'PRASUGREL HYDROCHLORIDE'? | A case of Dressler's syndrome successfully treated with colchicine and acetaminophen.
The incidence of Dressler's syndrome after myocardial infarction (MI) has decreased in the reperfusion therapy era. Although guidelines recommend high-dose aspirin for treatment based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era, bleeding and thrombotic concerns occurred upon aspirin administration after coronary stenting. A 69-year-old man with recent MI was admitted to our hospital. The patient presented with chest pain 1 week before admission. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change. Urgent coronary angiography demonstrated a left circumflex artery occlusion. He underwent PCI, and a sirolimus-eluting stent was deployed. Aspirin, prasugrel, and apixaban were administered. However, hospital discharge was delayed because he developed heart failure during hospitalization. Twenty-three days after admission, he developed a fever of >39 °C. Electrocardiography showed anterior ST segment elevation, and echocardiography revealed a 6-mm pericardial effusion. We diagnosed the patient with Dressler's syndrome, and colchicine 0.5 mg/day + acetaminophen 2000 mg/day were administered. His condition clinically improved after treatment and he was discharged 32 days after admission. There was hesitation about administration of high-dose aspirin in a patient who has undergone recent coronary stenting. Combination therapy of colchicine and acetaminophen could be a treatment option for Dressler's syndrome. <Learning objective: Guidelines recommend high-dose aspirin for the treatment of Dressler's syndrome based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era. However, bleeding and thrombotic concerns are present upon high-dose aspirin administration in patients who have undergone PCI. Therefore, a combination therapy of low-dose colchicine and acetaminophen could be a treatment option for patients with Dressler's syndrome who have undergone recent coronary stenting.>.
Introduction
The incidence of Dressler’s syndrome has decreased owing to reperfusion therapy. It can now be experienced only in patients with recent myocardial infarction (MI) who have not undergone primary percutaneous coronary intervention (PCI). Although guidelines recommend high-dose aspirin administration for the treatment of Dressler’s syndrome [1], [2], [3], the background evidence for these recommendations was amassed in the pre-PCI era. Although coronary stenting has become a standard therapy against MI, bleeding and thrombotic concerns on high-dose aspirin administration have occurred in the modern era. Herein, we present a case of Dressler’s syndrome successfully treated with colchicine and acetaminophen.
Case report
A 69-year-old man with no prior medical history visited a clinic for persistent chest discomfort. He presented with severe chest pain 1 week before admission; he was subsequently referred to our hospital for suspected acute coronary syndrome. On physical examination, the patient was afebrile with an irregular pulse of 108 beats/min and a blood pressure of 98/69 mmHg. The oxygen saturation was 98% on room air. No heart murmurs or edema were noted. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change (Fig. 1A). Moreover, echocardiography showed inferior-lateral wall asynergy, with mild mitral valve regurgitation and no pericardial effusion (Fig. 2A). Left ventricular contraction was preserved, with an ejection fraction of 50%. Laboratory tests showed an elevation of myocardial and liver enzymes and signs of heart failure as follows: white blood cell count, 11,000 cells/μL (neutrophils, 69%; eosinophils, 0.5%); C-reactive protein, 14.3 mg/dL; creatinine kinase (CK), 197 U/L; CK-muscle/brain, 7 U/L; troponin I, 4.4 ng/mL; B-type natriuretic peptide, 357 pg/mL; aspartate transaminase, 81 U/L; alanine aminotransferase, 77 U/L; and total bilirubin level, 2.1 mg/dL. Chest radiography revealed mild left pleural effusion with no congestion. Urgent coronary angiography demonstrated a middle left circumflex artery occlusion (Online Fig. S1). The patient underwent PCI, and a sirolimus-eluting stent was successfully deployed. The levels of myocardial enzymes were monitored by laboratory tests every 4 h after admission, although no CK elevation was noted. Considering the clinical course and results from the examinations, we diagnosed the patient with recent MI, which developed 1 week before admission. We administered aspirin 100 mg/day, prasugrel 3.75 mg/day, and apixaban 10 mg/day as antithrombotic therapy. Hospital discharge was delayed because of worsening heart failure. Considering the high bleeding risk, we reduced antiplatelet drugs to clopidogrel 75 mg/day (single antiplatelet therapy) on post-admission day 14. On post-admission day 23, the patient developed a fever of 39.6 °C and experienced a left lateral chest pain. Pericardial friction rub was audible on auscultation with the forward leaning position. Widespread ST segment elevation and PR segment depression were demonstrated in the electrocardiogram (Fig. 1B). No signs of infection or acute coronary syndrome were detected after performing laboratory tests, urinary test, computed tomography, echocardiography, and coronary angiography. The eosinophil count increased to 5.1% (291 cells/μL) in the laboratory test, and echocardiography revealed a newly detected pericardial effusion of 6 mm (Fig. 2B). We diagnosed the patient as having Dressler’s syndrome and administered colchicine and acetaminophen at 0.5 and 2000 mg/day, respectively. His physical signs and laboratory data improved within several days, and he was discharged on post-admission day 32 (Online Fig. S2).Fig. 1 Electrocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge.
Fig. 1
Fig. 2 Echocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge. The yellow arrowhead indicates the pericardial effusion.
Fig. 2
Three months later, his widespread ST segment elevation had returned to normal (Fig. 1C), and his pericardial effusion had improved (Fig. 2C). Colchicine 0.5 mg/day was continued without any side effects for 6 months, with no recurrence in symptoms noted or examinations repeated (Figs. 1D, 2D).
Discussion
We report a patient with Dressler’s syndrome successfully treated with colchicine and acetaminophen. Dressler’s syndrome, which is a secondary form of pericarditis that is typically demonstrated weeks to months after MI, is presumed to be mediated by an autoimmune mechanism [2]. The incidence of this syndrome has remarkably decreased in the reperfusion therapy era and is reported as only 0.1% in patients with acute MI [4].
High-dose aspirin administration (2000–4000 mg/day) is recommended as class I therapy in guidelines [1], [2], [3], and administration of other non-steroidal anti-inflammatory drugs should be avoided because they may impair scar formation [5] or diminish coronary blood flow [6]. Corticosteroids are suggested as a second option because of the risk of favoring the chronic evolution of the disease and promoting drug dependence [1]. However, the background evidence for these recommendations was amassed in the pre-PCI era, and there is no established treatment after primary PCI has become a standard therapy. Fig. 3 shows the history of PCI and the evidence of high-dose aspirin administration against Dressler’s syndrome over time. Dressler’s syndrome was first reported in 1956. The beneficial effects of aspirin were reported around the 1970s, which was before coronary stenting became a standard therapy in the 1990s. Evidence is lacking after primary PCI has become a standard therapy in MI patients due to the decreased morbidity.Fig. 3 The history of percutaneous coronary intervention and the evidence of high-dose aspirin administration against Dressler’s syndrome over time.
Fig. 3
There are thrombotic and bleeding concerns in the administration of high-dose aspirin in patients who underwent recent coronary stenting or those who take other antithrombotic drugs. High-dose aspirin may have a different antithrombotic effect compared with the low dose, a complex mechanism known as the aspirin dilemma. Aspirin inhibits two major mechanisms to obtain antithrombotic effects: platelet thromboxane-A2 production and cyclooxygenase enzyme in the vascular endothelium [7]. The antithrombotic effect differs according to the aspirin dose. While lower doses inhibit the endothelial cyclooxygenase activity mildly, higher doses can achieve the inhibition more completely and rapidly, which may weaken the antithrombotic effect [7]. Aspirin dilemma is a mechanism that occurs with high-dose aspirin and might have thrombotic concerns compared with the low dose. Therefore, we decided to continue clopidogrel and apixaban as antithrombotic therapy instead of prescribing high-dose aspirin. As atrial fibrillation was not observed after successful reperfusion therapy, there was an option to stop anticoagulants (i.e. apixaban). However, since the patient had developed heart failure during hospitalization, his CHA2DS2-VASc score was 3 points (age ≥65 years, heart failure, and vascular disease). Considering the result from the Canadian Registry of Atrial Fibrillation study that approximately half of all newly detected atrial fibrillations would recur [8], we chose to continue anticoagulants in this patient.
Colchicine is an anti-inflammatory medication that targets the white blood cells and causes microtubule depolymerization, which in turn causes motility, phagocytosis, and degranulation. It also inhibits interleukin-1 beta and interleukin-18 by interfering with the NLRP3 inflammasome protein complex, which is increasingly recognized to have a role in acute coronary syndrome. In addition to the fact that colchicine is an inexpensive drug with only a few reports of serious side effects, it may reduce adverse cardiovascular events [9] or recurrent pericarditis [1]. Under these circumstances, we suggest that colchicine administration could be a treatment option for Dressler’s syndrome.
Although the pathogenesis of early post-infarction pericarditis (typically a few days after acute MI) is believed to be different from that of Dressler’s syndrome, combination therapy of high-dose aspirin and colchicine is recommended for treatment. Colchicine is already reported as a useful agent for acute pericarditis to improve remission rates in the acute phase and reduce recurrence rates in the chronic phase [10]. From these reports, combination therapy of colchicine and acetaminophen can be one of the treatment options for acute pericarditis in patients with an indeterminate response to high-dose aspirin administration.
In the present case, there was hesitation about high-dose aspirin administration because the patient had undergone recent coronary stenting, and clopidogrel + apixaban were already prescribed. We successfully treated the patient with low-dose colchicine and acetaminophen without any side effects. Considering the risk of aspirin dilemma and the reported beneficial effect against recent MI, combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting. The pharmacological mechanism of aspirin dilemma remains unclear and further research is necessary. As a limitation of this case report, the use of colchicine for Dressler’s syndrome is not covered by insurance in Japan, and careful informed consent is necessary upon prescription. Furthermore, although guidelines recommend continuing colchicine for 3–6 months [3], it remains unclear when to stop the therapy. In our case, we stopped prescribing colchicine after 6 months from discharge.
In conclusion, we experienced a case of Dressler’s syndrome that developed during hospitalization. There was hesitation about the administration of high-dose aspirin in a patient who has undergone recent coronary stenting due to thrombotic and bleeding concerns. Combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting.
Conflict of interest
The authors declare that there is no conflict of interest.
Appendix A Supplementary data
The following are Supplementary data to this article:Fig. S1
Coronary angiography. (A) The right coronary artery is normal (left anterior oblique 45° view). (B) A middle left circumflex artery occlusion is revealed (right anterior oblique caudal view, yellow arrowhead). (C) The patient underwent urgent percutaneous coronary intervention, and reperfusion was achieved.
Fig. S2
A chart showing the serial change of body temperature, white blood cell count (WBC), and C-reactive protein (CRP) after developing Dressler’s syndrome.
Acknowledgment
None.
Appendix A Supplementary material related to this article can be found, in the online version, at https://doi.org/10.1016/j.jccase.2020.10.019. | 3.75MG/DAY | DrugDosageText | CC BY-NC-ND | 33717379 | 18,606,016 | 2021-03 |
What was the dosage of drug 'PRASUGREL'? | A case of Dressler's syndrome successfully treated with colchicine and acetaminophen.
The incidence of Dressler's syndrome after myocardial infarction (MI) has decreased in the reperfusion therapy era. Although guidelines recommend high-dose aspirin for treatment based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era, bleeding and thrombotic concerns occurred upon aspirin administration after coronary stenting. A 69-year-old man with recent MI was admitted to our hospital. The patient presented with chest pain 1 week before admission. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change. Urgent coronary angiography demonstrated a left circumflex artery occlusion. He underwent PCI, and a sirolimus-eluting stent was deployed. Aspirin, prasugrel, and apixaban were administered. However, hospital discharge was delayed because he developed heart failure during hospitalization. Twenty-three days after admission, he developed a fever of >39 °C. Electrocardiography showed anterior ST segment elevation, and echocardiography revealed a 6-mm pericardial effusion. We diagnosed the patient with Dressler's syndrome, and colchicine 0.5 mg/day + acetaminophen 2000 mg/day were administered. His condition clinically improved after treatment and he was discharged 32 days after admission. There was hesitation about administration of high-dose aspirin in a patient who has undergone recent coronary stenting. Combination therapy of colchicine and acetaminophen could be a treatment option for Dressler's syndrome. <Learning objective: Guidelines recommend high-dose aspirin for the treatment of Dressler's syndrome based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era. However, bleeding and thrombotic concerns are present upon high-dose aspirin administration in patients who have undergone PCI. Therefore, a combination therapy of low-dose colchicine and acetaminophen could be a treatment option for patients with Dressler's syndrome who have undergone recent coronary stenting.>.
Introduction
The incidence of Dressler’s syndrome has decreased owing to reperfusion therapy. It can now be experienced only in patients with recent myocardial infarction (MI) who have not undergone primary percutaneous coronary intervention (PCI). Although guidelines recommend high-dose aspirin administration for the treatment of Dressler’s syndrome [1], [2], [3], the background evidence for these recommendations was amassed in the pre-PCI era. Although coronary stenting has become a standard therapy against MI, bleeding and thrombotic concerns on high-dose aspirin administration have occurred in the modern era. Herein, we present a case of Dressler’s syndrome successfully treated with colchicine and acetaminophen.
Case report
A 69-year-old man with no prior medical history visited a clinic for persistent chest discomfort. He presented with severe chest pain 1 week before admission; he was subsequently referred to our hospital for suspected acute coronary syndrome. On physical examination, the patient was afebrile with an irregular pulse of 108 beats/min and a blood pressure of 98/69 mmHg. The oxygen saturation was 98% on room air. No heart murmurs or edema were noted. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change (Fig. 1A). Moreover, echocardiography showed inferior-lateral wall asynergy, with mild mitral valve regurgitation and no pericardial effusion (Fig. 2A). Left ventricular contraction was preserved, with an ejection fraction of 50%. Laboratory tests showed an elevation of myocardial and liver enzymes and signs of heart failure as follows: white blood cell count, 11,000 cells/μL (neutrophils, 69%; eosinophils, 0.5%); C-reactive protein, 14.3 mg/dL; creatinine kinase (CK), 197 U/L; CK-muscle/brain, 7 U/L; troponin I, 4.4 ng/mL; B-type natriuretic peptide, 357 pg/mL; aspartate transaminase, 81 U/L; alanine aminotransferase, 77 U/L; and total bilirubin level, 2.1 mg/dL. Chest radiography revealed mild left pleural effusion with no congestion. Urgent coronary angiography demonstrated a middle left circumflex artery occlusion (Online Fig. S1). The patient underwent PCI, and a sirolimus-eluting stent was successfully deployed. The levels of myocardial enzymes were monitored by laboratory tests every 4 h after admission, although no CK elevation was noted. Considering the clinical course and results from the examinations, we diagnosed the patient with recent MI, which developed 1 week before admission. We administered aspirin 100 mg/day, prasugrel 3.75 mg/day, and apixaban 10 mg/day as antithrombotic therapy. Hospital discharge was delayed because of worsening heart failure. Considering the high bleeding risk, we reduced antiplatelet drugs to clopidogrel 75 mg/day (single antiplatelet therapy) on post-admission day 14. On post-admission day 23, the patient developed a fever of 39.6 °C and experienced a left lateral chest pain. Pericardial friction rub was audible on auscultation with the forward leaning position. Widespread ST segment elevation and PR segment depression were demonstrated in the electrocardiogram (Fig. 1B). No signs of infection or acute coronary syndrome were detected after performing laboratory tests, urinary test, computed tomography, echocardiography, and coronary angiography. The eosinophil count increased to 5.1% (291 cells/μL) in the laboratory test, and echocardiography revealed a newly detected pericardial effusion of 6 mm (Fig. 2B). We diagnosed the patient as having Dressler’s syndrome and administered colchicine and acetaminophen at 0.5 and 2000 mg/day, respectively. His physical signs and laboratory data improved within several days, and he was discharged on post-admission day 32 (Online Fig. S2).Fig. 1 Electrocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge.
Fig. 1
Fig. 2 Echocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge. The yellow arrowhead indicates the pericardial effusion.
Fig. 2
Three months later, his widespread ST segment elevation had returned to normal (Fig. 1C), and his pericardial effusion had improved (Fig. 2C). Colchicine 0.5 mg/day was continued without any side effects for 6 months, with no recurrence in symptoms noted or examinations repeated (Figs. 1D, 2D).
Discussion
We report a patient with Dressler’s syndrome successfully treated with colchicine and acetaminophen. Dressler’s syndrome, which is a secondary form of pericarditis that is typically demonstrated weeks to months after MI, is presumed to be mediated by an autoimmune mechanism [2]. The incidence of this syndrome has remarkably decreased in the reperfusion therapy era and is reported as only 0.1% in patients with acute MI [4].
High-dose aspirin administration (2000–4000 mg/day) is recommended as class I therapy in guidelines [1], [2], [3], and administration of other non-steroidal anti-inflammatory drugs should be avoided because they may impair scar formation [5] or diminish coronary blood flow [6]. Corticosteroids are suggested as a second option because of the risk of favoring the chronic evolution of the disease and promoting drug dependence [1]. However, the background evidence for these recommendations was amassed in the pre-PCI era, and there is no established treatment after primary PCI has become a standard therapy. Fig. 3 shows the history of PCI and the evidence of high-dose aspirin administration against Dressler’s syndrome over time. Dressler’s syndrome was first reported in 1956. The beneficial effects of aspirin were reported around the 1970s, which was before coronary stenting became a standard therapy in the 1990s. Evidence is lacking after primary PCI has become a standard therapy in MI patients due to the decreased morbidity.Fig. 3 The history of percutaneous coronary intervention and the evidence of high-dose aspirin administration against Dressler’s syndrome over time.
Fig. 3
There are thrombotic and bleeding concerns in the administration of high-dose aspirin in patients who underwent recent coronary stenting or those who take other antithrombotic drugs. High-dose aspirin may have a different antithrombotic effect compared with the low dose, a complex mechanism known as the aspirin dilemma. Aspirin inhibits two major mechanisms to obtain antithrombotic effects: platelet thromboxane-A2 production and cyclooxygenase enzyme in the vascular endothelium [7]. The antithrombotic effect differs according to the aspirin dose. While lower doses inhibit the endothelial cyclooxygenase activity mildly, higher doses can achieve the inhibition more completely and rapidly, which may weaken the antithrombotic effect [7]. Aspirin dilemma is a mechanism that occurs with high-dose aspirin and might have thrombotic concerns compared with the low dose. Therefore, we decided to continue clopidogrel and apixaban as antithrombotic therapy instead of prescribing high-dose aspirin. As atrial fibrillation was not observed after successful reperfusion therapy, there was an option to stop anticoagulants (i.e. apixaban). However, since the patient had developed heart failure during hospitalization, his CHA2DS2-VASc score was 3 points (age ≥65 years, heart failure, and vascular disease). Considering the result from the Canadian Registry of Atrial Fibrillation study that approximately half of all newly detected atrial fibrillations would recur [8], we chose to continue anticoagulants in this patient.
Colchicine is an anti-inflammatory medication that targets the white blood cells and causes microtubule depolymerization, which in turn causes motility, phagocytosis, and degranulation. It also inhibits interleukin-1 beta and interleukin-18 by interfering with the NLRP3 inflammasome protein complex, which is increasingly recognized to have a role in acute coronary syndrome. In addition to the fact that colchicine is an inexpensive drug with only a few reports of serious side effects, it may reduce adverse cardiovascular events [9] or recurrent pericarditis [1]. Under these circumstances, we suggest that colchicine administration could be a treatment option for Dressler’s syndrome.
Although the pathogenesis of early post-infarction pericarditis (typically a few days after acute MI) is believed to be different from that of Dressler’s syndrome, combination therapy of high-dose aspirin and colchicine is recommended for treatment. Colchicine is already reported as a useful agent for acute pericarditis to improve remission rates in the acute phase and reduce recurrence rates in the chronic phase [10]. From these reports, combination therapy of colchicine and acetaminophen can be one of the treatment options for acute pericarditis in patients with an indeterminate response to high-dose aspirin administration.
In the present case, there was hesitation about high-dose aspirin administration because the patient had undergone recent coronary stenting, and clopidogrel + apixaban were already prescribed. We successfully treated the patient with low-dose colchicine and acetaminophen without any side effects. Considering the risk of aspirin dilemma and the reported beneficial effect against recent MI, combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting. The pharmacological mechanism of aspirin dilemma remains unclear and further research is necessary. As a limitation of this case report, the use of colchicine for Dressler’s syndrome is not covered by insurance in Japan, and careful informed consent is necessary upon prescription. Furthermore, although guidelines recommend continuing colchicine for 3–6 months [3], it remains unclear when to stop the therapy. In our case, we stopped prescribing colchicine after 6 months from discharge.
In conclusion, we experienced a case of Dressler’s syndrome that developed during hospitalization. There was hesitation about the administration of high-dose aspirin in a patient who has undergone recent coronary stenting due to thrombotic and bleeding concerns. Combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting.
Conflict of interest
The authors declare that there is no conflict of interest.
Appendix A Supplementary data
The following are Supplementary data to this article:Fig. S1
Coronary angiography. (A) The right coronary artery is normal (left anterior oblique 45° view). (B) A middle left circumflex artery occlusion is revealed (right anterior oblique caudal view, yellow arrowhead). (C) The patient underwent urgent percutaneous coronary intervention, and reperfusion was achieved.
Fig. S2
A chart showing the serial change of body temperature, white blood cell count (WBC), and C-reactive protein (CRP) after developing Dressler’s syndrome.
Acknowledgment
None.
Appendix A Supplementary material related to this article can be found, in the online version, at https://doi.org/10.1016/j.jccase.2020.10.019. | 3.75 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33717379 | 19,096,678 | 2021-03 |
What was the outcome of reaction 'Dressler^s syndrome'? | A case of Dressler's syndrome successfully treated with colchicine and acetaminophen.
The incidence of Dressler's syndrome after myocardial infarction (MI) has decreased in the reperfusion therapy era. Although guidelines recommend high-dose aspirin for treatment based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era, bleeding and thrombotic concerns occurred upon aspirin administration after coronary stenting. A 69-year-old man with recent MI was admitted to our hospital. The patient presented with chest pain 1 week before admission. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change. Urgent coronary angiography demonstrated a left circumflex artery occlusion. He underwent PCI, and a sirolimus-eluting stent was deployed. Aspirin, prasugrel, and apixaban were administered. However, hospital discharge was delayed because he developed heart failure during hospitalization. Twenty-three days after admission, he developed a fever of >39 °C. Electrocardiography showed anterior ST segment elevation, and echocardiography revealed a 6-mm pericardial effusion. We diagnosed the patient with Dressler's syndrome, and colchicine 0.5 mg/day + acetaminophen 2000 mg/day were administered. His condition clinically improved after treatment and he was discharged 32 days after admission. There was hesitation about administration of high-dose aspirin in a patient who has undergone recent coronary stenting. Combination therapy of colchicine and acetaminophen could be a treatment option for Dressler's syndrome. <Learning objective: Guidelines recommend high-dose aspirin for the treatment of Dressler's syndrome based on evidence from the pre-percutaneous coronary intervention (pre-PCI) era. However, bleeding and thrombotic concerns are present upon high-dose aspirin administration in patients who have undergone PCI. Therefore, a combination therapy of low-dose colchicine and acetaminophen could be a treatment option for patients with Dressler's syndrome who have undergone recent coronary stenting.>.
Introduction
The incidence of Dressler’s syndrome has decreased owing to reperfusion therapy. It can now be experienced only in patients with recent myocardial infarction (MI) who have not undergone primary percutaneous coronary intervention (PCI). Although guidelines recommend high-dose aspirin administration for the treatment of Dressler’s syndrome [1], [2], [3], the background evidence for these recommendations was amassed in the pre-PCI era. Although coronary stenting has become a standard therapy against MI, bleeding and thrombotic concerns on high-dose aspirin administration have occurred in the modern era. Herein, we present a case of Dressler’s syndrome successfully treated with colchicine and acetaminophen.
Case report
A 69-year-old man with no prior medical history visited a clinic for persistent chest discomfort. He presented with severe chest pain 1 week before admission; he was subsequently referred to our hospital for suspected acute coronary syndrome. On physical examination, the patient was afebrile with an irregular pulse of 108 beats/min and a blood pressure of 98/69 mmHg. The oxygen saturation was 98% on room air. No heart murmurs or edema were noted. Electrocardiography revealed newly detected atrial fibrillation with no ST segment change (Fig. 1A). Moreover, echocardiography showed inferior-lateral wall asynergy, with mild mitral valve regurgitation and no pericardial effusion (Fig. 2A). Left ventricular contraction was preserved, with an ejection fraction of 50%. Laboratory tests showed an elevation of myocardial and liver enzymes and signs of heart failure as follows: white blood cell count, 11,000 cells/μL (neutrophils, 69%; eosinophils, 0.5%); C-reactive protein, 14.3 mg/dL; creatinine kinase (CK), 197 U/L; CK-muscle/brain, 7 U/L; troponin I, 4.4 ng/mL; B-type natriuretic peptide, 357 pg/mL; aspartate transaminase, 81 U/L; alanine aminotransferase, 77 U/L; and total bilirubin level, 2.1 mg/dL. Chest radiography revealed mild left pleural effusion with no congestion. Urgent coronary angiography demonstrated a middle left circumflex artery occlusion (Online Fig. S1). The patient underwent PCI, and a sirolimus-eluting stent was successfully deployed. The levels of myocardial enzymes were monitored by laboratory tests every 4 h after admission, although no CK elevation was noted. Considering the clinical course and results from the examinations, we diagnosed the patient with recent MI, which developed 1 week before admission. We administered aspirin 100 mg/day, prasugrel 3.75 mg/day, and apixaban 10 mg/day as antithrombotic therapy. Hospital discharge was delayed because of worsening heart failure. Considering the high bleeding risk, we reduced antiplatelet drugs to clopidogrel 75 mg/day (single antiplatelet therapy) on post-admission day 14. On post-admission day 23, the patient developed a fever of 39.6 °C and experienced a left lateral chest pain. Pericardial friction rub was audible on auscultation with the forward leaning position. Widespread ST segment elevation and PR segment depression were demonstrated in the electrocardiogram (Fig. 1B). No signs of infection or acute coronary syndrome were detected after performing laboratory tests, urinary test, computed tomography, echocardiography, and coronary angiography. The eosinophil count increased to 5.1% (291 cells/μL) in the laboratory test, and echocardiography revealed a newly detected pericardial effusion of 6 mm (Fig. 2B). We diagnosed the patient as having Dressler’s syndrome and administered colchicine and acetaminophen at 0.5 and 2000 mg/day, respectively. His physical signs and laboratory data improved within several days, and he was discharged on post-admission day 32 (Online Fig. S2).Fig. 1 Electrocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge.
Fig. 1
Fig. 2 Echocardiography on admission (A), day 23 (B), and 3 (C) and 6 (D) months after discharge. The yellow arrowhead indicates the pericardial effusion.
Fig. 2
Three months later, his widespread ST segment elevation had returned to normal (Fig. 1C), and his pericardial effusion had improved (Fig. 2C). Colchicine 0.5 mg/day was continued without any side effects for 6 months, with no recurrence in symptoms noted or examinations repeated (Figs. 1D, 2D).
Discussion
We report a patient with Dressler’s syndrome successfully treated with colchicine and acetaminophen. Dressler’s syndrome, which is a secondary form of pericarditis that is typically demonstrated weeks to months after MI, is presumed to be mediated by an autoimmune mechanism [2]. The incidence of this syndrome has remarkably decreased in the reperfusion therapy era and is reported as only 0.1% in patients with acute MI [4].
High-dose aspirin administration (2000–4000 mg/day) is recommended as class I therapy in guidelines [1], [2], [3], and administration of other non-steroidal anti-inflammatory drugs should be avoided because they may impair scar formation [5] or diminish coronary blood flow [6]. Corticosteroids are suggested as a second option because of the risk of favoring the chronic evolution of the disease and promoting drug dependence [1]. However, the background evidence for these recommendations was amassed in the pre-PCI era, and there is no established treatment after primary PCI has become a standard therapy. Fig. 3 shows the history of PCI and the evidence of high-dose aspirin administration against Dressler’s syndrome over time. Dressler’s syndrome was first reported in 1956. The beneficial effects of aspirin were reported around the 1970s, which was before coronary stenting became a standard therapy in the 1990s. Evidence is lacking after primary PCI has become a standard therapy in MI patients due to the decreased morbidity.Fig. 3 The history of percutaneous coronary intervention and the evidence of high-dose aspirin administration against Dressler’s syndrome over time.
Fig. 3
There are thrombotic and bleeding concerns in the administration of high-dose aspirin in patients who underwent recent coronary stenting or those who take other antithrombotic drugs. High-dose aspirin may have a different antithrombotic effect compared with the low dose, a complex mechanism known as the aspirin dilemma. Aspirin inhibits two major mechanisms to obtain antithrombotic effects: platelet thromboxane-A2 production and cyclooxygenase enzyme in the vascular endothelium [7]. The antithrombotic effect differs according to the aspirin dose. While lower doses inhibit the endothelial cyclooxygenase activity mildly, higher doses can achieve the inhibition more completely and rapidly, which may weaken the antithrombotic effect [7]. Aspirin dilemma is a mechanism that occurs with high-dose aspirin and might have thrombotic concerns compared with the low dose. Therefore, we decided to continue clopidogrel and apixaban as antithrombotic therapy instead of prescribing high-dose aspirin. As atrial fibrillation was not observed after successful reperfusion therapy, there was an option to stop anticoagulants (i.e. apixaban). However, since the patient had developed heart failure during hospitalization, his CHA2DS2-VASc score was 3 points (age ≥65 years, heart failure, and vascular disease). Considering the result from the Canadian Registry of Atrial Fibrillation study that approximately half of all newly detected atrial fibrillations would recur [8], we chose to continue anticoagulants in this patient.
Colchicine is an anti-inflammatory medication that targets the white blood cells and causes microtubule depolymerization, which in turn causes motility, phagocytosis, and degranulation. It also inhibits interleukin-1 beta and interleukin-18 by interfering with the NLRP3 inflammasome protein complex, which is increasingly recognized to have a role in acute coronary syndrome. In addition to the fact that colchicine is an inexpensive drug with only a few reports of serious side effects, it may reduce adverse cardiovascular events [9] or recurrent pericarditis [1]. Under these circumstances, we suggest that colchicine administration could be a treatment option for Dressler’s syndrome.
Although the pathogenesis of early post-infarction pericarditis (typically a few days after acute MI) is believed to be different from that of Dressler’s syndrome, combination therapy of high-dose aspirin and colchicine is recommended for treatment. Colchicine is already reported as a useful agent for acute pericarditis to improve remission rates in the acute phase and reduce recurrence rates in the chronic phase [10]. From these reports, combination therapy of colchicine and acetaminophen can be one of the treatment options for acute pericarditis in patients with an indeterminate response to high-dose aspirin administration.
In the present case, there was hesitation about high-dose aspirin administration because the patient had undergone recent coronary stenting, and clopidogrel + apixaban were already prescribed. We successfully treated the patient with low-dose colchicine and acetaminophen without any side effects. Considering the risk of aspirin dilemma and the reported beneficial effect against recent MI, combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting. The pharmacological mechanism of aspirin dilemma remains unclear and further research is necessary. As a limitation of this case report, the use of colchicine for Dressler’s syndrome is not covered by insurance in Japan, and careful informed consent is necessary upon prescription. Furthermore, although guidelines recommend continuing colchicine for 3–6 months [3], it remains unclear when to stop the therapy. In our case, we stopped prescribing colchicine after 6 months from discharge.
In conclusion, we experienced a case of Dressler’s syndrome that developed during hospitalization. There was hesitation about the administration of high-dose aspirin in a patient who has undergone recent coronary stenting due to thrombotic and bleeding concerns. Combination therapy of colchicine and acetaminophen could be a treatment option for patients with Dressler’s syndrome who underwent recent coronary stenting.
Conflict of interest
The authors declare that there is no conflict of interest.
Appendix A Supplementary data
The following are Supplementary data to this article:Fig. S1
Coronary angiography. (A) The right coronary artery is normal (left anterior oblique 45° view). (B) A middle left circumflex artery occlusion is revealed (right anterior oblique caudal view, yellow arrowhead). (C) The patient underwent urgent percutaneous coronary intervention, and reperfusion was achieved.
Fig. S2
A chart showing the serial change of body temperature, white blood cell count (WBC), and C-reactive protein (CRP) after developing Dressler’s syndrome.
Acknowledgment
None.
Appendix A Supplementary material related to this article can be found, in the online version, at https://doi.org/10.1016/j.jccase.2020.10.019. | Recovered | ReactionOutcome | CC BY-NC-ND | 33717379 | 18,606,016 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tumour lysis syndrome'. | A rare cause of acute liver failure due to haemophagocytic lymphohistiocytosis secondary to diffuse large B-cell lymphoma.
Acute liver failure is a life-threatening condition commonly caused by drug-induced hepatotoxicity or viral hepatitides. However, there are a number of rarer causes such as haemophagocytic lymphohistiocytosis. Haemophagocytic lymphohistiocytosis is a syndrome of uncontrolled immune cell activation, triggered by infection or malignancy, which carries a high mortality. Whilst mild to moderate liver injury is commonly seen with haemophagocytic lymphohistiocytosis, acute liver failure has rarely been reported in adults. We present a case of a 74-year-old man with acute liver failure secondary to haemophagocytic lymphohistiocytosis triggered by undiagnosed large B-cell lymphoma. Initially treated for biliary sepsis, there was a delay in the diagnosis of haemophagocytic lymphohistiocytosis and despite initiating chemotherapy, he died soon after. This case highlights the importance of considering haemophagocytic lymphohistiocytosis as a rare cause of acute liver failure, as given the life-threatening potential of haemophagocytic lymphohistiocytosis, a prompt diagnosis may allow early initiation of chemotherapy for any chance of survival.
Background
Acute liver failure (ALF) is a rare condition that varies in aetiology and prognosis. Paracetamol-induced hepatotoxicity in the United Kingdom and viral hepatitis globally are the predominant causes; however, a significant number of cases remain undetermined.1,2 Haemophagocytic lymphohistiocytosis (HLH), a syndrome of uncontrolled immune cell activation, can occur as a primary or acquired disorder.3 Mild to moderate liver injury is a common complication of Haemophagocytic lymphohistiocytosis (HLH) in 80% of patients.4 However rarely, patients may present with Acute Liver Failure.5 The mortality of Haemophagocytic lymphohistiocytosis ranges between 41% and 75% and with associated Acute Liver Failure the prognosis is significantly poorer.4,6 Due to the rarity of the Acute Liver Failure caused by Haemophagocytic lymphohistiocytosis, the diagnosis is often not considered, resulting in delayed treatment and contributing to the high mortality. Herein we present a rare case of an elderly patient who developed Acute Liver Failure secondary to Haemophagocytic lymphohistiocytosi caused by an underlying newly diagnosed B-cell lymphoma, a review of the literature and lessons learnt.
Case presentation
A 74-year-old male presented with a one-month history of worsening pruritus, confusion with multiple falls and fever. He had suffered with lethargy and night sweats for a number of months. There was no history of liver disease but had had previous coronary stenting for ischaemic heart disease for which he was taking aspirin. He was a non-smoker and occasionally consumed alcohol.
On arrival, he was pyrexial and tachycardic but abdominal examination was unremarkable. Initial blood tests revealed: deranged liver function (Bilirubin 28, Alanine transaminase 106, Alkaline phosphatase 600) with synthetic impairment (INR 2.0, Albumin 29), pancytopenia (Haemoglobin 85; White Cell Count 2.7, Platelets 71) and raised C-reactive protein 55 (Figures 1 and 2). On the basis of a fever and deranged liver function, the patient was initiated on co-amoxiclav for biliary sepsis. However, an abdominal ultrasound showed a thickened gallbladder without any stones nor biliary duct dilatation, and a normal liver and portal venous flow. The spleen was enlarged at 16 cm containing a hypoechoic area 30 × 43 mm. The latter finding was confirmed by a CT abdomen (Figure 3). A subsequent magnetic resonance cholangiopancreatography was normal. The work-up for acute liver injury including viral serology, autoimmune screen and immunoglobulins was unrevealing. Several blood cultures taken for ongoing spiking temperature were negative. Figure 1. Full blood count and clotting results.
Figure 2. Liver function results.
Figure 3. CT image demonstrating an enlarged spleen at 16 cm.
Differential diagnosis
The differential diagnosis included a splenic abscess and haematological malignancy given the imaging so he was discussed in the haematology cancer multidisciplinary meeting.
Clinical course
Despite initial treatment with co-amoxiclav, he continued to spike fevers and suffered haemodynamic instability necessitating two medical emergency calls. Antibiotics were escalated to Piperacillin/Tazobactam on Day 4. Blood tests showed raised lactate, worsening pancytopenia, acute kidney injury and further deterioration in liver function with the development of jaundice and INR up to 2.0 (Figures 2 and 4). Initial Lactate dehydrogenase was raised at >2000 IU/L and ferritin >3000 ug/L. Figure 4. Urea and electrolyte results.
He had a staging CT as per haematology multidisciplinary team recommendation, which showed new bilateral pleural effusions, minimal ascites and peri-pancreatic stranding suggestive of mild pancreatitis. However, the clinical picture was not in keeping with acute pancreatitis and the amylase was only marginally raised at 125 iu/L, so this was deemed unlikely. The haematology team performed a bone marrow aspirate and trephine biopsy. The patient further deteriorated with development of hepatic encephalopathy, hypoxia and hypotensive with a persistent tachycardia. The patient was given fluid resuscitation, and the antibiotics were further escalated to Meropenem. A hepatology review recommended to check for Hepatitis A, Hepatitis E, Hepatitis B core antibody, leptospirosis, Brucella, and herpes simplex virus serology, all of which were normal.
Preliminary bone marrow biopsy results showed reactive changes only, indicating infection. There was no evidence of lymphoma, or haemophagocytosis. By Day 11, the patient had continued to deteriorate with development of multi-organ failure involving liver, bone marrow and kidneys. Despite the reactive bone marrow results, a clinical diagnosis of haemophagocytic lymphohistiocytosis was considered by the ward consultant as the patient met the clinical criteria for HLH-2004 (Table 1). After discussion with the haematology consultant, who agreed, a joint decision was made to administer 1 g of methylprednisolone to the patient, with the family’s consent. Unfortunately the patient then deteriorated rapidly and with intensive care input, there was a consensus of imminent death (pH 6.89, Lactate 17.8) and he soon after passed away on the ward. Table 1. HLH-2004 diagnostic criteria fulfilled.21
HLH [21] Our patient
Splenomegaly + +
Fever > 38.5 + +
Cytopenia (>1 lineages required)
Haemoglobin <90 g/l 85 g/l
Platelets <100 × 109/l 71 × 109/l
Neutrophils <1.0 × 109/l –
Hypertriglyceridemia or hypofibrinogenaemia
Hypertriglyceridemia ≥3.0 mmol/l 3.8 mmol/l
Hypofibrinogenaemia ≤1.5 g/L −
Haemophagocytosis in bone marrow + −
Low or absent nk cell activity + Not determined
Ferritin >500 ng/ml ≥500 ng/ml 11295 ng/ml
Elevated soluble CD25 ≥2400 U/ml Not determined
Bone marrow trephine biopsy result eventually confirmed diffuse large B-cell lymphoma with 80% blast, confirming haemophagocytic lymphohistiocytosis with underlying malignancy (Figure 5). Figure 5. Bone marrow trephine biopsy images. (a) Microscopy showing atypical cells with irregular nuclei and prominent nucleoli (×600). (b) Immunohistochemistry to show B cell nature of atypical cells (×400).
Outcome and follow-up
The patient died as an inpatient during his admission.
Discussion
Haemophagocytic lymphohistiocytosis is a clinical syndrome of excessive macrophage activation7 which rarely causes acute liver failure. Herein we have presented a case of acute liver failure secondary to haemophagocytic lymphohistiocytosis due to an undiagnosed large B-cell lymphoma in an elderly gentleman. haemophagocytic lymphohistiocytosis is classified as primary or secondary, resulting in defective natural killer cell function. The primary form, usually seen in infants and children, results from genetic missense mutations in the perforin genes, responsible for NK cell and cytotoxic T lymphocyte function.8,9 Secondary haemophagocytic lymphohistiocytosis, seen in adults, is caused by infections, malignancy, rheumatological and metabolic diseases. Epstein–Barr virus is the most consistent, in up to a third of secondary haemophagocytic lymphohistiocytosis.10 Malignancies are accountable for up to 27% of secondary haemophagocytic lymphohistiocytosis and of these haematological are of the highest prevalence.11
Malignancy-associated haemophagocytic lymphohistiocytosis
Previously a rare entity, malignancy-associated haemophagocytic lymphohistiocytosis has been shown in recent retrospective studies to be evident in up to 1% of underlying malignancies at diagnosis. For rare subtypes of B-cell lymphoma, it could be as high as 20% (intravascular B-cell lymphoma or B-cell lymphoma without peripheral adenopathies).12 Malignancy associated haemophagocytic lymphohistiocytosis may present as a feature of an undiagnosed malignancy as in our patient with B-cell lymphoma, or upon initiation of immune modulating therapies. It is understood that the disruption of immune homeostasis from malignancies and associated therapies promoting a degree of T-cell dysfunction can act as the trigger for Malignancy associated haemophagocytic lymphohistiocytosis.13
Liver injury in haemophagocytic lymphohistiocytosis
Liver injury is a common complication of haemophagocytic lymphohistiocytosis with varying degrees of insult but acute liver failure is rarely reported. The pathophysiology of acute liver failure in haemophagocytic lymphohistiocytosis remains largely unknown. It is theorised that infiltration of activated haemophagocytic histiocytes or the increased cytokine production associated with haemophagocytic lymphohistiocytosis results in liver injury.14 This can be further compounded by liver injury caused by the underlying disease.15,16 The histopathological findings in the liver of patients with haemophagocytic lymphohistiocytosis are non-specific and can include hepatocellular necrosis, sinusoidal dilatation, endothelialitis and steatosis.3
B-cell lymphoma can present rarely as acute liver failure17 and this is usually as a manifestation of end-stage malignant disease.18 The liver injury and extensive cholangitis are due to malignant infiltrates of intrahepatic ducts, hepatic venules and the hepatic parenchyma itself.19 In our case, imaging failed to demonstrate any liver infiltrates and the liver appeared normal, therefore suggesting haemophagocytic lymphohistiocytosis as the predominant cause of the acute liver failure rather than due to malignant infiltration.
Presentation and diagnosis of haemophagocytic lymphohistiocytosis
Diagnosis of haemophagocytic lymphohistiocytosis is challenging due to its rare occurrence and non-specific presentation.9 Patients with haemophagocytic lymphohistiocytosis characteristically present with a varying picture of cytopenia, fever and multiple organ involvement.20 The HLH-2004 study of paediatric patients devised criteria for diagnosis. The following clinical findings were common: Fever (95%), splenomegaly (89%), bicytopenia (92%), hypertriglyceridaemia or hypofibrinogenaemia (90%), haemophagocytosis (82%), ferritin >500 mcg/L (94%), low/absent NK cell activity (71%) and soluble CD25 elevation (97%).21,22 To fulfil the diagnostic criteria, five of the eight are required. Alternatively, it can be diagnosed with genetic testing.21 These criteria are based on paediatric patients and there is an unmet need for adult specific criteria, in particularly for m-haemophagocytic lymphohistiocytosis, in order to prevent missed or delayed diagnosis in adults.
Our patient met five out of the eight criteria required for diagnosis of haemophagocytic lymphohistiocytosis per HLH-2004 (Table 1). One of the remaining criteria of haemophagocytosis in the bone marrow was not seen in our case – it showed reactive changes only. In fact, often haemophagocytosis may not be seen on the initial bone marrow as pathological changes due to haemophagocytic lymphohistiocytosis may take days or weeks to manifest and it is not considered pathognomonic for haemophagocytic lymphohistiocytosis. Thus, the absence of haemophagocytosis on the initial bone marrow should not delay treatment in cases where there is a high clinical suspicion for haemophagocytic lymphohistiocytosis.13
The clinical course of Malignancy associated haemophagocytic lymphohistiocytosis is often rapidly progressing and characterised by poor outcomes.13 The management of Malignancy associated haemophagocytic lymphohistiocytosis is a focus of debate. Whilst it seems logical to treat the underlying cause, these patients are in a hyperinflammatory state with an ongoing cytokine storm and giving chemotherapy to treat an underlying malignancy may have a deleterious effect. An approach that involves controlling the cytokine storm and the underlying malignancy would be preferable.13
In our case, the underlying cause of haemophagocytic lymphohistiocytosis was unknown and we had no evidence to suggest that a malignant process was driving the haemophagocytic lymphohistiocytosis and the more common cause of viral infection was higher in the differential diagnosis. It was decided to initiate chemotherapy with methylprednisolone as the patient’s condition was deteriorating, in the hope that he may respond and with no other treatment options. Unfortunately, he most certainly developed tumour lysis syndrome due to undiagnosed B-cell lymphoma after giving methylprednisolone which hastened his death.
Conclusion
Our case emphasises the importance of considering haemophagocytic lymphohistiocytosis as a rare cause of acute liver failure. A condition more common in paediatrics, recent literature shows an increasing prevalence of haemophagocytic lymphohistiocytosis in adults with poor prognoses.23,24 A delay in diagnosis is a key contributor to the mortality rate,4,6,25 thus we hope to raise awareness amongst physicians about this diagnosis.
Patient consent
Written informed consent for patient information and images to be published was provided by the patient’s spouse.
Learning points/take home messages
Haemophagocytic lymphohistiocytosis is a rare cause of acute liver failure.
A high clinical suspicion of haemophagocytic lymphohistiocytosis, even without haemophagocytosis on bone marrow, could prompt early treatment and possibly reduce mortality.
A need for adult-specific diagnostic criteria for haemophagocytic lymphohistiocytosis which may lead to a prompt diagnosis.
To be aware of and avoid diagnostic momentum – in this case, a previous diagnosis of biliary sepsis, without any radiological evidence and non-response to antibiotics.
Acknowledgements
None.
Declarations
Provenance: Not commissioned.
ORCID iD: Andrew Coppola https://orcid.org/0000-0002-6757-9876
Competing Interests: None declared.
Funding: None declared.
Ethics approval: Written informed consent was obtained from the patient's spouse for publication of the case report and accompanying images.
Guarantor: MR.
Contributorship: All authors (AC, CC, EO and MR) were involved in the care of the patient. AC, CC and MR prepared the manuscript, EO assisted with revisions, and all authors approved the final version. | METHYLPREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33717491 | 19,225,049 | 2021-03 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | A rare cause of acute liver failure due to haemophagocytic lymphohistiocytosis secondary to diffuse large B-cell lymphoma.
Acute liver failure is a life-threatening condition commonly caused by drug-induced hepatotoxicity or viral hepatitides. However, there are a number of rarer causes such as haemophagocytic lymphohistiocytosis. Haemophagocytic lymphohistiocytosis is a syndrome of uncontrolled immune cell activation, triggered by infection or malignancy, which carries a high mortality. Whilst mild to moderate liver injury is commonly seen with haemophagocytic lymphohistiocytosis, acute liver failure has rarely been reported in adults. We present a case of a 74-year-old man with acute liver failure secondary to haemophagocytic lymphohistiocytosis triggered by undiagnosed large B-cell lymphoma. Initially treated for biliary sepsis, there was a delay in the diagnosis of haemophagocytic lymphohistiocytosis and despite initiating chemotherapy, he died soon after. This case highlights the importance of considering haemophagocytic lymphohistiocytosis as a rare cause of acute liver failure, as given the life-threatening potential of haemophagocytic lymphohistiocytosis, a prompt diagnosis may allow early initiation of chemotherapy for any chance of survival.
Background
Acute liver failure (ALF) is a rare condition that varies in aetiology and prognosis. Paracetamol-induced hepatotoxicity in the United Kingdom and viral hepatitis globally are the predominant causes; however, a significant number of cases remain undetermined.1,2 Haemophagocytic lymphohistiocytosis (HLH), a syndrome of uncontrolled immune cell activation, can occur as a primary or acquired disorder.3 Mild to moderate liver injury is a common complication of Haemophagocytic lymphohistiocytosis (HLH) in 80% of patients.4 However rarely, patients may present with Acute Liver Failure.5 The mortality of Haemophagocytic lymphohistiocytosis ranges between 41% and 75% and with associated Acute Liver Failure the prognosis is significantly poorer.4,6 Due to the rarity of the Acute Liver Failure caused by Haemophagocytic lymphohistiocytosis, the diagnosis is often not considered, resulting in delayed treatment and contributing to the high mortality. Herein we present a rare case of an elderly patient who developed Acute Liver Failure secondary to Haemophagocytic lymphohistiocytosi caused by an underlying newly diagnosed B-cell lymphoma, a review of the literature and lessons learnt.
Case presentation
A 74-year-old male presented with a one-month history of worsening pruritus, confusion with multiple falls and fever. He had suffered with lethargy and night sweats for a number of months. There was no history of liver disease but had had previous coronary stenting for ischaemic heart disease for which he was taking aspirin. He was a non-smoker and occasionally consumed alcohol.
On arrival, he was pyrexial and tachycardic but abdominal examination was unremarkable. Initial blood tests revealed: deranged liver function (Bilirubin 28, Alanine transaminase 106, Alkaline phosphatase 600) with synthetic impairment (INR 2.0, Albumin 29), pancytopenia (Haemoglobin 85; White Cell Count 2.7, Platelets 71) and raised C-reactive protein 55 (Figures 1 and 2). On the basis of a fever and deranged liver function, the patient was initiated on co-amoxiclav for biliary sepsis. However, an abdominal ultrasound showed a thickened gallbladder without any stones nor biliary duct dilatation, and a normal liver and portal venous flow. The spleen was enlarged at 16 cm containing a hypoechoic area 30 × 43 mm. The latter finding was confirmed by a CT abdomen (Figure 3). A subsequent magnetic resonance cholangiopancreatography was normal. The work-up for acute liver injury including viral serology, autoimmune screen and immunoglobulins was unrevealing. Several blood cultures taken for ongoing spiking temperature were negative. Figure 1. Full blood count and clotting results.
Figure 2. Liver function results.
Figure 3. CT image demonstrating an enlarged spleen at 16 cm.
Differential diagnosis
The differential diagnosis included a splenic abscess and haematological malignancy given the imaging so he was discussed in the haematology cancer multidisciplinary meeting.
Clinical course
Despite initial treatment with co-amoxiclav, he continued to spike fevers and suffered haemodynamic instability necessitating two medical emergency calls. Antibiotics were escalated to Piperacillin/Tazobactam on Day 4. Blood tests showed raised lactate, worsening pancytopenia, acute kidney injury and further deterioration in liver function with the development of jaundice and INR up to 2.0 (Figures 2 and 4). Initial Lactate dehydrogenase was raised at >2000 IU/L and ferritin >3000 ug/L. Figure 4. Urea and electrolyte results.
He had a staging CT as per haematology multidisciplinary team recommendation, which showed new bilateral pleural effusions, minimal ascites and peri-pancreatic stranding suggestive of mild pancreatitis. However, the clinical picture was not in keeping with acute pancreatitis and the amylase was only marginally raised at 125 iu/L, so this was deemed unlikely. The haematology team performed a bone marrow aspirate and trephine biopsy. The patient further deteriorated with development of hepatic encephalopathy, hypoxia and hypotensive with a persistent tachycardia. The patient was given fluid resuscitation, and the antibiotics were further escalated to Meropenem. A hepatology review recommended to check for Hepatitis A, Hepatitis E, Hepatitis B core antibody, leptospirosis, Brucella, and herpes simplex virus serology, all of which were normal.
Preliminary bone marrow biopsy results showed reactive changes only, indicating infection. There was no evidence of lymphoma, or haemophagocytosis. By Day 11, the patient had continued to deteriorate with development of multi-organ failure involving liver, bone marrow and kidneys. Despite the reactive bone marrow results, a clinical diagnosis of haemophagocytic lymphohistiocytosis was considered by the ward consultant as the patient met the clinical criteria for HLH-2004 (Table 1). After discussion with the haematology consultant, who agreed, a joint decision was made to administer 1 g of methylprednisolone to the patient, with the family’s consent. Unfortunately the patient then deteriorated rapidly and with intensive care input, there was a consensus of imminent death (pH 6.89, Lactate 17.8) and he soon after passed away on the ward. Table 1. HLH-2004 diagnostic criteria fulfilled.21
HLH [21] Our patient
Splenomegaly + +
Fever > 38.5 + +
Cytopenia (>1 lineages required)
Haemoglobin <90 g/l 85 g/l
Platelets <100 × 109/l 71 × 109/l
Neutrophils <1.0 × 109/l –
Hypertriglyceridemia or hypofibrinogenaemia
Hypertriglyceridemia ≥3.0 mmol/l 3.8 mmol/l
Hypofibrinogenaemia ≤1.5 g/L −
Haemophagocytosis in bone marrow + −
Low or absent nk cell activity + Not determined
Ferritin >500 ng/ml ≥500 ng/ml 11295 ng/ml
Elevated soluble CD25 ≥2400 U/ml Not determined
Bone marrow trephine biopsy result eventually confirmed diffuse large B-cell lymphoma with 80% blast, confirming haemophagocytic lymphohistiocytosis with underlying malignancy (Figure 5). Figure 5. Bone marrow trephine biopsy images. (a) Microscopy showing atypical cells with irregular nuclei and prominent nucleoli (×600). (b) Immunohistochemistry to show B cell nature of atypical cells (×400).
Outcome and follow-up
The patient died as an inpatient during his admission.
Discussion
Haemophagocytic lymphohistiocytosis is a clinical syndrome of excessive macrophage activation7 which rarely causes acute liver failure. Herein we have presented a case of acute liver failure secondary to haemophagocytic lymphohistiocytosis due to an undiagnosed large B-cell lymphoma in an elderly gentleman. haemophagocytic lymphohistiocytosis is classified as primary or secondary, resulting in defective natural killer cell function. The primary form, usually seen in infants and children, results from genetic missense mutations in the perforin genes, responsible for NK cell and cytotoxic T lymphocyte function.8,9 Secondary haemophagocytic lymphohistiocytosis, seen in adults, is caused by infections, malignancy, rheumatological and metabolic diseases. Epstein–Barr virus is the most consistent, in up to a third of secondary haemophagocytic lymphohistiocytosis.10 Malignancies are accountable for up to 27% of secondary haemophagocytic lymphohistiocytosis and of these haematological are of the highest prevalence.11
Malignancy-associated haemophagocytic lymphohistiocytosis
Previously a rare entity, malignancy-associated haemophagocytic lymphohistiocytosis has been shown in recent retrospective studies to be evident in up to 1% of underlying malignancies at diagnosis. For rare subtypes of B-cell lymphoma, it could be as high as 20% (intravascular B-cell lymphoma or B-cell lymphoma without peripheral adenopathies).12 Malignancy associated haemophagocytic lymphohistiocytosis may present as a feature of an undiagnosed malignancy as in our patient with B-cell lymphoma, or upon initiation of immune modulating therapies. It is understood that the disruption of immune homeostasis from malignancies and associated therapies promoting a degree of T-cell dysfunction can act as the trigger for Malignancy associated haemophagocytic lymphohistiocytosis.13
Liver injury in haemophagocytic lymphohistiocytosis
Liver injury is a common complication of haemophagocytic lymphohistiocytosis with varying degrees of insult but acute liver failure is rarely reported. The pathophysiology of acute liver failure in haemophagocytic lymphohistiocytosis remains largely unknown. It is theorised that infiltration of activated haemophagocytic histiocytes or the increased cytokine production associated with haemophagocytic lymphohistiocytosis results in liver injury.14 This can be further compounded by liver injury caused by the underlying disease.15,16 The histopathological findings in the liver of patients with haemophagocytic lymphohistiocytosis are non-specific and can include hepatocellular necrosis, sinusoidal dilatation, endothelialitis and steatosis.3
B-cell lymphoma can present rarely as acute liver failure17 and this is usually as a manifestation of end-stage malignant disease.18 The liver injury and extensive cholangitis are due to malignant infiltrates of intrahepatic ducts, hepatic venules and the hepatic parenchyma itself.19 In our case, imaging failed to demonstrate any liver infiltrates and the liver appeared normal, therefore suggesting haemophagocytic lymphohistiocytosis as the predominant cause of the acute liver failure rather than due to malignant infiltration.
Presentation and diagnosis of haemophagocytic lymphohistiocytosis
Diagnosis of haemophagocytic lymphohistiocytosis is challenging due to its rare occurrence and non-specific presentation.9 Patients with haemophagocytic lymphohistiocytosis characteristically present with a varying picture of cytopenia, fever and multiple organ involvement.20 The HLH-2004 study of paediatric patients devised criteria for diagnosis. The following clinical findings were common: Fever (95%), splenomegaly (89%), bicytopenia (92%), hypertriglyceridaemia or hypofibrinogenaemia (90%), haemophagocytosis (82%), ferritin >500 mcg/L (94%), low/absent NK cell activity (71%) and soluble CD25 elevation (97%).21,22 To fulfil the diagnostic criteria, five of the eight are required. Alternatively, it can be diagnosed with genetic testing.21 These criteria are based on paediatric patients and there is an unmet need for adult specific criteria, in particularly for m-haemophagocytic lymphohistiocytosis, in order to prevent missed or delayed diagnosis in adults.
Our patient met five out of the eight criteria required for diagnosis of haemophagocytic lymphohistiocytosis per HLH-2004 (Table 1). One of the remaining criteria of haemophagocytosis in the bone marrow was not seen in our case – it showed reactive changes only. In fact, often haemophagocytosis may not be seen on the initial bone marrow as pathological changes due to haemophagocytic lymphohistiocytosis may take days or weeks to manifest and it is not considered pathognomonic for haemophagocytic lymphohistiocytosis. Thus, the absence of haemophagocytosis on the initial bone marrow should not delay treatment in cases where there is a high clinical suspicion for haemophagocytic lymphohistiocytosis.13
The clinical course of Malignancy associated haemophagocytic lymphohistiocytosis is often rapidly progressing and characterised by poor outcomes.13 The management of Malignancy associated haemophagocytic lymphohistiocytosis is a focus of debate. Whilst it seems logical to treat the underlying cause, these patients are in a hyperinflammatory state with an ongoing cytokine storm and giving chemotherapy to treat an underlying malignancy may have a deleterious effect. An approach that involves controlling the cytokine storm and the underlying malignancy would be preferable.13
In our case, the underlying cause of haemophagocytic lymphohistiocytosis was unknown and we had no evidence to suggest that a malignant process was driving the haemophagocytic lymphohistiocytosis and the more common cause of viral infection was higher in the differential diagnosis. It was decided to initiate chemotherapy with methylprednisolone as the patient’s condition was deteriorating, in the hope that he may respond and with no other treatment options. Unfortunately, he most certainly developed tumour lysis syndrome due to undiagnosed B-cell lymphoma after giving methylprednisolone which hastened his death.
Conclusion
Our case emphasises the importance of considering haemophagocytic lymphohistiocytosis as a rare cause of acute liver failure. A condition more common in paediatrics, recent literature shows an increasing prevalence of haemophagocytic lymphohistiocytosis in adults with poor prognoses.23,24 A delay in diagnosis is a key contributor to the mortality rate,4,6,25 thus we hope to raise awareness amongst physicians about this diagnosis.
Patient consent
Written informed consent for patient information and images to be published was provided by the patient’s spouse.
Learning points/take home messages
Haemophagocytic lymphohistiocytosis is a rare cause of acute liver failure.
A high clinical suspicion of haemophagocytic lymphohistiocytosis, even without haemophagocytosis on bone marrow, could prompt early treatment and possibly reduce mortality.
A need for adult-specific diagnostic criteria for haemophagocytic lymphohistiocytosis which may lead to a prompt diagnosis.
To be aware of and avoid diagnostic momentum – in this case, a previous diagnosis of biliary sepsis, without any radiological evidence and non-response to antibiotics.
Acknowledgements
None.
Declarations
Provenance: Not commissioned.
ORCID iD: Andrew Coppola https://orcid.org/0000-0002-6757-9876
Competing Interests: None declared.
Funding: None declared.
Ethics approval: Written informed consent was obtained from the patient's spouse for publication of the case report and accompanying images.
Guarantor: MR.
Contributorship: All authors (AC, CC, EO and MR) were involved in the care of the patient. AC, CC and MR prepared the manuscript, EO assisted with revisions, and all authors approved the final version. | 1 g (grams). | DrugDosage | CC BY-NC | 33717491 | 19,225,049 | 2021-03 |
What was the outcome of reaction 'Tumour lysis syndrome'? | A rare cause of acute liver failure due to haemophagocytic lymphohistiocytosis secondary to diffuse large B-cell lymphoma.
Acute liver failure is a life-threatening condition commonly caused by drug-induced hepatotoxicity or viral hepatitides. However, there are a number of rarer causes such as haemophagocytic lymphohistiocytosis. Haemophagocytic lymphohistiocytosis is a syndrome of uncontrolled immune cell activation, triggered by infection or malignancy, which carries a high mortality. Whilst mild to moderate liver injury is commonly seen with haemophagocytic lymphohistiocytosis, acute liver failure has rarely been reported in adults. We present a case of a 74-year-old man with acute liver failure secondary to haemophagocytic lymphohistiocytosis triggered by undiagnosed large B-cell lymphoma. Initially treated for biliary sepsis, there was a delay in the diagnosis of haemophagocytic lymphohistiocytosis and despite initiating chemotherapy, he died soon after. This case highlights the importance of considering haemophagocytic lymphohistiocytosis as a rare cause of acute liver failure, as given the life-threatening potential of haemophagocytic lymphohistiocytosis, a prompt diagnosis may allow early initiation of chemotherapy for any chance of survival.
Background
Acute liver failure (ALF) is a rare condition that varies in aetiology and prognosis. Paracetamol-induced hepatotoxicity in the United Kingdom and viral hepatitis globally are the predominant causes; however, a significant number of cases remain undetermined.1,2 Haemophagocytic lymphohistiocytosis (HLH), a syndrome of uncontrolled immune cell activation, can occur as a primary or acquired disorder.3 Mild to moderate liver injury is a common complication of Haemophagocytic lymphohistiocytosis (HLH) in 80% of patients.4 However rarely, patients may present with Acute Liver Failure.5 The mortality of Haemophagocytic lymphohistiocytosis ranges between 41% and 75% and with associated Acute Liver Failure the prognosis is significantly poorer.4,6 Due to the rarity of the Acute Liver Failure caused by Haemophagocytic lymphohistiocytosis, the diagnosis is often not considered, resulting in delayed treatment and contributing to the high mortality. Herein we present a rare case of an elderly patient who developed Acute Liver Failure secondary to Haemophagocytic lymphohistiocytosi caused by an underlying newly diagnosed B-cell lymphoma, a review of the literature and lessons learnt.
Case presentation
A 74-year-old male presented with a one-month history of worsening pruritus, confusion with multiple falls and fever. He had suffered with lethargy and night sweats for a number of months. There was no history of liver disease but had had previous coronary stenting for ischaemic heart disease for which he was taking aspirin. He was a non-smoker and occasionally consumed alcohol.
On arrival, he was pyrexial and tachycardic but abdominal examination was unremarkable. Initial blood tests revealed: deranged liver function (Bilirubin 28, Alanine transaminase 106, Alkaline phosphatase 600) with synthetic impairment (INR 2.0, Albumin 29), pancytopenia (Haemoglobin 85; White Cell Count 2.7, Platelets 71) and raised C-reactive protein 55 (Figures 1 and 2). On the basis of a fever and deranged liver function, the patient was initiated on co-amoxiclav for biliary sepsis. However, an abdominal ultrasound showed a thickened gallbladder without any stones nor biliary duct dilatation, and a normal liver and portal venous flow. The spleen was enlarged at 16 cm containing a hypoechoic area 30 × 43 mm. The latter finding was confirmed by a CT abdomen (Figure 3). A subsequent magnetic resonance cholangiopancreatography was normal. The work-up for acute liver injury including viral serology, autoimmune screen and immunoglobulins was unrevealing. Several blood cultures taken for ongoing spiking temperature were negative. Figure 1. Full blood count and clotting results.
Figure 2. Liver function results.
Figure 3. CT image demonstrating an enlarged spleen at 16 cm.
Differential diagnosis
The differential diagnosis included a splenic abscess and haematological malignancy given the imaging so he was discussed in the haematology cancer multidisciplinary meeting.
Clinical course
Despite initial treatment with co-amoxiclav, he continued to spike fevers and suffered haemodynamic instability necessitating two medical emergency calls. Antibiotics were escalated to Piperacillin/Tazobactam on Day 4. Blood tests showed raised lactate, worsening pancytopenia, acute kidney injury and further deterioration in liver function with the development of jaundice and INR up to 2.0 (Figures 2 and 4). Initial Lactate dehydrogenase was raised at >2000 IU/L and ferritin >3000 ug/L. Figure 4. Urea and electrolyte results.
He had a staging CT as per haematology multidisciplinary team recommendation, which showed new bilateral pleural effusions, minimal ascites and peri-pancreatic stranding suggestive of mild pancreatitis. However, the clinical picture was not in keeping with acute pancreatitis and the amylase was only marginally raised at 125 iu/L, so this was deemed unlikely. The haematology team performed a bone marrow aspirate and trephine biopsy. The patient further deteriorated with development of hepatic encephalopathy, hypoxia and hypotensive with a persistent tachycardia. The patient was given fluid resuscitation, and the antibiotics were further escalated to Meropenem. A hepatology review recommended to check for Hepatitis A, Hepatitis E, Hepatitis B core antibody, leptospirosis, Brucella, and herpes simplex virus serology, all of which were normal.
Preliminary bone marrow biopsy results showed reactive changes only, indicating infection. There was no evidence of lymphoma, or haemophagocytosis. By Day 11, the patient had continued to deteriorate with development of multi-organ failure involving liver, bone marrow and kidneys. Despite the reactive bone marrow results, a clinical diagnosis of haemophagocytic lymphohistiocytosis was considered by the ward consultant as the patient met the clinical criteria for HLH-2004 (Table 1). After discussion with the haematology consultant, who agreed, a joint decision was made to administer 1 g of methylprednisolone to the patient, with the family’s consent. Unfortunately the patient then deteriorated rapidly and with intensive care input, there was a consensus of imminent death (pH 6.89, Lactate 17.8) and he soon after passed away on the ward. Table 1. HLH-2004 diagnostic criteria fulfilled.21
HLH [21] Our patient
Splenomegaly + +
Fever > 38.5 + +
Cytopenia (>1 lineages required)
Haemoglobin <90 g/l 85 g/l
Platelets <100 × 109/l 71 × 109/l
Neutrophils <1.0 × 109/l –
Hypertriglyceridemia or hypofibrinogenaemia
Hypertriglyceridemia ≥3.0 mmol/l 3.8 mmol/l
Hypofibrinogenaemia ≤1.5 g/L −
Haemophagocytosis in bone marrow + −
Low or absent nk cell activity + Not determined
Ferritin >500 ng/ml ≥500 ng/ml 11295 ng/ml
Elevated soluble CD25 ≥2400 U/ml Not determined
Bone marrow trephine biopsy result eventually confirmed diffuse large B-cell lymphoma with 80% blast, confirming haemophagocytic lymphohistiocytosis with underlying malignancy (Figure 5). Figure 5. Bone marrow trephine biopsy images. (a) Microscopy showing atypical cells with irregular nuclei and prominent nucleoli (×600). (b) Immunohistochemistry to show B cell nature of atypical cells (×400).
Outcome and follow-up
The patient died as an inpatient during his admission.
Discussion
Haemophagocytic lymphohistiocytosis is a clinical syndrome of excessive macrophage activation7 which rarely causes acute liver failure. Herein we have presented a case of acute liver failure secondary to haemophagocytic lymphohistiocytosis due to an undiagnosed large B-cell lymphoma in an elderly gentleman. haemophagocytic lymphohistiocytosis is classified as primary or secondary, resulting in defective natural killer cell function. The primary form, usually seen in infants and children, results from genetic missense mutations in the perforin genes, responsible for NK cell and cytotoxic T lymphocyte function.8,9 Secondary haemophagocytic lymphohistiocytosis, seen in adults, is caused by infections, malignancy, rheumatological and metabolic diseases. Epstein–Barr virus is the most consistent, in up to a third of secondary haemophagocytic lymphohistiocytosis.10 Malignancies are accountable for up to 27% of secondary haemophagocytic lymphohistiocytosis and of these haematological are of the highest prevalence.11
Malignancy-associated haemophagocytic lymphohistiocytosis
Previously a rare entity, malignancy-associated haemophagocytic lymphohistiocytosis has been shown in recent retrospective studies to be evident in up to 1% of underlying malignancies at diagnosis. For rare subtypes of B-cell lymphoma, it could be as high as 20% (intravascular B-cell lymphoma or B-cell lymphoma without peripheral adenopathies).12 Malignancy associated haemophagocytic lymphohistiocytosis may present as a feature of an undiagnosed malignancy as in our patient with B-cell lymphoma, or upon initiation of immune modulating therapies. It is understood that the disruption of immune homeostasis from malignancies and associated therapies promoting a degree of T-cell dysfunction can act as the trigger for Malignancy associated haemophagocytic lymphohistiocytosis.13
Liver injury in haemophagocytic lymphohistiocytosis
Liver injury is a common complication of haemophagocytic lymphohistiocytosis with varying degrees of insult but acute liver failure is rarely reported. The pathophysiology of acute liver failure in haemophagocytic lymphohistiocytosis remains largely unknown. It is theorised that infiltration of activated haemophagocytic histiocytes or the increased cytokine production associated with haemophagocytic lymphohistiocytosis results in liver injury.14 This can be further compounded by liver injury caused by the underlying disease.15,16 The histopathological findings in the liver of patients with haemophagocytic lymphohistiocytosis are non-specific and can include hepatocellular necrosis, sinusoidal dilatation, endothelialitis and steatosis.3
B-cell lymphoma can present rarely as acute liver failure17 and this is usually as a manifestation of end-stage malignant disease.18 The liver injury and extensive cholangitis are due to malignant infiltrates of intrahepatic ducts, hepatic venules and the hepatic parenchyma itself.19 In our case, imaging failed to demonstrate any liver infiltrates and the liver appeared normal, therefore suggesting haemophagocytic lymphohistiocytosis as the predominant cause of the acute liver failure rather than due to malignant infiltration.
Presentation and diagnosis of haemophagocytic lymphohistiocytosis
Diagnosis of haemophagocytic lymphohistiocytosis is challenging due to its rare occurrence and non-specific presentation.9 Patients with haemophagocytic lymphohistiocytosis characteristically present with a varying picture of cytopenia, fever and multiple organ involvement.20 The HLH-2004 study of paediatric patients devised criteria for diagnosis. The following clinical findings were common: Fever (95%), splenomegaly (89%), bicytopenia (92%), hypertriglyceridaemia or hypofibrinogenaemia (90%), haemophagocytosis (82%), ferritin >500 mcg/L (94%), low/absent NK cell activity (71%) and soluble CD25 elevation (97%).21,22 To fulfil the diagnostic criteria, five of the eight are required. Alternatively, it can be diagnosed with genetic testing.21 These criteria are based on paediatric patients and there is an unmet need for adult specific criteria, in particularly for m-haemophagocytic lymphohistiocytosis, in order to prevent missed or delayed diagnosis in adults.
Our patient met five out of the eight criteria required for diagnosis of haemophagocytic lymphohistiocytosis per HLH-2004 (Table 1). One of the remaining criteria of haemophagocytosis in the bone marrow was not seen in our case – it showed reactive changes only. In fact, often haemophagocytosis may not be seen on the initial bone marrow as pathological changes due to haemophagocytic lymphohistiocytosis may take days or weeks to manifest and it is not considered pathognomonic for haemophagocytic lymphohistiocytosis. Thus, the absence of haemophagocytosis on the initial bone marrow should not delay treatment in cases where there is a high clinical suspicion for haemophagocytic lymphohistiocytosis.13
The clinical course of Malignancy associated haemophagocytic lymphohistiocytosis is often rapidly progressing and characterised by poor outcomes.13 The management of Malignancy associated haemophagocytic lymphohistiocytosis is a focus of debate. Whilst it seems logical to treat the underlying cause, these patients are in a hyperinflammatory state with an ongoing cytokine storm and giving chemotherapy to treat an underlying malignancy may have a deleterious effect. An approach that involves controlling the cytokine storm and the underlying malignancy would be preferable.13
In our case, the underlying cause of haemophagocytic lymphohistiocytosis was unknown and we had no evidence to suggest that a malignant process was driving the haemophagocytic lymphohistiocytosis and the more common cause of viral infection was higher in the differential diagnosis. It was decided to initiate chemotherapy with methylprednisolone as the patient’s condition was deteriorating, in the hope that he may respond and with no other treatment options. Unfortunately, he most certainly developed tumour lysis syndrome due to undiagnosed B-cell lymphoma after giving methylprednisolone which hastened his death.
Conclusion
Our case emphasises the importance of considering haemophagocytic lymphohistiocytosis as a rare cause of acute liver failure. A condition more common in paediatrics, recent literature shows an increasing prevalence of haemophagocytic lymphohistiocytosis in adults with poor prognoses.23,24 A delay in diagnosis is a key contributor to the mortality rate,4,6,25 thus we hope to raise awareness amongst physicians about this diagnosis.
Patient consent
Written informed consent for patient information and images to be published was provided by the patient’s spouse.
Learning points/take home messages
Haemophagocytic lymphohistiocytosis is a rare cause of acute liver failure.
A high clinical suspicion of haemophagocytic lymphohistiocytosis, even without haemophagocytosis on bone marrow, could prompt early treatment and possibly reduce mortality.
A need for adult-specific diagnostic criteria for haemophagocytic lymphohistiocytosis which may lead to a prompt diagnosis.
To be aware of and avoid diagnostic momentum – in this case, a previous diagnosis of biliary sepsis, without any radiological evidence and non-response to antibiotics.
Acknowledgements
None.
Declarations
Provenance: Not commissioned.
ORCID iD: Andrew Coppola https://orcid.org/0000-0002-6757-9876
Competing Interests: None declared.
Funding: None declared.
Ethics approval: Written informed consent was obtained from the patient's spouse for publication of the case report and accompanying images.
Guarantor: MR.
Contributorship: All authors (AC, CC, EO and MR) were involved in the care of the patient. AC, CC and MR prepared the manuscript, EO assisted with revisions, and all authors approved the final version. | Not recovered | ReactionOutcome | CC BY-NC | 33717491 | 19,225,049 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | Atypical Hemolytic Uremic Syndrome: Cancer-Induced or Chemotherapy-Induced?
Atypical hemolytic uremic syndrome (aHUS) is an atypical type of thrombotic microangiopathy (TMA), which is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and thrombi in small blood vessels, leading to end-organ damage. aHUS causes an over-activation of the complement pathway. There are many etiologies of aHUS, including inherited and acquired. This condition has a high mortality rate, as it is often detected late in the disease course. Eculizumab, an inhibitor of the terminal complement pathway, needs to be prescribed as soon as the diagnosis is confirmed. There is limited evidence, however, regarding the duration of treatment. Therefore, it is vital to conduct further analysis on other alternatives and pharmacokinetics with this type of complement inhibitor.
Introduction
Hemolytic uremic syndrome (HUS), the most common subtype of thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. TMA are classified into three major categories, including Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS), thrombotic thrombocytopenic purpura (TTP), and aHUS [1].
The most common preceding factor leading to typical HUS is infective diarrhea caused specifically by Shiga toxin-producing Escherichia (E.) coli (STEC ) or E. coli O157:H7. Conversely, aHUS has many possible etiologies, including malignancy, pregnancy, organ transplantation, human immunodeficiency virus (HIV), upper respiratory tract infections, non-E. coli diarrheal illnesses, and the use of certain drugs such as oral contraceptives (OCPs), ticlopidine, quinine, cyclosporine, tacrolimus. aHUS accounts for 5%-10% of all documented cases of HUS and is associated with a poor prognosis [2].
Our objective is to present a patient diagnosed with aHUS due to an underlying malignancy. Early diagnosis and treatment is vital, as aHUS can be life-threatening.
Case presentation
A 67-year-old Caucasian male was diagnosed with an unresectable form of ductal adenocarcinoma of the pancreatic head (Figure 1) based on clinical impression and imaging modalities, including computed tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP). Prior to the diagnosis, he had persistent symptoms of infrequent vague abdomen pain for one year associated with early satiety, belching, and a seven to eight-pound weight loss.
Figure 1 CT scan abdomen: CA pancreas
Poorly delineated pancreatic head-neck junction mass measuring approximately 1.5 x 1 cm. There is ductal dilatation proximal to the mass up to 5 mm. Soft tissue density infiltration extending around the proximal portal vein, central superior mesenteric vein, central splenic vein, and proximal superior mesenteric artery is suspicious for locally advanced, unresectable disease. It also showed intra and extrahepatic biliary duct dilatation related to obstruction by the mass.
CT: computed tomography; CA: Cancer
Intravenous gemcitabine and albumin-bound paclitaxel chemotherapy regimens were administered for his stage T2a, N, M pancreatic cancer. After five months of gemcitabine therapy (cumulative dose 11,050 mg), the patient complained of severe fatigue, which was initially attributed to moderate anemia caused by the chemotherapy.
A baseline complete blood count (CBC) and serum chemistry panel were within the normal range (serum creatinine 0.72 mg/ dL ). His serum creatinine increased steadily to 3.96 mg/dL after six cycles of single-agent gemcitabine (cumulative dose of gemcitabine 11,050 mg), and his platelet count dropped to 90k/mcl. Peripheral blood smear (PBS) showed rare schistocytes (Figure 2 and Figure 3). LDH was 514 IU/L and haptoglobin <10 mg/dL. His C3 and C4 levels were within normal limits. Urinalysis showed hematuria and 2+ protein. ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was 53%. Direct and indirect Coomb’s test results were negative.
Figure 2 Peripheral blood film showing numerous schistocytes
Permission was taken from the original publisher; adapted from Jain et al. [3]
Figure 3 Schistocytes under magnification
Permission was taken from the original publisher; adapted from Jain et al. [3]
Gemcitabine was discontinued in view of possible TMA. There was no improvement in his hematologic or renal parameters for a few weeks after stopping the chemotherapy. A kidney biopsy was performed, which showed conclusive features of aHUS (Figures 4-5). ADAMTS13 activity assay values of 53% in our case ruled out TTP. Also, STEC-HUS as another differential diagnosis was excluded with no history of diarrhea and absence of Shiga toxin detection in the stool specimen.
Figure 4 Kidney biopsy
Jones silver stain
Figure 5 Kidney biopsy
Masson trichrome stain
Eculizumab 900 mg was administered subcutaneously on weekly basis for four weeks after meningococcal vaccination. His serum creatinine stabilized after eculizumab administration between 2.60-3.00 mg/dL. Due to a lack of viable options, as well as a poor performance status, the patient opted for palliative care and died four months later.
Discussion
There are two factors that give rise to TMA in patients with an underlying malignancy (Table 1). First, the malignancy itself can cause TMA, either via metastases of the microvasculature or direct spread to the bone marrow. Also, different chemotherapy regimens, including gemcitabine, cisplatin, bevacizumab, and mitomycin-C can induce TMA either through direct endothelial damage or by an immune-mediated mechanism with the development of drug-dependent autoantibodies [4-5].
Table 1 Mechanism of TMA in malignancy
Source: [5]
MAHA: microangiopathic hemolytic anemia; TMA: thrombotic microangiopathy
Cause of TMA MAHA and Thrombocytopenia Mechanism
Cancer-induced TMA Present Systemic microvascular metastases and bone marrow metastases or necrosis
Chemotherapy-induced TMA Present Dose-dependent toxicity and drug-dependent antibody reaction
Discerning malignancy-induced TMA versus medication-induced TMA is important for managing the patient appropriately [5]. Symptoms such as weakness, weight loss, cough, shortness of breath, and pain are commonly associated in patients with cancer-induced TMA [5]. Unusual findings of MAHA and thrombocytopenia without evidence of any end-organ damage are also important clues in considering the development of TMA. Our patient with pancreatic cancer suffered from gemcitabine-induced hemolytic uremic syndrome (GiHUS).
GiHUS should be suspected in a patient with malignancy when renal dysfunction occurs with no obvious cause. aHUS may not present at acute onset with all classic signs (i.e. thrombocytopenia, MAHA, acute renal failure). The diagnosis of aHUS can be challenging given the significant clinical overlap of the various TMAs (Table 2).
Table 2 Laboratory features of the three forms of thrombotic microangiopathy are presented
Source: [6]
aHUS: atypical hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; STEC-HUS: Shiga toxin-producing Escherichia coli hemolytic uremic syndrome
Anemia Thrombocytopenia Target organ injury ADAMTS 13 Shiga-Toxin Diagnosis
Present Present Present >5% Negative aHUS
Present Present Present <5% Negative TTP
Present Present Present Normal Positive STEC -HUS
The incidence of GiHUS has been reported to be between 0.02% and 2.2% [7-8]. The removal of the causative agent from the treatment is often sufficient to resolve abnormal hematological and renal parameters. Our patient did not demonstrate any substantial improvement despite being off the offending chemotherapeutic agent for one month.
Eculizumab, a complement component inhibitor, which binds to C5, blocks the generation of proinflammatory C5a and C5b-9 in the complement system. It has been shown to be effective in treating chemotherapy-induced TMA or aHUS [9]. A report of one case series on four patients with GiHUS who progressed despite stopping chemotherapy showed that eculizumab proved effective in all four patients. Their anemia and renal function improved, with no adverse events [9]. In our patient, treatment with eculizumab resulted in some improvement in his kidney function, likely due to the dysregulation of the complement pathway. Eculizumab has been approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), aHUS, and refractory generalized myasthenia gravis (gMG) [10]. This medication is associated with certain risks, one of them being the increased susceptibility to infection with Neisseria meningitidis or meningococcus [11]. All patients must be vaccinated with a meningococcal vaccine before beginning treatment. The potential long-term effects of this medication, including hepatotoxicity, have been reported [12-13]. So far, many trials have been conducted to study the effect of improved and alternative complement inhibitors. Phase III trials are currently ongoing to study the long-acting variant of eculizumab-ravulizumab in patients with PNH and aHUS [14-15].
Conclusions
In patients receiving gemcitabine for any malignancies, either therapeutic or palliative, clinicians should have a low threshold for suspecting HUS in the presence of worsening anemia, thrombocytopenia, and/or renal function. Eculizumab has been approved since 2011 in many developed countries for the treatment of aHUS, but its use is limited due to cost, unknown treatment duration, and vague dose intervals to keep patients in remission. New complement-directed therapeutics and the development of biomarkers that predict preclinical TMA should be the main drivers in preventing severe complement-related disorders.
Human Ethics
The completion of this undertaking could not have been possible without the participation and assistance of so many people whose names may not all be enumerated. Their contributions are sincerely appreciated and gratefully acknowledged. To all relatives, friends, and others who in one way or another shared their support, either morally, financially, and physically, thank you.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | GEMCITABINE\GEMCITABINE HYDROCHLORIDE, PACLITAXEL | DrugsGivenReaction | CC BY | 33717763 | 19,089,437 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atypical haemolytic uraemic syndrome'. | Atypical Hemolytic Uremic Syndrome: Cancer-Induced or Chemotherapy-Induced?
Atypical hemolytic uremic syndrome (aHUS) is an atypical type of thrombotic microangiopathy (TMA), which is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and thrombi in small blood vessels, leading to end-organ damage. aHUS causes an over-activation of the complement pathway. There are many etiologies of aHUS, including inherited and acquired. This condition has a high mortality rate, as it is often detected late in the disease course. Eculizumab, an inhibitor of the terminal complement pathway, needs to be prescribed as soon as the diagnosis is confirmed. There is limited evidence, however, regarding the duration of treatment. Therefore, it is vital to conduct further analysis on other alternatives and pharmacokinetics with this type of complement inhibitor.
Introduction
Hemolytic uremic syndrome (HUS), the most common subtype of thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. TMA are classified into three major categories, including Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS), thrombotic thrombocytopenic purpura (TTP), and aHUS [1].
The most common preceding factor leading to typical HUS is infective diarrhea caused specifically by Shiga toxin-producing Escherichia (E.) coli (STEC ) or E. coli O157:H7. Conversely, aHUS has many possible etiologies, including malignancy, pregnancy, organ transplantation, human immunodeficiency virus (HIV), upper respiratory tract infections, non-E. coli diarrheal illnesses, and the use of certain drugs such as oral contraceptives (OCPs), ticlopidine, quinine, cyclosporine, tacrolimus. aHUS accounts for 5%-10% of all documented cases of HUS and is associated with a poor prognosis [2].
Our objective is to present a patient diagnosed with aHUS due to an underlying malignancy. Early diagnosis and treatment is vital, as aHUS can be life-threatening.
Case presentation
A 67-year-old Caucasian male was diagnosed with an unresectable form of ductal adenocarcinoma of the pancreatic head (Figure 1) based on clinical impression and imaging modalities, including computed tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP). Prior to the diagnosis, he had persistent symptoms of infrequent vague abdomen pain for one year associated with early satiety, belching, and a seven to eight-pound weight loss.
Figure 1 CT scan abdomen: CA pancreas
Poorly delineated pancreatic head-neck junction mass measuring approximately 1.5 x 1 cm. There is ductal dilatation proximal to the mass up to 5 mm. Soft tissue density infiltration extending around the proximal portal vein, central superior mesenteric vein, central splenic vein, and proximal superior mesenteric artery is suspicious for locally advanced, unresectable disease. It also showed intra and extrahepatic biliary duct dilatation related to obstruction by the mass.
CT: computed tomography; CA: Cancer
Intravenous gemcitabine and albumin-bound paclitaxel chemotherapy regimens were administered for his stage T2a, N, M pancreatic cancer. After five months of gemcitabine therapy (cumulative dose 11,050 mg), the patient complained of severe fatigue, which was initially attributed to moderate anemia caused by the chemotherapy.
A baseline complete blood count (CBC) and serum chemistry panel were within the normal range (serum creatinine 0.72 mg/ dL ). His serum creatinine increased steadily to 3.96 mg/dL after six cycles of single-agent gemcitabine (cumulative dose of gemcitabine 11,050 mg), and his platelet count dropped to 90k/mcl. Peripheral blood smear (PBS) showed rare schistocytes (Figure 2 and Figure 3). LDH was 514 IU/L and haptoglobin <10 mg/dL. His C3 and C4 levels were within normal limits. Urinalysis showed hematuria and 2+ protein. ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was 53%. Direct and indirect Coomb’s test results were negative.
Figure 2 Peripheral blood film showing numerous schistocytes
Permission was taken from the original publisher; adapted from Jain et al. [3]
Figure 3 Schistocytes under magnification
Permission was taken from the original publisher; adapted from Jain et al. [3]
Gemcitabine was discontinued in view of possible TMA. There was no improvement in his hematologic or renal parameters for a few weeks after stopping the chemotherapy. A kidney biopsy was performed, which showed conclusive features of aHUS (Figures 4-5). ADAMTS13 activity assay values of 53% in our case ruled out TTP. Also, STEC-HUS as another differential diagnosis was excluded with no history of diarrhea and absence of Shiga toxin detection in the stool specimen.
Figure 4 Kidney biopsy
Jones silver stain
Figure 5 Kidney biopsy
Masson trichrome stain
Eculizumab 900 mg was administered subcutaneously on weekly basis for four weeks after meningococcal vaccination. His serum creatinine stabilized after eculizumab administration between 2.60-3.00 mg/dL. Due to a lack of viable options, as well as a poor performance status, the patient opted for palliative care and died four months later.
Discussion
There are two factors that give rise to TMA in patients with an underlying malignancy (Table 1). First, the malignancy itself can cause TMA, either via metastases of the microvasculature or direct spread to the bone marrow. Also, different chemotherapy regimens, including gemcitabine, cisplatin, bevacizumab, and mitomycin-C can induce TMA either through direct endothelial damage or by an immune-mediated mechanism with the development of drug-dependent autoantibodies [4-5].
Table 1 Mechanism of TMA in malignancy
Source: [5]
MAHA: microangiopathic hemolytic anemia; TMA: thrombotic microangiopathy
Cause of TMA MAHA and Thrombocytopenia Mechanism
Cancer-induced TMA Present Systemic microvascular metastases and bone marrow metastases or necrosis
Chemotherapy-induced TMA Present Dose-dependent toxicity and drug-dependent antibody reaction
Discerning malignancy-induced TMA versus medication-induced TMA is important for managing the patient appropriately [5]. Symptoms such as weakness, weight loss, cough, shortness of breath, and pain are commonly associated in patients with cancer-induced TMA [5]. Unusual findings of MAHA and thrombocytopenia without evidence of any end-organ damage are also important clues in considering the development of TMA. Our patient with pancreatic cancer suffered from gemcitabine-induced hemolytic uremic syndrome (GiHUS).
GiHUS should be suspected in a patient with malignancy when renal dysfunction occurs with no obvious cause. aHUS may not present at acute onset with all classic signs (i.e. thrombocytopenia, MAHA, acute renal failure). The diagnosis of aHUS can be challenging given the significant clinical overlap of the various TMAs (Table 2).
Table 2 Laboratory features of the three forms of thrombotic microangiopathy are presented
Source: [6]
aHUS: atypical hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; STEC-HUS: Shiga toxin-producing Escherichia coli hemolytic uremic syndrome
Anemia Thrombocytopenia Target organ injury ADAMTS 13 Shiga-Toxin Diagnosis
Present Present Present >5% Negative aHUS
Present Present Present <5% Negative TTP
Present Present Present Normal Positive STEC -HUS
The incidence of GiHUS has been reported to be between 0.02% and 2.2% [7-8]. The removal of the causative agent from the treatment is often sufficient to resolve abnormal hematological and renal parameters. Our patient did not demonstrate any substantial improvement despite being off the offending chemotherapeutic agent for one month.
Eculizumab, a complement component inhibitor, which binds to C5, blocks the generation of proinflammatory C5a and C5b-9 in the complement system. It has been shown to be effective in treating chemotherapy-induced TMA or aHUS [9]. A report of one case series on four patients with GiHUS who progressed despite stopping chemotherapy showed that eculizumab proved effective in all four patients. Their anemia and renal function improved, with no adverse events [9]. In our patient, treatment with eculizumab resulted in some improvement in his kidney function, likely due to the dysregulation of the complement pathway. Eculizumab has been approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), aHUS, and refractory generalized myasthenia gravis (gMG) [10]. This medication is associated with certain risks, one of them being the increased susceptibility to infection with Neisseria meningitidis or meningococcus [11]. All patients must be vaccinated with a meningococcal vaccine before beginning treatment. The potential long-term effects of this medication, including hepatotoxicity, have been reported [12-13]. So far, many trials have been conducted to study the effect of improved and alternative complement inhibitors. Phase III trials are currently ongoing to study the long-acting variant of eculizumab-ravulizumab in patients with PNH and aHUS [14-15].
Conclusions
In patients receiving gemcitabine for any malignancies, either therapeutic or palliative, clinicians should have a low threshold for suspecting HUS in the presence of worsening anemia, thrombocytopenia, and/or renal function. Eculizumab has been approved since 2011 in many developed countries for the treatment of aHUS, but its use is limited due to cost, unknown treatment duration, and vague dose intervals to keep patients in remission. New complement-directed therapeutics and the development of biomarkers that predict preclinical TMA should be the main drivers in preventing severe complement-related disorders.
Human Ethics
The completion of this undertaking could not have been possible without the participation and assistance of so many people whose names may not all be enumerated. Their contributions are sincerely appreciated and gratefully acknowledged. To all relatives, friends, and others who in one way or another shared their support, either morally, financially, and physically, thank you.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | GEMCITABINE\GEMCITABINE HYDROCHLORIDE, PACLITAXEL | DrugsGivenReaction | CC BY | 33717763 | 19,089,437 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'General physical health deterioration'. | Atypical Hemolytic Uremic Syndrome: Cancer-Induced or Chemotherapy-Induced?
Atypical hemolytic uremic syndrome (aHUS) is an atypical type of thrombotic microangiopathy (TMA), which is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and thrombi in small blood vessels, leading to end-organ damage. aHUS causes an over-activation of the complement pathway. There are many etiologies of aHUS, including inherited and acquired. This condition has a high mortality rate, as it is often detected late in the disease course. Eculizumab, an inhibitor of the terminal complement pathway, needs to be prescribed as soon as the diagnosis is confirmed. There is limited evidence, however, regarding the duration of treatment. Therefore, it is vital to conduct further analysis on other alternatives and pharmacokinetics with this type of complement inhibitor.
Introduction
Hemolytic uremic syndrome (HUS), the most common subtype of thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. TMA are classified into three major categories, including Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS), thrombotic thrombocytopenic purpura (TTP), and aHUS [1].
The most common preceding factor leading to typical HUS is infective diarrhea caused specifically by Shiga toxin-producing Escherichia (E.) coli (STEC ) or E. coli O157:H7. Conversely, aHUS has many possible etiologies, including malignancy, pregnancy, organ transplantation, human immunodeficiency virus (HIV), upper respiratory tract infections, non-E. coli diarrheal illnesses, and the use of certain drugs such as oral contraceptives (OCPs), ticlopidine, quinine, cyclosporine, tacrolimus. aHUS accounts for 5%-10% of all documented cases of HUS and is associated with a poor prognosis [2].
Our objective is to present a patient diagnosed with aHUS due to an underlying malignancy. Early diagnosis and treatment is vital, as aHUS can be life-threatening.
Case presentation
A 67-year-old Caucasian male was diagnosed with an unresectable form of ductal adenocarcinoma of the pancreatic head (Figure 1) based on clinical impression and imaging modalities, including computed tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP). Prior to the diagnosis, he had persistent symptoms of infrequent vague abdomen pain for one year associated with early satiety, belching, and a seven to eight-pound weight loss.
Figure 1 CT scan abdomen: CA pancreas
Poorly delineated pancreatic head-neck junction mass measuring approximately 1.5 x 1 cm. There is ductal dilatation proximal to the mass up to 5 mm. Soft tissue density infiltration extending around the proximal portal vein, central superior mesenteric vein, central splenic vein, and proximal superior mesenteric artery is suspicious for locally advanced, unresectable disease. It also showed intra and extrahepatic biliary duct dilatation related to obstruction by the mass.
CT: computed tomography; CA: Cancer
Intravenous gemcitabine and albumin-bound paclitaxel chemotherapy regimens were administered for his stage T2a, N, M pancreatic cancer. After five months of gemcitabine therapy (cumulative dose 11,050 mg), the patient complained of severe fatigue, which was initially attributed to moderate anemia caused by the chemotherapy.
A baseline complete blood count (CBC) and serum chemistry panel were within the normal range (serum creatinine 0.72 mg/ dL ). His serum creatinine increased steadily to 3.96 mg/dL after six cycles of single-agent gemcitabine (cumulative dose of gemcitabine 11,050 mg), and his platelet count dropped to 90k/mcl. Peripheral blood smear (PBS) showed rare schistocytes (Figure 2 and Figure 3). LDH was 514 IU/L and haptoglobin <10 mg/dL. His C3 and C4 levels were within normal limits. Urinalysis showed hematuria and 2+ protein. ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was 53%. Direct and indirect Coomb’s test results were negative.
Figure 2 Peripheral blood film showing numerous schistocytes
Permission was taken from the original publisher; adapted from Jain et al. [3]
Figure 3 Schistocytes under magnification
Permission was taken from the original publisher; adapted from Jain et al. [3]
Gemcitabine was discontinued in view of possible TMA. There was no improvement in his hematologic or renal parameters for a few weeks after stopping the chemotherapy. A kidney biopsy was performed, which showed conclusive features of aHUS (Figures 4-5). ADAMTS13 activity assay values of 53% in our case ruled out TTP. Also, STEC-HUS as another differential diagnosis was excluded with no history of diarrhea and absence of Shiga toxin detection in the stool specimen.
Figure 4 Kidney biopsy
Jones silver stain
Figure 5 Kidney biopsy
Masson trichrome stain
Eculizumab 900 mg was administered subcutaneously on weekly basis for four weeks after meningococcal vaccination. His serum creatinine stabilized after eculizumab administration between 2.60-3.00 mg/dL. Due to a lack of viable options, as well as a poor performance status, the patient opted for palliative care and died four months later.
Discussion
There are two factors that give rise to TMA in patients with an underlying malignancy (Table 1). First, the malignancy itself can cause TMA, either via metastases of the microvasculature or direct spread to the bone marrow. Also, different chemotherapy regimens, including gemcitabine, cisplatin, bevacizumab, and mitomycin-C can induce TMA either through direct endothelial damage or by an immune-mediated mechanism with the development of drug-dependent autoantibodies [4-5].
Table 1 Mechanism of TMA in malignancy
Source: [5]
MAHA: microangiopathic hemolytic anemia; TMA: thrombotic microangiopathy
Cause of TMA MAHA and Thrombocytopenia Mechanism
Cancer-induced TMA Present Systemic microvascular metastases and bone marrow metastases or necrosis
Chemotherapy-induced TMA Present Dose-dependent toxicity and drug-dependent antibody reaction
Discerning malignancy-induced TMA versus medication-induced TMA is important for managing the patient appropriately [5]. Symptoms such as weakness, weight loss, cough, shortness of breath, and pain are commonly associated in patients with cancer-induced TMA [5]. Unusual findings of MAHA and thrombocytopenia without evidence of any end-organ damage are also important clues in considering the development of TMA. Our patient with pancreatic cancer suffered from gemcitabine-induced hemolytic uremic syndrome (GiHUS).
GiHUS should be suspected in a patient with malignancy when renal dysfunction occurs with no obvious cause. aHUS may not present at acute onset with all classic signs (i.e. thrombocytopenia, MAHA, acute renal failure). The diagnosis of aHUS can be challenging given the significant clinical overlap of the various TMAs (Table 2).
Table 2 Laboratory features of the three forms of thrombotic microangiopathy are presented
Source: [6]
aHUS: atypical hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; STEC-HUS: Shiga toxin-producing Escherichia coli hemolytic uremic syndrome
Anemia Thrombocytopenia Target organ injury ADAMTS 13 Shiga-Toxin Diagnosis
Present Present Present >5% Negative aHUS
Present Present Present <5% Negative TTP
Present Present Present Normal Positive STEC -HUS
The incidence of GiHUS has been reported to be between 0.02% and 2.2% [7-8]. The removal of the causative agent from the treatment is often sufficient to resolve abnormal hematological and renal parameters. Our patient did not demonstrate any substantial improvement despite being off the offending chemotherapeutic agent for one month.
Eculizumab, a complement component inhibitor, which binds to C5, blocks the generation of proinflammatory C5a and C5b-9 in the complement system. It has been shown to be effective in treating chemotherapy-induced TMA or aHUS [9]. A report of one case series on four patients with GiHUS who progressed despite stopping chemotherapy showed that eculizumab proved effective in all four patients. Their anemia and renal function improved, with no adverse events [9]. In our patient, treatment with eculizumab resulted in some improvement in his kidney function, likely due to the dysregulation of the complement pathway. Eculizumab has been approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), aHUS, and refractory generalized myasthenia gravis (gMG) [10]. This medication is associated with certain risks, one of them being the increased susceptibility to infection with Neisseria meningitidis or meningococcus [11]. All patients must be vaccinated with a meningococcal vaccine before beginning treatment. The potential long-term effects of this medication, including hepatotoxicity, have been reported [12-13]. So far, many trials have been conducted to study the effect of improved and alternative complement inhibitors. Phase III trials are currently ongoing to study the long-acting variant of eculizumab-ravulizumab in patients with PNH and aHUS [14-15].
Conclusions
In patients receiving gemcitabine for any malignancies, either therapeutic or palliative, clinicians should have a low threshold for suspecting HUS in the presence of worsening anemia, thrombocytopenia, and/or renal function. Eculizumab has been approved since 2011 in many developed countries for the treatment of aHUS, but its use is limited due to cost, unknown treatment duration, and vague dose intervals to keep patients in remission. New complement-directed therapeutics and the development of biomarkers that predict preclinical TMA should be the main drivers in preventing severe complement-related disorders.
Human Ethics
The completion of this undertaking could not have been possible without the participation and assistance of so many people whose names may not all be enumerated. Their contributions are sincerely appreciated and gratefully acknowledged. To all relatives, friends, and others who in one way or another shared their support, either morally, financially, and physically, thank you.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | ECULIZUMAB | DrugsGivenReaction | CC BY | 33717763 | 19,046,622 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Atypical Hemolytic Uremic Syndrome: Cancer-Induced or Chemotherapy-Induced?
Atypical hemolytic uremic syndrome (aHUS) is an atypical type of thrombotic microangiopathy (TMA), which is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and thrombi in small blood vessels, leading to end-organ damage. aHUS causes an over-activation of the complement pathway. There are many etiologies of aHUS, including inherited and acquired. This condition has a high mortality rate, as it is often detected late in the disease course. Eculizumab, an inhibitor of the terminal complement pathway, needs to be prescribed as soon as the diagnosis is confirmed. There is limited evidence, however, regarding the duration of treatment. Therefore, it is vital to conduct further analysis on other alternatives and pharmacokinetics with this type of complement inhibitor.
Introduction
Hemolytic uremic syndrome (HUS), the most common subtype of thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. TMA are classified into three major categories, including Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS), thrombotic thrombocytopenic purpura (TTP), and aHUS [1].
The most common preceding factor leading to typical HUS is infective diarrhea caused specifically by Shiga toxin-producing Escherichia (E.) coli (STEC ) or E. coli O157:H7. Conversely, aHUS has many possible etiologies, including malignancy, pregnancy, organ transplantation, human immunodeficiency virus (HIV), upper respiratory tract infections, non-E. coli diarrheal illnesses, and the use of certain drugs such as oral contraceptives (OCPs), ticlopidine, quinine, cyclosporine, tacrolimus. aHUS accounts for 5%-10% of all documented cases of HUS and is associated with a poor prognosis [2].
Our objective is to present a patient diagnosed with aHUS due to an underlying malignancy. Early diagnosis and treatment is vital, as aHUS can be life-threatening.
Case presentation
A 67-year-old Caucasian male was diagnosed with an unresectable form of ductal adenocarcinoma of the pancreatic head (Figure 1) based on clinical impression and imaging modalities, including computed tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP). Prior to the diagnosis, he had persistent symptoms of infrequent vague abdomen pain for one year associated with early satiety, belching, and a seven to eight-pound weight loss.
Figure 1 CT scan abdomen: CA pancreas
Poorly delineated pancreatic head-neck junction mass measuring approximately 1.5 x 1 cm. There is ductal dilatation proximal to the mass up to 5 mm. Soft tissue density infiltration extending around the proximal portal vein, central superior mesenteric vein, central splenic vein, and proximal superior mesenteric artery is suspicious for locally advanced, unresectable disease. It also showed intra and extrahepatic biliary duct dilatation related to obstruction by the mass.
CT: computed tomography; CA: Cancer
Intravenous gemcitabine and albumin-bound paclitaxel chemotherapy regimens were administered for his stage T2a, N, M pancreatic cancer. After five months of gemcitabine therapy (cumulative dose 11,050 mg), the patient complained of severe fatigue, which was initially attributed to moderate anemia caused by the chemotherapy.
A baseline complete blood count (CBC) and serum chemistry panel were within the normal range (serum creatinine 0.72 mg/ dL ). His serum creatinine increased steadily to 3.96 mg/dL after six cycles of single-agent gemcitabine (cumulative dose of gemcitabine 11,050 mg), and his platelet count dropped to 90k/mcl. Peripheral blood smear (PBS) showed rare schistocytes (Figure 2 and Figure 3). LDH was 514 IU/L and haptoglobin <10 mg/dL. His C3 and C4 levels were within normal limits. Urinalysis showed hematuria and 2+ protein. ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was 53%. Direct and indirect Coomb’s test results were negative.
Figure 2 Peripheral blood film showing numerous schistocytes
Permission was taken from the original publisher; adapted from Jain et al. [3]
Figure 3 Schistocytes under magnification
Permission was taken from the original publisher; adapted from Jain et al. [3]
Gemcitabine was discontinued in view of possible TMA. There was no improvement in his hematologic or renal parameters for a few weeks after stopping the chemotherapy. A kidney biopsy was performed, which showed conclusive features of aHUS (Figures 4-5). ADAMTS13 activity assay values of 53% in our case ruled out TTP. Also, STEC-HUS as another differential diagnosis was excluded with no history of diarrhea and absence of Shiga toxin detection in the stool specimen.
Figure 4 Kidney biopsy
Jones silver stain
Figure 5 Kidney biopsy
Masson trichrome stain
Eculizumab 900 mg was administered subcutaneously on weekly basis for four weeks after meningococcal vaccination. His serum creatinine stabilized after eculizumab administration between 2.60-3.00 mg/dL. Due to a lack of viable options, as well as a poor performance status, the patient opted for palliative care and died four months later.
Discussion
There are two factors that give rise to TMA in patients with an underlying malignancy (Table 1). First, the malignancy itself can cause TMA, either via metastases of the microvasculature or direct spread to the bone marrow. Also, different chemotherapy regimens, including gemcitabine, cisplatin, bevacizumab, and mitomycin-C can induce TMA either through direct endothelial damage or by an immune-mediated mechanism with the development of drug-dependent autoantibodies [4-5].
Table 1 Mechanism of TMA in malignancy
Source: [5]
MAHA: microangiopathic hemolytic anemia; TMA: thrombotic microangiopathy
Cause of TMA MAHA and Thrombocytopenia Mechanism
Cancer-induced TMA Present Systemic microvascular metastases and bone marrow metastases or necrosis
Chemotherapy-induced TMA Present Dose-dependent toxicity and drug-dependent antibody reaction
Discerning malignancy-induced TMA versus medication-induced TMA is important for managing the patient appropriately [5]. Symptoms such as weakness, weight loss, cough, shortness of breath, and pain are commonly associated in patients with cancer-induced TMA [5]. Unusual findings of MAHA and thrombocytopenia without evidence of any end-organ damage are also important clues in considering the development of TMA. Our patient with pancreatic cancer suffered from gemcitabine-induced hemolytic uremic syndrome (GiHUS).
GiHUS should be suspected in a patient with malignancy when renal dysfunction occurs with no obvious cause. aHUS may not present at acute onset with all classic signs (i.e. thrombocytopenia, MAHA, acute renal failure). The diagnosis of aHUS can be challenging given the significant clinical overlap of the various TMAs (Table 2).
Table 2 Laboratory features of the three forms of thrombotic microangiopathy are presented
Source: [6]
aHUS: atypical hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; STEC-HUS: Shiga toxin-producing Escherichia coli hemolytic uremic syndrome
Anemia Thrombocytopenia Target organ injury ADAMTS 13 Shiga-Toxin Diagnosis
Present Present Present >5% Negative aHUS
Present Present Present <5% Negative TTP
Present Present Present Normal Positive STEC -HUS
The incidence of GiHUS has been reported to be between 0.02% and 2.2% [7-8]. The removal of the causative agent from the treatment is often sufficient to resolve abnormal hematological and renal parameters. Our patient did not demonstrate any substantial improvement despite being off the offending chemotherapeutic agent for one month.
Eculizumab, a complement component inhibitor, which binds to C5, blocks the generation of proinflammatory C5a and C5b-9 in the complement system. It has been shown to be effective in treating chemotherapy-induced TMA or aHUS [9]. A report of one case series on four patients with GiHUS who progressed despite stopping chemotherapy showed that eculizumab proved effective in all four patients. Their anemia and renal function improved, with no adverse events [9]. In our patient, treatment with eculizumab resulted in some improvement in his kidney function, likely due to the dysregulation of the complement pathway. Eculizumab has been approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), aHUS, and refractory generalized myasthenia gravis (gMG) [10]. This medication is associated with certain risks, one of them being the increased susceptibility to infection with Neisseria meningitidis or meningococcus [11]. All patients must be vaccinated with a meningococcal vaccine before beginning treatment. The potential long-term effects of this medication, including hepatotoxicity, have been reported [12-13]. So far, many trials have been conducted to study the effect of improved and alternative complement inhibitors. Phase III trials are currently ongoing to study the long-acting variant of eculizumab-ravulizumab in patients with PNH and aHUS [14-15].
Conclusions
In patients receiving gemcitabine for any malignancies, either therapeutic or palliative, clinicians should have a low threshold for suspecting HUS in the presence of worsening anemia, thrombocytopenia, and/or renal function. Eculizumab has been approved since 2011 in many developed countries for the treatment of aHUS, but its use is limited due to cost, unknown treatment duration, and vague dose intervals to keep patients in remission. New complement-directed therapeutics and the development of biomarkers that predict preclinical TMA should be the main drivers in preventing severe complement-related disorders.
Human Ethics
The completion of this undertaking could not have been possible without the participation and assistance of so many people whose names may not all be enumerated. Their contributions are sincerely appreciated and gratefully acknowledged. To all relatives, friends, and others who in one way or another shared their support, either morally, financially, and physically, thank you.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | GEMCITABINE\GEMCITABINE HYDROCHLORIDE, PACLITAXEL | DrugsGivenReaction | CC BY | 33717763 | 19,089,437 | 2021-02-10 |
What was the administration route of drug 'ECULIZUMAB'? | Atypical Hemolytic Uremic Syndrome: Cancer-Induced or Chemotherapy-Induced?
Atypical hemolytic uremic syndrome (aHUS) is an atypical type of thrombotic microangiopathy (TMA), which is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and thrombi in small blood vessels, leading to end-organ damage. aHUS causes an over-activation of the complement pathway. There are many etiologies of aHUS, including inherited and acquired. This condition has a high mortality rate, as it is often detected late in the disease course. Eculizumab, an inhibitor of the terminal complement pathway, needs to be prescribed as soon as the diagnosis is confirmed. There is limited evidence, however, regarding the duration of treatment. Therefore, it is vital to conduct further analysis on other alternatives and pharmacokinetics with this type of complement inhibitor.
Introduction
Hemolytic uremic syndrome (HUS), the most common subtype of thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. TMA are classified into three major categories, including Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS), thrombotic thrombocytopenic purpura (TTP), and aHUS [1].
The most common preceding factor leading to typical HUS is infective diarrhea caused specifically by Shiga toxin-producing Escherichia (E.) coli (STEC ) or E. coli O157:H7. Conversely, aHUS has many possible etiologies, including malignancy, pregnancy, organ transplantation, human immunodeficiency virus (HIV), upper respiratory tract infections, non-E. coli diarrheal illnesses, and the use of certain drugs such as oral contraceptives (OCPs), ticlopidine, quinine, cyclosporine, tacrolimus. aHUS accounts for 5%-10% of all documented cases of HUS and is associated with a poor prognosis [2].
Our objective is to present a patient diagnosed with aHUS due to an underlying malignancy. Early diagnosis and treatment is vital, as aHUS can be life-threatening.
Case presentation
A 67-year-old Caucasian male was diagnosed with an unresectable form of ductal adenocarcinoma of the pancreatic head (Figure 1) based on clinical impression and imaging modalities, including computed tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP). Prior to the diagnosis, he had persistent symptoms of infrequent vague abdomen pain for one year associated with early satiety, belching, and a seven to eight-pound weight loss.
Figure 1 CT scan abdomen: CA pancreas
Poorly delineated pancreatic head-neck junction mass measuring approximately 1.5 x 1 cm. There is ductal dilatation proximal to the mass up to 5 mm. Soft tissue density infiltration extending around the proximal portal vein, central superior mesenteric vein, central splenic vein, and proximal superior mesenteric artery is suspicious for locally advanced, unresectable disease. It also showed intra and extrahepatic biliary duct dilatation related to obstruction by the mass.
CT: computed tomography; CA: Cancer
Intravenous gemcitabine and albumin-bound paclitaxel chemotherapy regimens were administered for his stage T2a, N, M pancreatic cancer. After five months of gemcitabine therapy (cumulative dose 11,050 mg), the patient complained of severe fatigue, which was initially attributed to moderate anemia caused by the chemotherapy.
A baseline complete blood count (CBC) and serum chemistry panel were within the normal range (serum creatinine 0.72 mg/ dL ). His serum creatinine increased steadily to 3.96 mg/dL after six cycles of single-agent gemcitabine (cumulative dose of gemcitabine 11,050 mg), and his platelet count dropped to 90k/mcl. Peripheral blood smear (PBS) showed rare schistocytes (Figure 2 and Figure 3). LDH was 514 IU/L and haptoglobin <10 mg/dL. His C3 and C4 levels were within normal limits. Urinalysis showed hematuria and 2+ protein. ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was 53%. Direct and indirect Coomb’s test results were negative.
Figure 2 Peripheral blood film showing numerous schistocytes
Permission was taken from the original publisher; adapted from Jain et al. [3]
Figure 3 Schistocytes under magnification
Permission was taken from the original publisher; adapted from Jain et al. [3]
Gemcitabine was discontinued in view of possible TMA. There was no improvement in his hematologic or renal parameters for a few weeks after stopping the chemotherapy. A kidney biopsy was performed, which showed conclusive features of aHUS (Figures 4-5). ADAMTS13 activity assay values of 53% in our case ruled out TTP. Also, STEC-HUS as another differential diagnosis was excluded with no history of diarrhea and absence of Shiga toxin detection in the stool specimen.
Figure 4 Kidney biopsy
Jones silver stain
Figure 5 Kidney biopsy
Masson trichrome stain
Eculizumab 900 mg was administered subcutaneously on weekly basis for four weeks after meningococcal vaccination. His serum creatinine stabilized after eculizumab administration between 2.60-3.00 mg/dL. Due to a lack of viable options, as well as a poor performance status, the patient opted for palliative care and died four months later.
Discussion
There are two factors that give rise to TMA in patients with an underlying malignancy (Table 1). First, the malignancy itself can cause TMA, either via metastases of the microvasculature or direct spread to the bone marrow. Also, different chemotherapy regimens, including gemcitabine, cisplatin, bevacizumab, and mitomycin-C can induce TMA either through direct endothelial damage or by an immune-mediated mechanism with the development of drug-dependent autoantibodies [4-5].
Table 1 Mechanism of TMA in malignancy
Source: [5]
MAHA: microangiopathic hemolytic anemia; TMA: thrombotic microangiopathy
Cause of TMA MAHA and Thrombocytopenia Mechanism
Cancer-induced TMA Present Systemic microvascular metastases and bone marrow metastases or necrosis
Chemotherapy-induced TMA Present Dose-dependent toxicity and drug-dependent antibody reaction
Discerning malignancy-induced TMA versus medication-induced TMA is important for managing the patient appropriately [5]. Symptoms such as weakness, weight loss, cough, shortness of breath, and pain are commonly associated in patients with cancer-induced TMA [5]. Unusual findings of MAHA and thrombocytopenia without evidence of any end-organ damage are also important clues in considering the development of TMA. Our patient with pancreatic cancer suffered from gemcitabine-induced hemolytic uremic syndrome (GiHUS).
GiHUS should be suspected in a patient with malignancy when renal dysfunction occurs with no obvious cause. aHUS may not present at acute onset with all classic signs (i.e. thrombocytopenia, MAHA, acute renal failure). The diagnosis of aHUS can be challenging given the significant clinical overlap of the various TMAs (Table 2).
Table 2 Laboratory features of the three forms of thrombotic microangiopathy are presented
Source: [6]
aHUS: atypical hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; STEC-HUS: Shiga toxin-producing Escherichia coli hemolytic uremic syndrome
Anemia Thrombocytopenia Target organ injury ADAMTS 13 Shiga-Toxin Diagnosis
Present Present Present >5% Negative aHUS
Present Present Present <5% Negative TTP
Present Present Present Normal Positive STEC -HUS
The incidence of GiHUS has been reported to be between 0.02% and 2.2% [7-8]. The removal of the causative agent from the treatment is often sufficient to resolve abnormal hematological and renal parameters. Our patient did not demonstrate any substantial improvement despite being off the offending chemotherapeutic agent for one month.
Eculizumab, a complement component inhibitor, which binds to C5, blocks the generation of proinflammatory C5a and C5b-9 in the complement system. It has been shown to be effective in treating chemotherapy-induced TMA or aHUS [9]. A report of one case series on four patients with GiHUS who progressed despite stopping chemotherapy showed that eculizumab proved effective in all four patients. Their anemia and renal function improved, with no adverse events [9]. In our patient, treatment with eculizumab resulted in some improvement in his kidney function, likely due to the dysregulation of the complement pathway. Eculizumab has been approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), aHUS, and refractory generalized myasthenia gravis (gMG) [10]. This medication is associated with certain risks, one of them being the increased susceptibility to infection with Neisseria meningitidis or meningococcus [11]. All patients must be vaccinated with a meningococcal vaccine before beginning treatment. The potential long-term effects of this medication, including hepatotoxicity, have been reported [12-13]. So far, many trials have been conducted to study the effect of improved and alternative complement inhibitors. Phase III trials are currently ongoing to study the long-acting variant of eculizumab-ravulizumab in patients with PNH and aHUS [14-15].
Conclusions
In patients receiving gemcitabine for any malignancies, either therapeutic or palliative, clinicians should have a low threshold for suspecting HUS in the presence of worsening anemia, thrombocytopenia, and/or renal function. Eculizumab has been approved since 2011 in many developed countries for the treatment of aHUS, but its use is limited due to cost, unknown treatment duration, and vague dose intervals to keep patients in remission. New complement-directed therapeutics and the development of biomarkers that predict preclinical TMA should be the main drivers in preventing severe complement-related disorders.
Human Ethics
The completion of this undertaking could not have been possible without the participation and assistance of so many people whose names may not all be enumerated. Their contributions are sincerely appreciated and gratefully acknowledged. To all relatives, friends, and others who in one way or another shared their support, either morally, financially, and physically, thank you.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Subcutaneous | DrugAdministrationRoute | CC BY | 33717763 | 19,046,622 | 2021-02-10 |
What was the administration route of drug 'GEMCITABINE\GEMCITABINE HYDROCHLORIDE'? | Atypical Hemolytic Uremic Syndrome: Cancer-Induced or Chemotherapy-Induced?
Atypical hemolytic uremic syndrome (aHUS) is an atypical type of thrombotic microangiopathy (TMA), which is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and thrombi in small blood vessels, leading to end-organ damage. aHUS causes an over-activation of the complement pathway. There are many etiologies of aHUS, including inherited and acquired. This condition has a high mortality rate, as it is often detected late in the disease course. Eculizumab, an inhibitor of the terminal complement pathway, needs to be prescribed as soon as the diagnosis is confirmed. There is limited evidence, however, regarding the duration of treatment. Therefore, it is vital to conduct further analysis on other alternatives and pharmacokinetics with this type of complement inhibitor.
Introduction
Hemolytic uremic syndrome (HUS), the most common subtype of thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. TMA are classified into three major categories, including Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS), thrombotic thrombocytopenic purpura (TTP), and aHUS [1].
The most common preceding factor leading to typical HUS is infective diarrhea caused specifically by Shiga toxin-producing Escherichia (E.) coli (STEC ) or E. coli O157:H7. Conversely, aHUS has many possible etiologies, including malignancy, pregnancy, organ transplantation, human immunodeficiency virus (HIV), upper respiratory tract infections, non-E. coli diarrheal illnesses, and the use of certain drugs such as oral contraceptives (OCPs), ticlopidine, quinine, cyclosporine, tacrolimus. aHUS accounts for 5%-10% of all documented cases of HUS and is associated with a poor prognosis [2].
Our objective is to present a patient diagnosed with aHUS due to an underlying malignancy. Early diagnosis and treatment is vital, as aHUS can be life-threatening.
Case presentation
A 67-year-old Caucasian male was diagnosed with an unresectable form of ductal adenocarcinoma of the pancreatic head (Figure 1) based on clinical impression and imaging modalities, including computed tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP). Prior to the diagnosis, he had persistent symptoms of infrequent vague abdomen pain for one year associated with early satiety, belching, and a seven to eight-pound weight loss.
Figure 1 CT scan abdomen: CA pancreas
Poorly delineated pancreatic head-neck junction mass measuring approximately 1.5 x 1 cm. There is ductal dilatation proximal to the mass up to 5 mm. Soft tissue density infiltration extending around the proximal portal vein, central superior mesenteric vein, central splenic vein, and proximal superior mesenteric artery is suspicious for locally advanced, unresectable disease. It also showed intra and extrahepatic biliary duct dilatation related to obstruction by the mass.
CT: computed tomography; CA: Cancer
Intravenous gemcitabine and albumin-bound paclitaxel chemotherapy regimens were administered for his stage T2a, N, M pancreatic cancer. After five months of gemcitabine therapy (cumulative dose 11,050 mg), the patient complained of severe fatigue, which was initially attributed to moderate anemia caused by the chemotherapy.
A baseline complete blood count (CBC) and serum chemistry panel were within the normal range (serum creatinine 0.72 mg/ dL ). His serum creatinine increased steadily to 3.96 mg/dL after six cycles of single-agent gemcitabine (cumulative dose of gemcitabine 11,050 mg), and his platelet count dropped to 90k/mcl. Peripheral blood smear (PBS) showed rare schistocytes (Figure 2 and Figure 3). LDH was 514 IU/L and haptoglobin <10 mg/dL. His C3 and C4 levels were within normal limits. Urinalysis showed hematuria and 2+ protein. ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was 53%. Direct and indirect Coomb’s test results were negative.
Figure 2 Peripheral blood film showing numerous schistocytes
Permission was taken from the original publisher; adapted from Jain et al. [3]
Figure 3 Schistocytes under magnification
Permission was taken from the original publisher; adapted from Jain et al. [3]
Gemcitabine was discontinued in view of possible TMA. There was no improvement in his hematologic or renal parameters for a few weeks after stopping the chemotherapy. A kidney biopsy was performed, which showed conclusive features of aHUS (Figures 4-5). ADAMTS13 activity assay values of 53% in our case ruled out TTP. Also, STEC-HUS as another differential diagnosis was excluded with no history of diarrhea and absence of Shiga toxin detection in the stool specimen.
Figure 4 Kidney biopsy
Jones silver stain
Figure 5 Kidney biopsy
Masson trichrome stain
Eculizumab 900 mg was administered subcutaneously on weekly basis for four weeks after meningococcal vaccination. His serum creatinine stabilized after eculizumab administration between 2.60-3.00 mg/dL. Due to a lack of viable options, as well as a poor performance status, the patient opted for palliative care and died four months later.
Discussion
There are two factors that give rise to TMA in patients with an underlying malignancy (Table 1). First, the malignancy itself can cause TMA, either via metastases of the microvasculature or direct spread to the bone marrow. Also, different chemotherapy regimens, including gemcitabine, cisplatin, bevacizumab, and mitomycin-C can induce TMA either through direct endothelial damage or by an immune-mediated mechanism with the development of drug-dependent autoantibodies [4-5].
Table 1 Mechanism of TMA in malignancy
Source: [5]
MAHA: microangiopathic hemolytic anemia; TMA: thrombotic microangiopathy
Cause of TMA MAHA and Thrombocytopenia Mechanism
Cancer-induced TMA Present Systemic microvascular metastases and bone marrow metastases or necrosis
Chemotherapy-induced TMA Present Dose-dependent toxicity and drug-dependent antibody reaction
Discerning malignancy-induced TMA versus medication-induced TMA is important for managing the patient appropriately [5]. Symptoms such as weakness, weight loss, cough, shortness of breath, and pain are commonly associated in patients with cancer-induced TMA [5]. Unusual findings of MAHA and thrombocytopenia without evidence of any end-organ damage are also important clues in considering the development of TMA. Our patient with pancreatic cancer suffered from gemcitabine-induced hemolytic uremic syndrome (GiHUS).
GiHUS should be suspected in a patient with malignancy when renal dysfunction occurs with no obvious cause. aHUS may not present at acute onset with all classic signs (i.e. thrombocytopenia, MAHA, acute renal failure). The diagnosis of aHUS can be challenging given the significant clinical overlap of the various TMAs (Table 2).
Table 2 Laboratory features of the three forms of thrombotic microangiopathy are presented
Source: [6]
aHUS: atypical hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; STEC-HUS: Shiga toxin-producing Escherichia coli hemolytic uremic syndrome
Anemia Thrombocytopenia Target organ injury ADAMTS 13 Shiga-Toxin Diagnosis
Present Present Present >5% Negative aHUS
Present Present Present <5% Negative TTP
Present Present Present Normal Positive STEC -HUS
The incidence of GiHUS has been reported to be between 0.02% and 2.2% [7-8]. The removal of the causative agent from the treatment is often sufficient to resolve abnormal hematological and renal parameters. Our patient did not demonstrate any substantial improvement despite being off the offending chemotherapeutic agent for one month.
Eculizumab, a complement component inhibitor, which binds to C5, blocks the generation of proinflammatory C5a and C5b-9 in the complement system. It has been shown to be effective in treating chemotherapy-induced TMA or aHUS [9]. A report of one case series on four patients with GiHUS who progressed despite stopping chemotherapy showed that eculizumab proved effective in all four patients. Their anemia and renal function improved, with no adverse events [9]. In our patient, treatment with eculizumab resulted in some improvement in his kidney function, likely due to the dysregulation of the complement pathway. Eculizumab has been approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), aHUS, and refractory generalized myasthenia gravis (gMG) [10]. This medication is associated with certain risks, one of them being the increased susceptibility to infection with Neisseria meningitidis or meningococcus [11]. All patients must be vaccinated with a meningococcal vaccine before beginning treatment. The potential long-term effects of this medication, including hepatotoxicity, have been reported [12-13]. So far, many trials have been conducted to study the effect of improved and alternative complement inhibitors. Phase III trials are currently ongoing to study the long-acting variant of eculizumab-ravulizumab in patients with PNH and aHUS [14-15].
Conclusions
In patients receiving gemcitabine for any malignancies, either therapeutic or palliative, clinicians should have a low threshold for suspecting HUS in the presence of worsening anemia, thrombocytopenia, and/or renal function. Eculizumab has been approved since 2011 in many developed countries for the treatment of aHUS, but its use is limited due to cost, unknown treatment duration, and vague dose intervals to keep patients in remission. New complement-directed therapeutics and the development of biomarkers that predict preclinical TMA should be the main drivers in preventing severe complement-related disorders.
Human Ethics
The completion of this undertaking could not have been possible without the participation and assistance of so many people whose names may not all be enumerated. Their contributions are sincerely appreciated and gratefully acknowledged. To all relatives, friends, and others who in one way or another shared their support, either morally, financially, and physically, thank you.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33717763 | 19,089,437 | 2021-02-10 |
What was the outcome of reaction 'General physical health deterioration'? | Atypical Hemolytic Uremic Syndrome: Cancer-Induced or Chemotherapy-Induced?
Atypical hemolytic uremic syndrome (aHUS) is an atypical type of thrombotic microangiopathy (TMA), which is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and thrombi in small blood vessels, leading to end-organ damage. aHUS causes an over-activation of the complement pathway. There are many etiologies of aHUS, including inherited and acquired. This condition has a high mortality rate, as it is often detected late in the disease course. Eculizumab, an inhibitor of the terminal complement pathway, needs to be prescribed as soon as the diagnosis is confirmed. There is limited evidence, however, regarding the duration of treatment. Therefore, it is vital to conduct further analysis on other alternatives and pharmacokinetics with this type of complement inhibitor.
Introduction
Hemolytic uremic syndrome (HUS), the most common subtype of thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. TMA are classified into three major categories, including Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS), thrombotic thrombocytopenic purpura (TTP), and aHUS [1].
The most common preceding factor leading to typical HUS is infective diarrhea caused specifically by Shiga toxin-producing Escherichia (E.) coli (STEC ) or E. coli O157:H7. Conversely, aHUS has many possible etiologies, including malignancy, pregnancy, organ transplantation, human immunodeficiency virus (HIV), upper respiratory tract infections, non-E. coli diarrheal illnesses, and the use of certain drugs such as oral contraceptives (OCPs), ticlopidine, quinine, cyclosporine, tacrolimus. aHUS accounts for 5%-10% of all documented cases of HUS and is associated with a poor prognosis [2].
Our objective is to present a patient diagnosed with aHUS due to an underlying malignancy. Early diagnosis and treatment is vital, as aHUS can be life-threatening.
Case presentation
A 67-year-old Caucasian male was diagnosed with an unresectable form of ductal adenocarcinoma of the pancreatic head (Figure 1) based on clinical impression and imaging modalities, including computed tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP). Prior to the diagnosis, he had persistent symptoms of infrequent vague abdomen pain for one year associated with early satiety, belching, and a seven to eight-pound weight loss.
Figure 1 CT scan abdomen: CA pancreas
Poorly delineated pancreatic head-neck junction mass measuring approximately 1.5 x 1 cm. There is ductal dilatation proximal to the mass up to 5 mm. Soft tissue density infiltration extending around the proximal portal vein, central superior mesenteric vein, central splenic vein, and proximal superior mesenteric artery is suspicious for locally advanced, unresectable disease. It also showed intra and extrahepatic biliary duct dilatation related to obstruction by the mass.
CT: computed tomography; CA: Cancer
Intravenous gemcitabine and albumin-bound paclitaxel chemotherapy regimens were administered for his stage T2a, N, M pancreatic cancer. After five months of gemcitabine therapy (cumulative dose 11,050 mg), the patient complained of severe fatigue, which was initially attributed to moderate anemia caused by the chemotherapy.
A baseline complete blood count (CBC) and serum chemistry panel were within the normal range (serum creatinine 0.72 mg/ dL ). His serum creatinine increased steadily to 3.96 mg/dL after six cycles of single-agent gemcitabine (cumulative dose of gemcitabine 11,050 mg), and his platelet count dropped to 90k/mcl. Peripheral blood smear (PBS) showed rare schistocytes (Figure 2 and Figure 3). LDH was 514 IU/L and haptoglobin <10 mg/dL. His C3 and C4 levels were within normal limits. Urinalysis showed hematuria and 2+ protein. ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was 53%. Direct and indirect Coomb’s test results were negative.
Figure 2 Peripheral blood film showing numerous schistocytes
Permission was taken from the original publisher; adapted from Jain et al. [3]
Figure 3 Schistocytes under magnification
Permission was taken from the original publisher; adapted from Jain et al. [3]
Gemcitabine was discontinued in view of possible TMA. There was no improvement in his hematologic or renal parameters for a few weeks after stopping the chemotherapy. A kidney biopsy was performed, which showed conclusive features of aHUS (Figures 4-5). ADAMTS13 activity assay values of 53% in our case ruled out TTP. Also, STEC-HUS as another differential diagnosis was excluded with no history of diarrhea and absence of Shiga toxin detection in the stool specimen.
Figure 4 Kidney biopsy
Jones silver stain
Figure 5 Kidney biopsy
Masson trichrome stain
Eculizumab 900 mg was administered subcutaneously on weekly basis for four weeks after meningococcal vaccination. His serum creatinine stabilized after eculizumab administration between 2.60-3.00 mg/dL. Due to a lack of viable options, as well as a poor performance status, the patient opted for palliative care and died four months later.
Discussion
There are two factors that give rise to TMA in patients with an underlying malignancy (Table 1). First, the malignancy itself can cause TMA, either via metastases of the microvasculature or direct spread to the bone marrow. Also, different chemotherapy regimens, including gemcitabine, cisplatin, bevacizumab, and mitomycin-C can induce TMA either through direct endothelial damage or by an immune-mediated mechanism with the development of drug-dependent autoantibodies [4-5].
Table 1 Mechanism of TMA in malignancy
Source: [5]
MAHA: microangiopathic hemolytic anemia; TMA: thrombotic microangiopathy
Cause of TMA MAHA and Thrombocytopenia Mechanism
Cancer-induced TMA Present Systemic microvascular metastases and bone marrow metastases or necrosis
Chemotherapy-induced TMA Present Dose-dependent toxicity and drug-dependent antibody reaction
Discerning malignancy-induced TMA versus medication-induced TMA is important for managing the patient appropriately [5]. Symptoms such as weakness, weight loss, cough, shortness of breath, and pain are commonly associated in patients with cancer-induced TMA [5]. Unusual findings of MAHA and thrombocytopenia without evidence of any end-organ damage are also important clues in considering the development of TMA. Our patient with pancreatic cancer suffered from gemcitabine-induced hemolytic uremic syndrome (GiHUS).
GiHUS should be suspected in a patient with malignancy when renal dysfunction occurs with no obvious cause. aHUS may not present at acute onset with all classic signs (i.e. thrombocytopenia, MAHA, acute renal failure). The diagnosis of aHUS can be challenging given the significant clinical overlap of the various TMAs (Table 2).
Table 2 Laboratory features of the three forms of thrombotic microangiopathy are presented
Source: [6]
aHUS: atypical hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; STEC-HUS: Shiga toxin-producing Escherichia coli hemolytic uremic syndrome
Anemia Thrombocytopenia Target organ injury ADAMTS 13 Shiga-Toxin Diagnosis
Present Present Present >5% Negative aHUS
Present Present Present <5% Negative TTP
Present Present Present Normal Positive STEC -HUS
The incidence of GiHUS has been reported to be between 0.02% and 2.2% [7-8]. The removal of the causative agent from the treatment is often sufficient to resolve abnormal hematological and renal parameters. Our patient did not demonstrate any substantial improvement despite being off the offending chemotherapeutic agent for one month.
Eculizumab, a complement component inhibitor, which binds to C5, blocks the generation of proinflammatory C5a and C5b-9 in the complement system. It has been shown to be effective in treating chemotherapy-induced TMA or aHUS [9]. A report of one case series on four patients with GiHUS who progressed despite stopping chemotherapy showed that eculizumab proved effective in all four patients. Their anemia and renal function improved, with no adverse events [9]. In our patient, treatment with eculizumab resulted in some improvement in his kidney function, likely due to the dysregulation of the complement pathway. Eculizumab has been approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), aHUS, and refractory generalized myasthenia gravis (gMG) [10]. This medication is associated with certain risks, one of them being the increased susceptibility to infection with Neisseria meningitidis or meningococcus [11]. All patients must be vaccinated with a meningococcal vaccine before beginning treatment. The potential long-term effects of this medication, including hepatotoxicity, have been reported [12-13]. So far, many trials have been conducted to study the effect of improved and alternative complement inhibitors. Phase III trials are currently ongoing to study the long-acting variant of eculizumab-ravulizumab in patients with PNH and aHUS [14-15].
Conclusions
In patients receiving gemcitabine for any malignancies, either therapeutic or palliative, clinicians should have a low threshold for suspecting HUS in the presence of worsening anemia, thrombocytopenia, and/or renal function. Eculizumab has been approved since 2011 in many developed countries for the treatment of aHUS, but its use is limited due to cost, unknown treatment duration, and vague dose intervals to keep patients in remission. New complement-directed therapeutics and the development of biomarkers that predict preclinical TMA should be the main drivers in preventing severe complement-related disorders.
Human Ethics
The completion of this undertaking could not have been possible without the participation and assistance of so many people whose names may not all be enumerated. Their contributions are sincerely appreciated and gratefully acknowledged. To all relatives, friends, and others who in one way or another shared their support, either morally, financially, and physically, thank you.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33717763 | 19,046,622 | 2021-02-10 |
What was the administration route of drug 'LINACLOTIDE'? | Pill to Pain: First Case of Topiramate-Induced Chronic Spontaneous Coronary Artery Dissection (SCAD).
Spontaneous coronary artery dissection (SCAD) is a non-traumatic, non-iatrogenic, and non-atherosclerotic coronary artery disorder that manifests clinically as acute coronary syndrome (ACS), arrhythmia, or sudden cardiac death (SCD). It is a rare cause of ACS (1.7%-4%) and SCD (0.5%), more common in women than men. It was first reported in 1931 in a 42-year-old female at autopsy, who had SCAD after violent retching and vomiting. We report a case of a 51-year-old female who developed sudden-onset chest pain after taking topiramate (TPM). Her chest pain persisted for 1.5 months prior to her outpatient evaluation, which led to further cardiac workup. An urgent left heart catheterization (LHC) revealed a SCAD. Her symptoms improved with percutaneous coronary intervention (PCI), and she was discharged home on aspirin, statins, and beta-blockers.
Introduction
Spontaneous coronary artery dissection (SCAD) is a non-obstructive coronary artery disease clinically representing as acute coronary syndrome (ACS), arrhythmia, or sudden cardiac death (SCD). SCAD is a rare cause of ACS (1.7%-4%) [1] and SCD (0.5%) [2]. First reported in 1931 in an autopsy of a 42-year-old female who was diagnosed with SCAD following vigorous retching and vomiting [3]. More than 50% of patients recall a precipitating factor, including intense exercise (isometric or aerobic), intense Valsalva, retching, vomiting, bowel movement, coughing, lifting heavy objects, intense emotional stress, labor, and delivery, and recreational drugs (cocaine, methamphetamines), exogenous hormones/hormone modulators β-hCG injections, corticosteroids [4].
The prevalence of SCAD might be higher than previously thought. A recent study showed the occurrence of SCAD in 4% of cases out of 326 patients, who underwent routine optical coherence tomography (OCT) [1]. The mean age of the SCAD population was 44±9 years, and 92% were women with low rates of atherosclerotic risk factors [5]. Recent case series suggest women accounted for over 90% of cases of SCAD [6]. Patients with pregnancy-related SCAD trended toward more often having a prior history of infertility treatment (28% vs. 16%; p = 0.055), including selective estrogen receptor modulators (8 of 15), gonadotropin therapy (5 of 15), and aromatase inhibitors (2 of 15) [7]. During the peripartum period, cocaine-abusing women were highly susceptible to MI caused by the effect of cocaine on a heart that is already stressed by hemodynamic changes of pregnancy. The diagnosis of SCAD should be considered in any postpartum patient who presents with MI, particularly in the setting of cocaine use [8]. The report of SCAD occurring soon after triptan exposure could be due to triptan-induced vasoconstriction in patients with underlying vascular fragility [9].
Case presentation
The patient is a 51-year-old female who presented to her cardiologist’s office with complaints of sudden-onset chest pain continuing for 1.5 months. The pain was first-time experienced shortly after taking her doubled dose migraine pill (topiramate). The pain was intermittent, a pressure-like sensation associated with diaphoresis, radiation down her left arm at rest, and worsened with any activity. Since the onset, her chest pain occurred on a daily basis including waking her up in the morning from severe pain. She has known gastroesophageal reflux disease (GERD) and called her gastroenterologist but was subsequently referred to the cardiologist’s office to rule out acute coronary syndrome (ACS). The cardiologist sent her to the emergency room (ER) due to the history of resting chest pain and abnormal electrocardiogram (ECG). She was not in pain on presentation to the ER. The patient denied any shortness of breath, nausea, vomiting, or syncope except for some diaphoresis. Her heart rate and blood pressures were 82 bpm and 128/70 mmHg, respectively. No murmur was heard on physical exam, and the lungs were clear to auscultation without any crackles or wheezing.
Past medical history was significant for chronic migraine headaches, fibromyalgia, anxiety disorder, pseudo-seizures, irritable bowel syndrome, gastroesophageal reflux disease (GERD), severe protein-calorie malnutrition, and premature surgical menopause. Her migraines have been so debilitating that she had to go on disability.
Medications included albuterol two puffs every four hours as needed for shortness of breath, baclofen 10 mg twice a day, diazepam 5 mg three times a day as needed, esomeprazole 40 mg twice a day, famotidine 40 mg daily, linaclotide 20 mcg oral daily, metoprolol 12.5 mg twice a day, ondansetron 8 mg three times a day as needed, topiramate 300 mg twice a day (increased from 200 mg twice a day). She is a lifetime non-smoker, non-alcoholic, and never used illicit drugs.
The differential diagnosis included ACS, coronary vasospasm, GERD, and panic attack.
ECG upon presentation to the ER was significant for mild ST-segment depression at II, III, aVF, and V3-V6 (Figure 1). Troponins (TnI) were negative and remained negative throughout the admission. She tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Figure 1 ECG upon presentation to the ER
ECG upon presentation to the ER showed mild ST-segment depression at II, III, aVF, and V3-V6.
ECG: electrocardiogram; ER: emergency room
Given her recurrent chest pain, EKG with ST depressions in the anterior leads and premature surgical menopause, a decision was made to go for left heart catheterization (LHC) after beginning aspirin and metoprolol. She was very reluctant to take any medications and has multiple drug intolerances. The left main coronary artery was free of angiographic evidence of coronary artery disease. The proximal and mid-portion of the LAD artery contained a long 99% and 40% stenosis, respectively, with thrombolysis in myocardial infarction (TIMI) 1 flow (Figure 2).
Figure 2 The proximal and mid-portion of the LAD artery contained 99% and 40% stenosis, respectively, with TIMI 1 flow
LAD: left anterior descending; TIMI: thrombolysis in myocardial infarction
The diagonal, circumflex (LCX), obtuse marginal (OM), and right coronary arteries (RCA) did not show any dissection but luminal irregularities throughout the vessel. Left ventricular ejection fraction (LVEF) was measured at 60%. The proximal LAD lesion appeared to be a chronic SCAD with the diminished flow into the mildly diseased mid and distal LAD. This patient with unstable anginal symptoms and a high-grade lesion involving the LAD treated percutaneously with a drug-eluting stent. A successful PCI of the proximal left anterior descending artery was performed using a Luge wire to carefully traverse the dissection and stay in the true lumen (Figure 3).
Figure 3 SCAD was successfully crossed with the Luge wire and predilated
SCAD: spontaneous coronary artery dissection
The lesion was stented and post dilated successfully. Post-PCI stenosis was 0% with TIMI 3 flow (Figure 4).
Figure 4 The successful placement of the DES to LAD with post-PCI stenosis of 0% with the restoration of normal TIMI 3 flow
DES: drug-eluting stent; LAD: left anterior descending; PCI: percutaneous coronary intervention; TIMI: thrombolysis in myocardial infarction
The left ventricular end-diastolic pressure and left ventricular ejection fraction were normal. Post-PCI ECG showed mild improvement of ST-segment depressions, new T-wave inversions, and flattening over the precordial leads (Figure 5).
Figure 5 Post-PCI ECG showed ST-segment depressions improvement, new T-wave inversions, and flattening over the precordial leads
PCI: percutaneous coronary intervention; ECG: electrocardiogram
The patient was continued on aspirin 81 mg daily, metoprolol 12.5 mg twice a day, and was placed on ticagrelor 90 mg twice a day and rosuvastatin 10 mg daily.
Discussion
This is the first reported case to our knowledge of topiramate-induced SCAD. The patient was allergic to sumatriptan and was placed on topiramate with an eventual increase in dose. The patient was already prone to SCAD due to having the diagnosis of fibromyalgia and was a female of reproductive age. The patient had intermittent chest pain for approximately 1.5 months mimicking the presentation as unstable angina yet had a very distinct history of developing the abrupt onset of pain within a short time of taking her migraine medication. The absence of a wall motion abnormality or a troponin elevation despite resting pains suggests that the flow through the true lumen remained adequate enough to avoid infarction of the anterior wall. This type of varying pain is very consistent with our experience with other SCAD patients who develop waxing and waning symptoms, which can, at times, result in ST-segment elevation and then resolve spontaneously with medication therapy. Our patient had type 2 SCAD with a long, diffuse, and smooth narrowing of the proximal and mid-portion of LAD, which ultimately required stent treatment due to ongoing ischemic-like resting chest pains and TIMI 1 flow. There have been reports on triptan-induced SCAD but none on topiramate-induced SCAD to our knowledge [9-10]. Fibromuscular dysplasia (FMD) was found to be a comorbid factor in both case reports. In contrast to the previous cases, our patient was older and had been diagnosed with fibromyalgia, which has never been associated with vasculopathy, though we have not searched for evidence of FMD. Furthermore, our patient did have some evidence of mild CAD on the angiogram, especially in the LAD just beyond the distal edge of the proximal dissection. Ironically, this mild CAD plaque acted as a barrier to the propagation of the dissection plane so that it contained the SCAD to the proximal vessel and may have prevented an acute myocardial infarction.
Topiramate has several mechanisms of action, most commonly known as a voltage-gated sodium channel blocker. FDA approved it in 2004 for migraine prophylaxis but the exact mechanism of action remains unknown [11]. There is scope to find out if there is any association of topiramate with adverse cardiac outcomes.
Conclusions
In summary, to the best of our knowledge, this is the first reported case of topiramate-induced SCAD. Though we are not aware of the exact mechanism, it is worthwhile to report this case as further research is necessary to rule out any cardiovascular side effects of this medication.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33717765 | 19,089,312 | 2021-02-10 |
What was the dosage of drug 'ALBUTEROL'? | Pill to Pain: First Case of Topiramate-Induced Chronic Spontaneous Coronary Artery Dissection (SCAD).
Spontaneous coronary artery dissection (SCAD) is a non-traumatic, non-iatrogenic, and non-atherosclerotic coronary artery disorder that manifests clinically as acute coronary syndrome (ACS), arrhythmia, or sudden cardiac death (SCD). It is a rare cause of ACS (1.7%-4%) and SCD (0.5%), more common in women than men. It was first reported in 1931 in a 42-year-old female at autopsy, who had SCAD after violent retching and vomiting. We report a case of a 51-year-old female who developed sudden-onset chest pain after taking topiramate (TPM). Her chest pain persisted for 1.5 months prior to her outpatient evaluation, which led to further cardiac workup. An urgent left heart catheterization (LHC) revealed a SCAD. Her symptoms improved with percutaneous coronary intervention (PCI), and she was discharged home on aspirin, statins, and beta-blockers.
Introduction
Spontaneous coronary artery dissection (SCAD) is a non-obstructive coronary artery disease clinically representing as acute coronary syndrome (ACS), arrhythmia, or sudden cardiac death (SCD). SCAD is a rare cause of ACS (1.7%-4%) [1] and SCD (0.5%) [2]. First reported in 1931 in an autopsy of a 42-year-old female who was diagnosed with SCAD following vigorous retching and vomiting [3]. More than 50% of patients recall a precipitating factor, including intense exercise (isometric or aerobic), intense Valsalva, retching, vomiting, bowel movement, coughing, lifting heavy objects, intense emotional stress, labor, and delivery, and recreational drugs (cocaine, methamphetamines), exogenous hormones/hormone modulators β-hCG injections, corticosteroids [4].
The prevalence of SCAD might be higher than previously thought. A recent study showed the occurrence of SCAD in 4% of cases out of 326 patients, who underwent routine optical coherence tomography (OCT) [1]. The mean age of the SCAD population was 44±9 years, and 92% were women with low rates of atherosclerotic risk factors [5]. Recent case series suggest women accounted for over 90% of cases of SCAD [6]. Patients with pregnancy-related SCAD trended toward more often having a prior history of infertility treatment (28% vs. 16%; p = 0.055), including selective estrogen receptor modulators (8 of 15), gonadotropin therapy (5 of 15), and aromatase inhibitors (2 of 15) [7]. During the peripartum period, cocaine-abusing women were highly susceptible to MI caused by the effect of cocaine on a heart that is already stressed by hemodynamic changes of pregnancy. The diagnosis of SCAD should be considered in any postpartum patient who presents with MI, particularly in the setting of cocaine use [8]. The report of SCAD occurring soon after triptan exposure could be due to triptan-induced vasoconstriction in patients with underlying vascular fragility [9].
Case presentation
The patient is a 51-year-old female who presented to her cardiologist’s office with complaints of sudden-onset chest pain continuing for 1.5 months. The pain was first-time experienced shortly after taking her doubled dose migraine pill (topiramate). The pain was intermittent, a pressure-like sensation associated with diaphoresis, radiation down her left arm at rest, and worsened with any activity. Since the onset, her chest pain occurred on a daily basis including waking her up in the morning from severe pain. She has known gastroesophageal reflux disease (GERD) and called her gastroenterologist but was subsequently referred to the cardiologist’s office to rule out acute coronary syndrome (ACS). The cardiologist sent her to the emergency room (ER) due to the history of resting chest pain and abnormal electrocardiogram (ECG). She was not in pain on presentation to the ER. The patient denied any shortness of breath, nausea, vomiting, or syncope except for some diaphoresis. Her heart rate and blood pressures were 82 bpm and 128/70 mmHg, respectively. No murmur was heard on physical exam, and the lungs were clear to auscultation without any crackles or wheezing.
Past medical history was significant for chronic migraine headaches, fibromyalgia, anxiety disorder, pseudo-seizures, irritable bowel syndrome, gastroesophageal reflux disease (GERD), severe protein-calorie malnutrition, and premature surgical menopause. Her migraines have been so debilitating that she had to go on disability.
Medications included albuterol two puffs every four hours as needed for shortness of breath, baclofen 10 mg twice a day, diazepam 5 mg three times a day as needed, esomeprazole 40 mg twice a day, famotidine 40 mg daily, linaclotide 20 mcg oral daily, metoprolol 12.5 mg twice a day, ondansetron 8 mg three times a day as needed, topiramate 300 mg twice a day (increased from 200 mg twice a day). She is a lifetime non-smoker, non-alcoholic, and never used illicit drugs.
The differential diagnosis included ACS, coronary vasospasm, GERD, and panic attack.
ECG upon presentation to the ER was significant for mild ST-segment depression at II, III, aVF, and V3-V6 (Figure 1). Troponins (TnI) were negative and remained negative throughout the admission. She tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Figure 1 ECG upon presentation to the ER
ECG upon presentation to the ER showed mild ST-segment depression at II, III, aVF, and V3-V6.
ECG: electrocardiogram; ER: emergency room
Given her recurrent chest pain, EKG with ST depressions in the anterior leads and premature surgical menopause, a decision was made to go for left heart catheterization (LHC) after beginning aspirin and metoprolol. She was very reluctant to take any medications and has multiple drug intolerances. The left main coronary artery was free of angiographic evidence of coronary artery disease. The proximal and mid-portion of the LAD artery contained a long 99% and 40% stenosis, respectively, with thrombolysis in myocardial infarction (TIMI) 1 flow (Figure 2).
Figure 2 The proximal and mid-portion of the LAD artery contained 99% and 40% stenosis, respectively, with TIMI 1 flow
LAD: left anterior descending; TIMI: thrombolysis in myocardial infarction
The diagonal, circumflex (LCX), obtuse marginal (OM), and right coronary arteries (RCA) did not show any dissection but luminal irregularities throughout the vessel. Left ventricular ejection fraction (LVEF) was measured at 60%. The proximal LAD lesion appeared to be a chronic SCAD with the diminished flow into the mildly diseased mid and distal LAD. This patient with unstable anginal symptoms and a high-grade lesion involving the LAD treated percutaneously with a drug-eluting stent. A successful PCI of the proximal left anterior descending artery was performed using a Luge wire to carefully traverse the dissection and stay in the true lumen (Figure 3).
Figure 3 SCAD was successfully crossed with the Luge wire and predilated
SCAD: spontaneous coronary artery dissection
The lesion was stented and post dilated successfully. Post-PCI stenosis was 0% with TIMI 3 flow (Figure 4).
Figure 4 The successful placement of the DES to LAD with post-PCI stenosis of 0% with the restoration of normal TIMI 3 flow
DES: drug-eluting stent; LAD: left anterior descending; PCI: percutaneous coronary intervention; TIMI: thrombolysis in myocardial infarction
The left ventricular end-diastolic pressure and left ventricular ejection fraction were normal. Post-PCI ECG showed mild improvement of ST-segment depressions, new T-wave inversions, and flattening over the precordial leads (Figure 5).
Figure 5 Post-PCI ECG showed ST-segment depressions improvement, new T-wave inversions, and flattening over the precordial leads
PCI: percutaneous coronary intervention; ECG: electrocardiogram
The patient was continued on aspirin 81 mg daily, metoprolol 12.5 mg twice a day, and was placed on ticagrelor 90 mg twice a day and rosuvastatin 10 mg daily.
Discussion
This is the first reported case to our knowledge of topiramate-induced SCAD. The patient was allergic to sumatriptan and was placed on topiramate with an eventual increase in dose. The patient was already prone to SCAD due to having the diagnosis of fibromyalgia and was a female of reproductive age. The patient had intermittent chest pain for approximately 1.5 months mimicking the presentation as unstable angina yet had a very distinct history of developing the abrupt onset of pain within a short time of taking her migraine medication. The absence of a wall motion abnormality or a troponin elevation despite resting pains suggests that the flow through the true lumen remained adequate enough to avoid infarction of the anterior wall. This type of varying pain is very consistent with our experience with other SCAD patients who develop waxing and waning symptoms, which can, at times, result in ST-segment elevation and then resolve spontaneously with medication therapy. Our patient had type 2 SCAD with a long, diffuse, and smooth narrowing of the proximal and mid-portion of LAD, which ultimately required stent treatment due to ongoing ischemic-like resting chest pains and TIMI 1 flow. There have been reports on triptan-induced SCAD but none on topiramate-induced SCAD to our knowledge [9-10]. Fibromuscular dysplasia (FMD) was found to be a comorbid factor in both case reports. In contrast to the previous cases, our patient was older and had been diagnosed with fibromyalgia, which has never been associated with vasculopathy, though we have not searched for evidence of FMD. Furthermore, our patient did have some evidence of mild CAD on the angiogram, especially in the LAD just beyond the distal edge of the proximal dissection. Ironically, this mild CAD plaque acted as a barrier to the propagation of the dissection plane so that it contained the SCAD to the proximal vessel and may have prevented an acute myocardial infarction.
Topiramate has several mechanisms of action, most commonly known as a voltage-gated sodium channel blocker. FDA approved it in 2004 for migraine prophylaxis but the exact mechanism of action remains unknown [11]. There is scope to find out if there is any association of topiramate with adverse cardiac outcomes.
Conclusions
In summary, to the best of our knowledge, this is the first reported case of topiramate-induced SCAD. Though we are not aware of the exact mechanism, it is worthwhile to report this case as further research is necessary to rule out any cardiovascular side effects of this medication.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | TWO PUFFS EVERY FOUR HOURS AS NEEDED | DrugDosageText | CC BY | 33717765 | 19,089,312 | 2021-02-10 |
What was the dosage of drug 'ASPIRIN'? | Pill to Pain: First Case of Topiramate-Induced Chronic Spontaneous Coronary Artery Dissection (SCAD).
Spontaneous coronary artery dissection (SCAD) is a non-traumatic, non-iatrogenic, and non-atherosclerotic coronary artery disorder that manifests clinically as acute coronary syndrome (ACS), arrhythmia, or sudden cardiac death (SCD). It is a rare cause of ACS (1.7%-4%) and SCD (0.5%), more common in women than men. It was first reported in 1931 in a 42-year-old female at autopsy, who had SCAD after violent retching and vomiting. We report a case of a 51-year-old female who developed sudden-onset chest pain after taking topiramate (TPM). Her chest pain persisted for 1.5 months prior to her outpatient evaluation, which led to further cardiac workup. An urgent left heart catheterization (LHC) revealed a SCAD. Her symptoms improved with percutaneous coronary intervention (PCI), and she was discharged home on aspirin, statins, and beta-blockers.
Introduction
Spontaneous coronary artery dissection (SCAD) is a non-obstructive coronary artery disease clinically representing as acute coronary syndrome (ACS), arrhythmia, or sudden cardiac death (SCD). SCAD is a rare cause of ACS (1.7%-4%) [1] and SCD (0.5%) [2]. First reported in 1931 in an autopsy of a 42-year-old female who was diagnosed with SCAD following vigorous retching and vomiting [3]. More than 50% of patients recall a precipitating factor, including intense exercise (isometric or aerobic), intense Valsalva, retching, vomiting, bowel movement, coughing, lifting heavy objects, intense emotional stress, labor, and delivery, and recreational drugs (cocaine, methamphetamines), exogenous hormones/hormone modulators β-hCG injections, corticosteroids [4].
The prevalence of SCAD might be higher than previously thought. A recent study showed the occurrence of SCAD in 4% of cases out of 326 patients, who underwent routine optical coherence tomography (OCT) [1]. The mean age of the SCAD population was 44±9 years, and 92% were women with low rates of atherosclerotic risk factors [5]. Recent case series suggest women accounted for over 90% of cases of SCAD [6]. Patients with pregnancy-related SCAD trended toward more often having a prior history of infertility treatment (28% vs. 16%; p = 0.055), including selective estrogen receptor modulators (8 of 15), gonadotropin therapy (5 of 15), and aromatase inhibitors (2 of 15) [7]. During the peripartum period, cocaine-abusing women were highly susceptible to MI caused by the effect of cocaine on a heart that is already stressed by hemodynamic changes of pregnancy. The diagnosis of SCAD should be considered in any postpartum patient who presents with MI, particularly in the setting of cocaine use [8]. The report of SCAD occurring soon after triptan exposure could be due to triptan-induced vasoconstriction in patients with underlying vascular fragility [9].
Case presentation
The patient is a 51-year-old female who presented to her cardiologist’s office with complaints of sudden-onset chest pain continuing for 1.5 months. The pain was first-time experienced shortly after taking her doubled dose migraine pill (topiramate). The pain was intermittent, a pressure-like sensation associated with diaphoresis, radiation down her left arm at rest, and worsened with any activity. Since the onset, her chest pain occurred on a daily basis including waking her up in the morning from severe pain. She has known gastroesophageal reflux disease (GERD) and called her gastroenterologist but was subsequently referred to the cardiologist’s office to rule out acute coronary syndrome (ACS). The cardiologist sent her to the emergency room (ER) due to the history of resting chest pain and abnormal electrocardiogram (ECG). She was not in pain on presentation to the ER. The patient denied any shortness of breath, nausea, vomiting, or syncope except for some diaphoresis. Her heart rate and blood pressures were 82 bpm and 128/70 mmHg, respectively. No murmur was heard on physical exam, and the lungs were clear to auscultation without any crackles or wheezing.
Past medical history was significant for chronic migraine headaches, fibromyalgia, anxiety disorder, pseudo-seizures, irritable bowel syndrome, gastroesophageal reflux disease (GERD), severe protein-calorie malnutrition, and premature surgical menopause. Her migraines have been so debilitating that she had to go on disability.
Medications included albuterol two puffs every four hours as needed for shortness of breath, baclofen 10 mg twice a day, diazepam 5 mg three times a day as needed, esomeprazole 40 mg twice a day, famotidine 40 mg daily, linaclotide 20 mcg oral daily, metoprolol 12.5 mg twice a day, ondansetron 8 mg three times a day as needed, topiramate 300 mg twice a day (increased from 200 mg twice a day). She is a lifetime non-smoker, non-alcoholic, and never used illicit drugs.
The differential diagnosis included ACS, coronary vasospasm, GERD, and panic attack.
ECG upon presentation to the ER was significant for mild ST-segment depression at II, III, aVF, and V3-V6 (Figure 1). Troponins (TnI) were negative and remained negative throughout the admission. She tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Figure 1 ECG upon presentation to the ER
ECG upon presentation to the ER showed mild ST-segment depression at II, III, aVF, and V3-V6.
ECG: electrocardiogram; ER: emergency room
Given her recurrent chest pain, EKG with ST depressions in the anterior leads and premature surgical menopause, a decision was made to go for left heart catheterization (LHC) after beginning aspirin and metoprolol. She was very reluctant to take any medications and has multiple drug intolerances. The left main coronary artery was free of angiographic evidence of coronary artery disease. The proximal and mid-portion of the LAD artery contained a long 99% and 40% stenosis, respectively, with thrombolysis in myocardial infarction (TIMI) 1 flow (Figure 2).
Figure 2 The proximal and mid-portion of the LAD artery contained 99% and 40% stenosis, respectively, with TIMI 1 flow
LAD: left anterior descending; TIMI: thrombolysis in myocardial infarction
The diagonal, circumflex (LCX), obtuse marginal (OM), and right coronary arteries (RCA) did not show any dissection but luminal irregularities throughout the vessel. Left ventricular ejection fraction (LVEF) was measured at 60%. The proximal LAD lesion appeared to be a chronic SCAD with the diminished flow into the mildly diseased mid and distal LAD. This patient with unstable anginal symptoms and a high-grade lesion involving the LAD treated percutaneously with a drug-eluting stent. A successful PCI of the proximal left anterior descending artery was performed using a Luge wire to carefully traverse the dissection and stay in the true lumen (Figure 3).
Figure 3 SCAD was successfully crossed with the Luge wire and predilated
SCAD: spontaneous coronary artery dissection
The lesion was stented and post dilated successfully. Post-PCI stenosis was 0% with TIMI 3 flow (Figure 4).
Figure 4 The successful placement of the DES to LAD with post-PCI stenosis of 0% with the restoration of normal TIMI 3 flow
DES: drug-eluting stent; LAD: left anterior descending; PCI: percutaneous coronary intervention; TIMI: thrombolysis in myocardial infarction
The left ventricular end-diastolic pressure and left ventricular ejection fraction were normal. Post-PCI ECG showed mild improvement of ST-segment depressions, new T-wave inversions, and flattening over the precordial leads (Figure 5).
Figure 5 Post-PCI ECG showed ST-segment depressions improvement, new T-wave inversions, and flattening over the precordial leads
PCI: percutaneous coronary intervention; ECG: electrocardiogram
The patient was continued on aspirin 81 mg daily, metoprolol 12.5 mg twice a day, and was placed on ticagrelor 90 mg twice a day and rosuvastatin 10 mg daily.
Discussion
This is the first reported case to our knowledge of topiramate-induced SCAD. The patient was allergic to sumatriptan and was placed on topiramate with an eventual increase in dose. The patient was already prone to SCAD due to having the diagnosis of fibromyalgia and was a female of reproductive age. The patient had intermittent chest pain for approximately 1.5 months mimicking the presentation as unstable angina yet had a very distinct history of developing the abrupt onset of pain within a short time of taking her migraine medication. The absence of a wall motion abnormality or a troponin elevation despite resting pains suggests that the flow through the true lumen remained adequate enough to avoid infarction of the anterior wall. This type of varying pain is very consistent with our experience with other SCAD patients who develop waxing and waning symptoms, which can, at times, result in ST-segment elevation and then resolve spontaneously with medication therapy. Our patient had type 2 SCAD with a long, diffuse, and smooth narrowing of the proximal and mid-portion of LAD, which ultimately required stent treatment due to ongoing ischemic-like resting chest pains and TIMI 1 flow. There have been reports on triptan-induced SCAD but none on topiramate-induced SCAD to our knowledge [9-10]. Fibromuscular dysplasia (FMD) was found to be a comorbid factor in both case reports. In contrast to the previous cases, our patient was older and had been diagnosed with fibromyalgia, which has never been associated with vasculopathy, though we have not searched for evidence of FMD. Furthermore, our patient did have some evidence of mild CAD on the angiogram, especially in the LAD just beyond the distal edge of the proximal dissection. Ironically, this mild CAD plaque acted as a barrier to the propagation of the dissection plane so that it contained the SCAD to the proximal vessel and may have prevented an acute myocardial infarction.
Topiramate has several mechanisms of action, most commonly known as a voltage-gated sodium channel blocker. FDA approved it in 2004 for migraine prophylaxis but the exact mechanism of action remains unknown [11]. There is scope to find out if there is any association of topiramate with adverse cardiac outcomes.
Conclusions
In summary, to the best of our knowledge, this is the first reported case of topiramate-induced SCAD. Though we are not aware of the exact mechanism, it is worthwhile to report this case as further research is necessary to rule out any cardiovascular side effects of this medication.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | 81 mg (milligrams). | DrugDosage | CC BY | 33717765 | 19,089,312 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute respiratory distress syndrome'. | Usefulness of serial lung ultrasound for a severe COVID-19 patient on extracorporeal membrane oxygenation.
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO). Notably, lung ultrasound (LUS) is a favored alternative imaging modality due to its ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost. We demonstrated that serial LUS compares favorably with other imaging modalities in terms of usefulness for evaluating lung aeration and recovery in an ECMO-managed COVID-19 patient.
1 Introduction
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis [1,2]. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO) [3,4]. Notably, lung ultrasound (LUS) is an alternative favored imaging modality due to its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 patients in whom lung pathology is a key characteristic5.6. LUS also has other advantages, including ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost [5,6].
2 Case presentation
A 57-year-old male office worker presented to his local hospital with a 3-day history of malaise and fever. He later developed shortness of breath that led to his hospitalization. Furthermore, a polymerase chain reaction–based test for severe acute respiratory syndrome coronavirus 2 in a nasopharyngeal swab sample returned positive results (Cobas SARS-CoV-2 Test; Roche Diagnostics, Rotkreuz, Switzerland). The patient was a heavy smoker, and his medical history included diabetes (HbA1c, 6.6; on insulin). After two days in the local hospital, he was transported to our emergency room (ER) due to worsening symptoms.
Upon admission to the ER, his vital signs were as follows: respiratory rate, 30 breaths/min; oxygen saturation, 97% on an oxygen mask at 6 L/min; heart rate, 135 beats/min; and blood pressure, 153/103 mmHg. A physical examination showed an alert man with no rashes or swelling. On auscultation, he had significant bilateral wheezing. He was therefore intubated and ventilated in the intensive care unit. After intubation, static lung compliance and airway occlusion pressure at 100 ms (P0.1) were measured (Table 1) [7].Table 1 Clinical parameters.
Table 1Measure Day 1 Day 3 Day 5 Day 7 Day 9 Day 13 Day 14 Day 26
Laboratory findings During ECMO management
White blood cell count (/μL) 7,900 3,200 6,400 4,600 7,000 7,200 11,000 6,200
Absolute lymphocyte count (/μL) 979 714 761 961 1,379 1,044
C-reactive protein (mg/dL) 7.09 15.8 31.5 17.8 20.4 8.25 4.2 4.4
Lactate Dehydrogenase (U/L) 500 820 845 705 634 533 407 294
Krebs von den Lungen‐6 (ng/mL) 287 – 1,070 842 792 588 – 672
Respiratory parameter
Respiratory rate (/min) 24 26 6 6 6 15 16 12
Minute volume (L/min) 10.5 13.3 1.9 1.9 1.9 3.6 8.5 6.2
PaO2/FIO2 ratio 224 118 69 223 170 242 285 280
P0.1 (cmH2O) 0.8 6.4 – 0.6 0.8 1.6 0.8 0.8
Static Lung Compliance (mL/cmH2O) 60 50 46 – – 68 – –
Lung Ultrasound Score 9 21 25 25 23 18 13 15
FiO2, fraction of inspired oxygen; P0.1, airway occlusion pressure at 100 ms; PaO2, partial pressure of oxygen.
The laboratory finding on admission are shown in Table 1. Chest radiography and CT findings showed pale, bilateral, ground-glass opacities (day 1; Fig. 1). LUS was performed at 6 points per hemithorax (superior and inferior regions anteriorly, laterally, and posteriorly) bilaterally (day 1; Fig. 1) [8]. A linear probe was placed in the intercostal muscles to evaluate the lungs. LUS was performed and graded by three emergency physicians who were experienced in performing LUS. The LUS Score (LUSS) was evaluated at the bedside as previously described [9]. Briefly, 0–3 points were allocated for each of the 12 pre-determined anatomical regions according to the ultrasound pattern: normal = 0, well-defined B-lines = 1, coalescent B-lines = 2, and consolidation = 3 (total score ranges from 0 to 36). Lung consolidations (scoring 3) were noted only when the thickness (measured perpendicular from the pleura) was greater than 15 mm. Sub-pleural thickening and sub-pleural consolidations (thickness: 15 mm or thinner) were graded as a score of 2. Each score with the detail of each zone was recorded day by day in a table and kept in the patient medical record.Fig. 1 Chest X-ray, CT, and LUS findings on days 1 and 3.
Day 1: Chest radiography and CT scan: pale bilateral ground-glass opacities.
LUSS: total 9 points. A-lines or <3 B-lines appeared in the bilateral upper lobes, and multiple B-lines appeared in the bilateral lower lobes.
Day 3: Chest radiography and CT scan: pulmonary consolidation appeared in the bilateral lower lobes, and bilateral ground-glass opacities were prominent in the right upper lobe.
LUSS: total 21 points. Multiple B-lines appeared in the upper bilateral lobes, and coalescent B-lines appeared in the bilateral lower lobes.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 1
After admission, bacterial pneumonia was considered; hence, ceftriaxone (1 g) and azithromycin (500 mg) were administered. To treat COVID-19, favipiravir (1,200 mg) and ciclesonide (800 μg) were also administered (Fig. 2). On day 2, although his C-reactive protein level had increased and his chest radiography findings remained unchange, his oxygenation improved (P/F ratio > 300 mmHg). Therefore, the ventilator settings were changed from pressure control ventilation (PCV; driving pressure).Fig. 2 Time course of physical conditions, therapeutic interventions, and ECMO status of this patient.
ECMO: extracorporeal membrane oxygenation; PCV: pressure control ventilation; PSV: pressure support ventilation; PEEP: positive end-expiratory pressure; VV-ECMO: veno-venous ECMO.
Fig. 2
10 cmH2O; positive end-expiratory pressure [PEEP], 10 cmH2O) to pressure support ventilation (PSV; fraction of inspired oxygen, 30%; PEEP, 5 cmH2O; pressure support, 5 cmH2O).
On day 3, his breathing pattern worsened, and he was in distress (Additional file 1). We evaluated the patient with a P0.1 measurement and an LUSS-based evaluation. His P0.1 was high at 6.4 cmH2O (Table 1), and the LUSS results had worsened (day 3; Fig. 1) [10]. The P/F ratio and chest radiography findings continued to worsen; thus, the ventilator setting was changed back from PSV to PCV because a higher PEEP and driving pressure were needed to maintain oxygenation. We then performed a CT scan to evaluate his lungs (day 3; Fig. 1). Patient self-inflicted lung injury (P-SILI) was diagnosed because the CT images showed acute respiratory distress syndrome (ARDS) [11]. Accordingly, continuous infusion of muscle relaxants was administered to prevent excessive spontaneous breathing.
On day 5, all parameters worsened (Table 1 and Fig. 3). Therefore, we decided to initiate veno-venous extracorporeal membrane oxygenation (VV-ECMO). The right internal jugular vein was cannulated with a 25-Fr heparin-coated cannula for blood access, and the right femoral vein was cannulated with a 21-Fr heparin-coated cannula for blood return. The procedure was performed safely, and no complications occurred.Fig. 3 Chest X-ray, CT, and LUS findings on days 5 and 14.
Day 5: Chest radiography and CT: pulmonary consolidation worsened in the bilateral lower lobes, and bilateral ground-glass opacities also worsened in the bilateral upper lobes.
LUSS: total 25 points. Coalescent B-lines were prominent in the bilateral anterior and lateral lobes. Subpleural consolidation appeared in the bilateral posterior lobe.
Day 14: Chest radiography and CT: pulmonary consolidation improved in the bilateral lower lobes, and bilateral ground-glass opacities decreased in the bilateral upper lobes.
LUSS: total 13 points. Multiple B-lines and subpleural consolidation decreased, and A-lines reemerged in the anterior lobe.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 3
After the initiation of VV-ECMO, the patient's breathing pattern stabilized. The continuous infusion of muscle relaxants was stopped, and his lung function was reevaluated every day (P0.1 measurement, physical assessment, LUSS, chest radiography, and laboratory testing; Table 1). We performed a tracheostomy on day 7. Remdesivir (200 mg on the first day, 100 mg/day thereafter) was administered as a replacement for favipiravir on day 9. On day 13, his chest radiography findings, static lung compliance, and LUSS improved. VV-ECMO was eventually discontinued on day 14 (Fig. 3). The chest radiography and CT findings after weaning of VV-ECMO showed consistent daily improvements. On day 26, he was transferred to the hospital where he was previously admitted. Two months later, he was discharged home.
3 Discussion
3.1 Strategy for managing patients with severe COVID-19
Currently, VV-ECMO has been established as a standard step in managing ARDS when other treatments fail [12]. Although an effective treatment for COVID-19 has not been established, VV-ECMO has been used as the ultimate symptomatic treatment for COVID-19 [[13], [14], [15]]. Gattinoni et al. reported variations in the respiratory mechanics profiles of invasively ventilated patients with COVID-19 pneumonitis [16], and the following two clinical phenotypes were identified: (1) type L, which was characterized by low elastance, a low ventilation-to-perfusion ratio, a low lung weight, and low recruitability, and (2) type H, which was characterized by high elastance, a pronounced right-to-left shunt, high lung weight, and high recruitability. The transition from Type L to Type H may be due to the worsening of COVID-19 severity or due to an injury caused by high-stress ventilation.
Besides the severity of the disease itself, the depth of negative intrathoracic pressure may also play a possible key role in the phenotype shift from Type L to Type H [17]. Transpulmonary pressure (TPP), which is the distending force applied to the lungs, is the difference between the alveolar and intrathoracic pressures. TPP will increase with strong spontaneous breathing. Higher TPP and lung permeability due to inflammation result in interstitial lung edema. This phenomenon has recently been recognized as P-SILI [11].
Effective treatment for severe COVID-19 pneumonitis may prevent the occurrence of P-SILI and its progression from Type L to Type H. Systemic steroid administration, which was not used in this study, has been thought to reduce inflammation, thereby suppressing strong spontaneous breathing and improving the prognosis of patients on mechanical ventilation [18]. However, if the lungs are severely damaged, ECMO is the only way to gain time with lung-protective ventilation until recovery. In fact, we have previously reported successful treatment of a COVID-19 pneumonitis patient with VV-ECMO in 7 days [14].
3.2 Evaluation of lung condition during ECMO
Although VV-ECMO is one way to save lives, it is risky and associated with some complications, primarily including bleeding and infection [1]. Therefore, clinicians perform daily lung evaluations to determine when VV-ECMO should be induced and when a patient should be weaned off it.
It has been reported that CT scans provide the most reliable assessment of lung condition in COVID-19 pneumonitis patients [1,20]. However, during a pandemic, the transportation of critically ill ventilated patients to radiology facilities is challenging, especially for ECMO-managed patients3,4. Although increased levels of D-dimer, C-reactive protein, ferritin, and lactate dehydrogenase have also been reported as markers of severity for COVID-19, they are not specific to the lungs [21]. The serum Krebs von den Lungen‐6 (KL‐6) concentration is a lung-specific biomarker, and its usefulness in COVID-19 has been reported [22]. However, the measurement of KL-6 levels is time-consuming and cannot be done at all facilities. Notably, LUS is the preferred imaging modality because of its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 pneumonitis cases where lung pathology is a characteristic feature [5,6]. LUS provides results that are similar to chest CT findings, and it is superior to chest radiography for the evaluation of COVID-19 [[23], [24], [25]]. However, the existing literature contains only a few case reports supporting the usefulness of serial LUS in ECMO-managed severe COVID-19 patients [26].
3.3 Usefulness of serial LUS in an ECMO-managed patient with severe COVID-19
We believe that serial LUS was very useful in our patient's case. First, the LUSS was associated with the progression and improvement of the patient's lung condition, as observed in CT images (Fig. 1, Fig. 3) and laboratory findings (Table 1). The longer the ECMO management, the more complications patients have [19]. However, it is uncertain how long we should protect the lungs with ECMO. Because the condition of the lungs varies from case to case, laboratory findings like P/F ratios do not directly correlate with the improvement of lung condition during ECMO. LUS can be evaluated individually and specifically for the lungs, and the reemergence of A-lines suggests an improvement in lung condition [[3], [4], [5], [6],8]. Although serial LUS evaluation is also considered appropriate for patients on ECMO, few studies have examined its appropriateness for COVID-19 patients [27].
Second, LUS can be performed quickly by one clinician without displacing the patient or requiring radiation exposure [22]. Accordingly, LUS is faster, easier, and safer than other imaging modalities, with significant advantages during a pandemic [5,6].
Third, in this case, the LUSS increased sharply from day 1 to day 3 (score: from 9 to 21). We believe that P-SILI occurred on day 3 because the patient's P0.1 value increased and his respiratory patterns appeared distressed (Additional file 1). Given that there was an improvement in oxygenation, but not yet in inflammation, changing the ventilator setting from PCV to PSV probably led to increased respiratory efforts, increased transpulmonary pressure, and P-SILI. It has been reported that P-SILI increases transmural pulmonary vascular pressure, thereby resulting in increased vascular permeability and pulmonary edema [11]. Therefore, we suspect that the appearance of multiple B-lines, especially those in the lateral and posterior regions, might have been due to negative intrathoracic pressure generated by strong spontaneous breathing. Although no studies have demonstrated a relationship between P-SILI and LUS, we thought that the rapid increase of the LUSS suggested the occurrence of P-SILI.
This case study has several limitations. One limitation is that the inter-rater reliability was not evaluated, although three experienced emergency physicians performed LUS. The other limitation is that the pandemic is ongoing, and the existing knowledge about COVID-19 might be modified by future findings.
4 Conclusion
This case report demonstrated that serial LUS was useful for evaluating lung condition in a COVID-19 patient requiring ECMO. The present findings suggest that LUS may be useful for the detection of P-SILI. However, further prospective studies are needed to test this hypothesis.
Declaration of competing interest
The authors have no conflicts of interest directly relevant to the content of this article.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101383. | AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, CICLESONIDE, FAVIPIRAVIR, HEPARIN SODIUM, INSULIN NOS, REMDESIVIR | DrugsGivenReaction | CC BY-NC-ND | 33717868 | 19,854,293 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Usefulness of serial lung ultrasound for a severe COVID-19 patient on extracorporeal membrane oxygenation.
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO). Notably, lung ultrasound (LUS) is a favored alternative imaging modality due to its ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost. We demonstrated that serial LUS compares favorably with other imaging modalities in terms of usefulness for evaluating lung aeration and recovery in an ECMO-managed COVID-19 patient.
1 Introduction
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis [1,2]. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO) [3,4]. Notably, lung ultrasound (LUS) is an alternative favored imaging modality due to its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 patients in whom lung pathology is a key characteristic5.6. LUS also has other advantages, including ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost [5,6].
2 Case presentation
A 57-year-old male office worker presented to his local hospital with a 3-day history of malaise and fever. He later developed shortness of breath that led to his hospitalization. Furthermore, a polymerase chain reaction–based test for severe acute respiratory syndrome coronavirus 2 in a nasopharyngeal swab sample returned positive results (Cobas SARS-CoV-2 Test; Roche Diagnostics, Rotkreuz, Switzerland). The patient was a heavy smoker, and his medical history included diabetes (HbA1c, 6.6; on insulin). After two days in the local hospital, he was transported to our emergency room (ER) due to worsening symptoms.
Upon admission to the ER, his vital signs were as follows: respiratory rate, 30 breaths/min; oxygen saturation, 97% on an oxygen mask at 6 L/min; heart rate, 135 beats/min; and blood pressure, 153/103 mmHg. A physical examination showed an alert man with no rashes or swelling. On auscultation, he had significant bilateral wheezing. He was therefore intubated and ventilated in the intensive care unit. After intubation, static lung compliance and airway occlusion pressure at 100 ms (P0.1) were measured (Table 1) [7].Table 1 Clinical parameters.
Table 1Measure Day 1 Day 3 Day 5 Day 7 Day 9 Day 13 Day 14 Day 26
Laboratory findings During ECMO management
White blood cell count (/μL) 7,900 3,200 6,400 4,600 7,000 7,200 11,000 6,200
Absolute lymphocyte count (/μL) 979 714 761 961 1,379 1,044
C-reactive protein (mg/dL) 7.09 15.8 31.5 17.8 20.4 8.25 4.2 4.4
Lactate Dehydrogenase (U/L) 500 820 845 705 634 533 407 294
Krebs von den Lungen‐6 (ng/mL) 287 – 1,070 842 792 588 – 672
Respiratory parameter
Respiratory rate (/min) 24 26 6 6 6 15 16 12
Minute volume (L/min) 10.5 13.3 1.9 1.9 1.9 3.6 8.5 6.2
PaO2/FIO2 ratio 224 118 69 223 170 242 285 280
P0.1 (cmH2O) 0.8 6.4 – 0.6 0.8 1.6 0.8 0.8
Static Lung Compliance (mL/cmH2O) 60 50 46 – – 68 – –
Lung Ultrasound Score 9 21 25 25 23 18 13 15
FiO2, fraction of inspired oxygen; P0.1, airway occlusion pressure at 100 ms; PaO2, partial pressure of oxygen.
The laboratory finding on admission are shown in Table 1. Chest radiography and CT findings showed pale, bilateral, ground-glass opacities (day 1; Fig. 1). LUS was performed at 6 points per hemithorax (superior and inferior regions anteriorly, laterally, and posteriorly) bilaterally (day 1; Fig. 1) [8]. A linear probe was placed in the intercostal muscles to evaluate the lungs. LUS was performed and graded by three emergency physicians who were experienced in performing LUS. The LUS Score (LUSS) was evaluated at the bedside as previously described [9]. Briefly, 0–3 points were allocated for each of the 12 pre-determined anatomical regions according to the ultrasound pattern: normal = 0, well-defined B-lines = 1, coalescent B-lines = 2, and consolidation = 3 (total score ranges from 0 to 36). Lung consolidations (scoring 3) were noted only when the thickness (measured perpendicular from the pleura) was greater than 15 mm. Sub-pleural thickening and sub-pleural consolidations (thickness: 15 mm or thinner) were graded as a score of 2. Each score with the detail of each zone was recorded day by day in a table and kept in the patient medical record.Fig. 1 Chest X-ray, CT, and LUS findings on days 1 and 3.
Day 1: Chest radiography and CT scan: pale bilateral ground-glass opacities.
LUSS: total 9 points. A-lines or <3 B-lines appeared in the bilateral upper lobes, and multiple B-lines appeared in the bilateral lower lobes.
Day 3: Chest radiography and CT scan: pulmonary consolidation appeared in the bilateral lower lobes, and bilateral ground-glass opacities were prominent in the right upper lobe.
LUSS: total 21 points. Multiple B-lines appeared in the upper bilateral lobes, and coalescent B-lines appeared in the bilateral lower lobes.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 1
After admission, bacterial pneumonia was considered; hence, ceftriaxone (1 g) and azithromycin (500 mg) were administered. To treat COVID-19, favipiravir (1,200 mg) and ciclesonide (800 μg) were also administered (Fig. 2). On day 2, although his C-reactive protein level had increased and his chest radiography findings remained unchange, his oxygenation improved (P/F ratio > 300 mmHg). Therefore, the ventilator settings were changed from pressure control ventilation (PCV; driving pressure).Fig. 2 Time course of physical conditions, therapeutic interventions, and ECMO status of this patient.
ECMO: extracorporeal membrane oxygenation; PCV: pressure control ventilation; PSV: pressure support ventilation; PEEP: positive end-expiratory pressure; VV-ECMO: veno-venous ECMO.
Fig. 2
10 cmH2O; positive end-expiratory pressure [PEEP], 10 cmH2O) to pressure support ventilation (PSV; fraction of inspired oxygen, 30%; PEEP, 5 cmH2O; pressure support, 5 cmH2O).
On day 3, his breathing pattern worsened, and he was in distress (Additional file 1). We evaluated the patient with a P0.1 measurement and an LUSS-based evaluation. His P0.1 was high at 6.4 cmH2O (Table 1), and the LUSS results had worsened (day 3; Fig. 1) [10]. The P/F ratio and chest radiography findings continued to worsen; thus, the ventilator setting was changed back from PSV to PCV because a higher PEEP and driving pressure were needed to maintain oxygenation. We then performed a CT scan to evaluate his lungs (day 3; Fig. 1). Patient self-inflicted lung injury (P-SILI) was diagnosed because the CT images showed acute respiratory distress syndrome (ARDS) [11]. Accordingly, continuous infusion of muscle relaxants was administered to prevent excessive spontaneous breathing.
On day 5, all parameters worsened (Table 1 and Fig. 3). Therefore, we decided to initiate veno-venous extracorporeal membrane oxygenation (VV-ECMO). The right internal jugular vein was cannulated with a 25-Fr heparin-coated cannula for blood access, and the right femoral vein was cannulated with a 21-Fr heparin-coated cannula for blood return. The procedure was performed safely, and no complications occurred.Fig. 3 Chest X-ray, CT, and LUS findings on days 5 and 14.
Day 5: Chest radiography and CT: pulmonary consolidation worsened in the bilateral lower lobes, and bilateral ground-glass opacities also worsened in the bilateral upper lobes.
LUSS: total 25 points. Coalescent B-lines were prominent in the bilateral anterior and lateral lobes. Subpleural consolidation appeared in the bilateral posterior lobe.
Day 14: Chest radiography and CT: pulmonary consolidation improved in the bilateral lower lobes, and bilateral ground-glass opacities decreased in the bilateral upper lobes.
LUSS: total 13 points. Multiple B-lines and subpleural consolidation decreased, and A-lines reemerged in the anterior lobe.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 3
After the initiation of VV-ECMO, the patient's breathing pattern stabilized. The continuous infusion of muscle relaxants was stopped, and his lung function was reevaluated every day (P0.1 measurement, physical assessment, LUSS, chest radiography, and laboratory testing; Table 1). We performed a tracheostomy on day 7. Remdesivir (200 mg on the first day, 100 mg/day thereafter) was administered as a replacement for favipiravir on day 9. On day 13, his chest radiography findings, static lung compliance, and LUSS improved. VV-ECMO was eventually discontinued on day 14 (Fig. 3). The chest radiography and CT findings after weaning of VV-ECMO showed consistent daily improvements. On day 26, he was transferred to the hospital where he was previously admitted. Two months later, he was discharged home.
3 Discussion
3.1 Strategy for managing patients with severe COVID-19
Currently, VV-ECMO has been established as a standard step in managing ARDS when other treatments fail [12]. Although an effective treatment for COVID-19 has not been established, VV-ECMO has been used as the ultimate symptomatic treatment for COVID-19 [[13], [14], [15]]. Gattinoni et al. reported variations in the respiratory mechanics profiles of invasively ventilated patients with COVID-19 pneumonitis [16], and the following two clinical phenotypes were identified: (1) type L, which was characterized by low elastance, a low ventilation-to-perfusion ratio, a low lung weight, and low recruitability, and (2) type H, which was characterized by high elastance, a pronounced right-to-left shunt, high lung weight, and high recruitability. The transition from Type L to Type H may be due to the worsening of COVID-19 severity or due to an injury caused by high-stress ventilation.
Besides the severity of the disease itself, the depth of negative intrathoracic pressure may also play a possible key role in the phenotype shift from Type L to Type H [17]. Transpulmonary pressure (TPP), which is the distending force applied to the lungs, is the difference between the alveolar and intrathoracic pressures. TPP will increase with strong spontaneous breathing. Higher TPP and lung permeability due to inflammation result in interstitial lung edema. This phenomenon has recently been recognized as P-SILI [11].
Effective treatment for severe COVID-19 pneumonitis may prevent the occurrence of P-SILI and its progression from Type L to Type H. Systemic steroid administration, which was not used in this study, has been thought to reduce inflammation, thereby suppressing strong spontaneous breathing and improving the prognosis of patients on mechanical ventilation [18]. However, if the lungs are severely damaged, ECMO is the only way to gain time with lung-protective ventilation until recovery. In fact, we have previously reported successful treatment of a COVID-19 pneumonitis patient with VV-ECMO in 7 days [14].
3.2 Evaluation of lung condition during ECMO
Although VV-ECMO is one way to save lives, it is risky and associated with some complications, primarily including bleeding and infection [1]. Therefore, clinicians perform daily lung evaluations to determine when VV-ECMO should be induced and when a patient should be weaned off it.
It has been reported that CT scans provide the most reliable assessment of lung condition in COVID-19 pneumonitis patients [1,20]. However, during a pandemic, the transportation of critically ill ventilated patients to radiology facilities is challenging, especially for ECMO-managed patients3,4. Although increased levels of D-dimer, C-reactive protein, ferritin, and lactate dehydrogenase have also been reported as markers of severity for COVID-19, they are not specific to the lungs [21]. The serum Krebs von den Lungen‐6 (KL‐6) concentration is a lung-specific biomarker, and its usefulness in COVID-19 has been reported [22]. However, the measurement of KL-6 levels is time-consuming and cannot be done at all facilities. Notably, LUS is the preferred imaging modality because of its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 pneumonitis cases where lung pathology is a characteristic feature [5,6]. LUS provides results that are similar to chest CT findings, and it is superior to chest radiography for the evaluation of COVID-19 [[23], [24], [25]]. However, the existing literature contains only a few case reports supporting the usefulness of serial LUS in ECMO-managed severe COVID-19 patients [26].
3.3 Usefulness of serial LUS in an ECMO-managed patient with severe COVID-19
We believe that serial LUS was very useful in our patient's case. First, the LUSS was associated with the progression and improvement of the patient's lung condition, as observed in CT images (Fig. 1, Fig. 3) and laboratory findings (Table 1). The longer the ECMO management, the more complications patients have [19]. However, it is uncertain how long we should protect the lungs with ECMO. Because the condition of the lungs varies from case to case, laboratory findings like P/F ratios do not directly correlate with the improvement of lung condition during ECMO. LUS can be evaluated individually and specifically for the lungs, and the reemergence of A-lines suggests an improvement in lung condition [[3], [4], [5], [6],8]. Although serial LUS evaluation is also considered appropriate for patients on ECMO, few studies have examined its appropriateness for COVID-19 patients [27].
Second, LUS can be performed quickly by one clinician without displacing the patient or requiring radiation exposure [22]. Accordingly, LUS is faster, easier, and safer than other imaging modalities, with significant advantages during a pandemic [5,6].
Third, in this case, the LUSS increased sharply from day 1 to day 3 (score: from 9 to 21). We believe that P-SILI occurred on day 3 because the patient's P0.1 value increased and his respiratory patterns appeared distressed (Additional file 1). Given that there was an improvement in oxygenation, but not yet in inflammation, changing the ventilator setting from PCV to PSV probably led to increased respiratory efforts, increased transpulmonary pressure, and P-SILI. It has been reported that P-SILI increases transmural pulmonary vascular pressure, thereby resulting in increased vascular permeability and pulmonary edema [11]. Therefore, we suspect that the appearance of multiple B-lines, especially those in the lateral and posterior regions, might have been due to negative intrathoracic pressure generated by strong spontaneous breathing. Although no studies have demonstrated a relationship between P-SILI and LUS, we thought that the rapid increase of the LUSS suggested the occurrence of P-SILI.
This case study has several limitations. One limitation is that the inter-rater reliability was not evaluated, although three experienced emergency physicians performed LUS. The other limitation is that the pandemic is ongoing, and the existing knowledge about COVID-19 might be modified by future findings.
4 Conclusion
This case report demonstrated that serial LUS was useful for evaluating lung condition in a COVID-19 patient requiring ECMO. The present findings suggest that LUS may be useful for the detection of P-SILI. However, further prospective studies are needed to test this hypothesis.
Declaration of competing interest
The authors have no conflicts of interest directly relevant to the content of this article.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101383. | AZITHROMYCIN ANHYDROUS, CEFTRIAXONE, CICLESONIDE, FAVIPIRAVIR, HEPARIN SODIUM, INSULIN NOS, REMDESIVIR | DrugsGivenReaction | CC BY-NC-ND | 33717868 | 19,854,293 | 2021 |
What was the dosage of drug 'AZITHROMYCIN ANHYDROUS'? | Usefulness of serial lung ultrasound for a severe COVID-19 patient on extracorporeal membrane oxygenation.
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO). Notably, lung ultrasound (LUS) is a favored alternative imaging modality due to its ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost. We demonstrated that serial LUS compares favorably with other imaging modalities in terms of usefulness for evaluating lung aeration and recovery in an ECMO-managed COVID-19 patient.
1 Introduction
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis [1,2]. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO) [3,4]. Notably, lung ultrasound (LUS) is an alternative favored imaging modality due to its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 patients in whom lung pathology is a key characteristic5.6. LUS also has other advantages, including ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost [5,6].
2 Case presentation
A 57-year-old male office worker presented to his local hospital with a 3-day history of malaise and fever. He later developed shortness of breath that led to his hospitalization. Furthermore, a polymerase chain reaction–based test for severe acute respiratory syndrome coronavirus 2 in a nasopharyngeal swab sample returned positive results (Cobas SARS-CoV-2 Test; Roche Diagnostics, Rotkreuz, Switzerland). The patient was a heavy smoker, and his medical history included diabetes (HbA1c, 6.6; on insulin). After two days in the local hospital, he was transported to our emergency room (ER) due to worsening symptoms.
Upon admission to the ER, his vital signs were as follows: respiratory rate, 30 breaths/min; oxygen saturation, 97% on an oxygen mask at 6 L/min; heart rate, 135 beats/min; and blood pressure, 153/103 mmHg. A physical examination showed an alert man with no rashes or swelling. On auscultation, he had significant bilateral wheezing. He was therefore intubated and ventilated in the intensive care unit. After intubation, static lung compliance and airway occlusion pressure at 100 ms (P0.1) were measured (Table 1) [7].Table 1 Clinical parameters.
Table 1Measure Day 1 Day 3 Day 5 Day 7 Day 9 Day 13 Day 14 Day 26
Laboratory findings During ECMO management
White blood cell count (/μL) 7,900 3,200 6,400 4,600 7,000 7,200 11,000 6,200
Absolute lymphocyte count (/μL) 979 714 761 961 1,379 1,044
C-reactive protein (mg/dL) 7.09 15.8 31.5 17.8 20.4 8.25 4.2 4.4
Lactate Dehydrogenase (U/L) 500 820 845 705 634 533 407 294
Krebs von den Lungen‐6 (ng/mL) 287 – 1,070 842 792 588 – 672
Respiratory parameter
Respiratory rate (/min) 24 26 6 6 6 15 16 12
Minute volume (L/min) 10.5 13.3 1.9 1.9 1.9 3.6 8.5 6.2
PaO2/FIO2 ratio 224 118 69 223 170 242 285 280
P0.1 (cmH2O) 0.8 6.4 – 0.6 0.8 1.6 0.8 0.8
Static Lung Compliance (mL/cmH2O) 60 50 46 – – 68 – –
Lung Ultrasound Score 9 21 25 25 23 18 13 15
FiO2, fraction of inspired oxygen; P0.1, airway occlusion pressure at 100 ms; PaO2, partial pressure of oxygen.
The laboratory finding on admission are shown in Table 1. Chest radiography and CT findings showed pale, bilateral, ground-glass opacities (day 1; Fig. 1). LUS was performed at 6 points per hemithorax (superior and inferior regions anteriorly, laterally, and posteriorly) bilaterally (day 1; Fig. 1) [8]. A linear probe was placed in the intercostal muscles to evaluate the lungs. LUS was performed and graded by three emergency physicians who were experienced in performing LUS. The LUS Score (LUSS) was evaluated at the bedside as previously described [9]. Briefly, 0–3 points were allocated for each of the 12 pre-determined anatomical regions according to the ultrasound pattern: normal = 0, well-defined B-lines = 1, coalescent B-lines = 2, and consolidation = 3 (total score ranges from 0 to 36). Lung consolidations (scoring 3) were noted only when the thickness (measured perpendicular from the pleura) was greater than 15 mm. Sub-pleural thickening and sub-pleural consolidations (thickness: 15 mm or thinner) were graded as a score of 2. Each score with the detail of each zone was recorded day by day in a table and kept in the patient medical record.Fig. 1 Chest X-ray, CT, and LUS findings on days 1 and 3.
Day 1: Chest radiography and CT scan: pale bilateral ground-glass opacities.
LUSS: total 9 points. A-lines or <3 B-lines appeared in the bilateral upper lobes, and multiple B-lines appeared in the bilateral lower lobes.
Day 3: Chest radiography and CT scan: pulmonary consolidation appeared in the bilateral lower lobes, and bilateral ground-glass opacities were prominent in the right upper lobe.
LUSS: total 21 points. Multiple B-lines appeared in the upper bilateral lobes, and coalescent B-lines appeared in the bilateral lower lobes.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 1
After admission, bacterial pneumonia was considered; hence, ceftriaxone (1 g) and azithromycin (500 mg) were administered. To treat COVID-19, favipiravir (1,200 mg) and ciclesonide (800 μg) were also administered (Fig. 2). On day 2, although his C-reactive protein level had increased and his chest radiography findings remained unchange, his oxygenation improved (P/F ratio > 300 mmHg). Therefore, the ventilator settings were changed from pressure control ventilation (PCV; driving pressure).Fig. 2 Time course of physical conditions, therapeutic interventions, and ECMO status of this patient.
ECMO: extracorporeal membrane oxygenation; PCV: pressure control ventilation; PSV: pressure support ventilation; PEEP: positive end-expiratory pressure; VV-ECMO: veno-venous ECMO.
Fig. 2
10 cmH2O; positive end-expiratory pressure [PEEP], 10 cmH2O) to pressure support ventilation (PSV; fraction of inspired oxygen, 30%; PEEP, 5 cmH2O; pressure support, 5 cmH2O).
On day 3, his breathing pattern worsened, and he was in distress (Additional file 1). We evaluated the patient with a P0.1 measurement and an LUSS-based evaluation. His P0.1 was high at 6.4 cmH2O (Table 1), and the LUSS results had worsened (day 3; Fig. 1) [10]. The P/F ratio and chest radiography findings continued to worsen; thus, the ventilator setting was changed back from PSV to PCV because a higher PEEP and driving pressure were needed to maintain oxygenation. We then performed a CT scan to evaluate his lungs (day 3; Fig. 1). Patient self-inflicted lung injury (P-SILI) was diagnosed because the CT images showed acute respiratory distress syndrome (ARDS) [11]. Accordingly, continuous infusion of muscle relaxants was administered to prevent excessive spontaneous breathing.
On day 5, all parameters worsened (Table 1 and Fig. 3). Therefore, we decided to initiate veno-venous extracorporeal membrane oxygenation (VV-ECMO). The right internal jugular vein was cannulated with a 25-Fr heparin-coated cannula for blood access, and the right femoral vein was cannulated with a 21-Fr heparin-coated cannula for blood return. The procedure was performed safely, and no complications occurred.Fig. 3 Chest X-ray, CT, and LUS findings on days 5 and 14.
Day 5: Chest radiography and CT: pulmonary consolidation worsened in the bilateral lower lobes, and bilateral ground-glass opacities also worsened in the bilateral upper lobes.
LUSS: total 25 points. Coalescent B-lines were prominent in the bilateral anterior and lateral lobes. Subpleural consolidation appeared in the bilateral posterior lobe.
Day 14: Chest radiography and CT: pulmonary consolidation improved in the bilateral lower lobes, and bilateral ground-glass opacities decreased in the bilateral upper lobes.
LUSS: total 13 points. Multiple B-lines and subpleural consolidation decreased, and A-lines reemerged in the anterior lobe.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 3
After the initiation of VV-ECMO, the patient's breathing pattern stabilized. The continuous infusion of muscle relaxants was stopped, and his lung function was reevaluated every day (P0.1 measurement, physical assessment, LUSS, chest radiography, and laboratory testing; Table 1). We performed a tracheostomy on day 7. Remdesivir (200 mg on the first day, 100 mg/day thereafter) was administered as a replacement for favipiravir on day 9. On day 13, his chest radiography findings, static lung compliance, and LUSS improved. VV-ECMO was eventually discontinued on day 14 (Fig. 3). The chest radiography and CT findings after weaning of VV-ECMO showed consistent daily improvements. On day 26, he was transferred to the hospital where he was previously admitted. Two months later, he was discharged home.
3 Discussion
3.1 Strategy for managing patients with severe COVID-19
Currently, VV-ECMO has been established as a standard step in managing ARDS when other treatments fail [12]. Although an effective treatment for COVID-19 has not been established, VV-ECMO has been used as the ultimate symptomatic treatment for COVID-19 [[13], [14], [15]]. Gattinoni et al. reported variations in the respiratory mechanics profiles of invasively ventilated patients with COVID-19 pneumonitis [16], and the following two clinical phenotypes were identified: (1) type L, which was characterized by low elastance, a low ventilation-to-perfusion ratio, a low lung weight, and low recruitability, and (2) type H, which was characterized by high elastance, a pronounced right-to-left shunt, high lung weight, and high recruitability. The transition from Type L to Type H may be due to the worsening of COVID-19 severity or due to an injury caused by high-stress ventilation.
Besides the severity of the disease itself, the depth of negative intrathoracic pressure may also play a possible key role in the phenotype shift from Type L to Type H [17]. Transpulmonary pressure (TPP), which is the distending force applied to the lungs, is the difference between the alveolar and intrathoracic pressures. TPP will increase with strong spontaneous breathing. Higher TPP and lung permeability due to inflammation result in interstitial lung edema. This phenomenon has recently been recognized as P-SILI [11].
Effective treatment for severe COVID-19 pneumonitis may prevent the occurrence of P-SILI and its progression from Type L to Type H. Systemic steroid administration, which was not used in this study, has been thought to reduce inflammation, thereby suppressing strong spontaneous breathing and improving the prognosis of patients on mechanical ventilation [18]. However, if the lungs are severely damaged, ECMO is the only way to gain time with lung-protective ventilation until recovery. In fact, we have previously reported successful treatment of a COVID-19 pneumonitis patient with VV-ECMO in 7 days [14].
3.2 Evaluation of lung condition during ECMO
Although VV-ECMO is one way to save lives, it is risky and associated with some complications, primarily including bleeding and infection [1]. Therefore, clinicians perform daily lung evaluations to determine when VV-ECMO should be induced and when a patient should be weaned off it.
It has been reported that CT scans provide the most reliable assessment of lung condition in COVID-19 pneumonitis patients [1,20]. However, during a pandemic, the transportation of critically ill ventilated patients to radiology facilities is challenging, especially for ECMO-managed patients3,4. Although increased levels of D-dimer, C-reactive protein, ferritin, and lactate dehydrogenase have also been reported as markers of severity for COVID-19, they are not specific to the lungs [21]. The serum Krebs von den Lungen‐6 (KL‐6) concentration is a lung-specific biomarker, and its usefulness in COVID-19 has been reported [22]. However, the measurement of KL-6 levels is time-consuming and cannot be done at all facilities. Notably, LUS is the preferred imaging modality because of its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 pneumonitis cases where lung pathology is a characteristic feature [5,6]. LUS provides results that are similar to chest CT findings, and it is superior to chest radiography for the evaluation of COVID-19 [[23], [24], [25]]. However, the existing literature contains only a few case reports supporting the usefulness of serial LUS in ECMO-managed severe COVID-19 patients [26].
3.3 Usefulness of serial LUS in an ECMO-managed patient with severe COVID-19
We believe that serial LUS was very useful in our patient's case. First, the LUSS was associated with the progression and improvement of the patient's lung condition, as observed in CT images (Fig. 1, Fig. 3) and laboratory findings (Table 1). The longer the ECMO management, the more complications patients have [19]. However, it is uncertain how long we should protect the lungs with ECMO. Because the condition of the lungs varies from case to case, laboratory findings like P/F ratios do not directly correlate with the improvement of lung condition during ECMO. LUS can be evaluated individually and specifically for the lungs, and the reemergence of A-lines suggests an improvement in lung condition [[3], [4], [5], [6],8]. Although serial LUS evaluation is also considered appropriate for patients on ECMO, few studies have examined its appropriateness for COVID-19 patients [27].
Second, LUS can be performed quickly by one clinician without displacing the patient or requiring radiation exposure [22]. Accordingly, LUS is faster, easier, and safer than other imaging modalities, with significant advantages during a pandemic [5,6].
Third, in this case, the LUSS increased sharply from day 1 to day 3 (score: from 9 to 21). We believe that P-SILI occurred on day 3 because the patient's P0.1 value increased and his respiratory patterns appeared distressed (Additional file 1). Given that there was an improvement in oxygenation, but not yet in inflammation, changing the ventilator setting from PCV to PSV probably led to increased respiratory efforts, increased transpulmonary pressure, and P-SILI. It has been reported that P-SILI increases transmural pulmonary vascular pressure, thereby resulting in increased vascular permeability and pulmonary edema [11]. Therefore, we suspect that the appearance of multiple B-lines, especially those in the lateral and posterior regions, might have been due to negative intrathoracic pressure generated by strong spontaneous breathing. Although no studies have demonstrated a relationship between P-SILI and LUS, we thought that the rapid increase of the LUSS suggested the occurrence of P-SILI.
This case study has several limitations. One limitation is that the inter-rater reliability was not evaluated, although three experienced emergency physicians performed LUS. The other limitation is that the pandemic is ongoing, and the existing knowledge about COVID-19 might be modified by future findings.
4 Conclusion
This case report demonstrated that serial LUS was useful for evaluating lung condition in a COVID-19 patient requiring ECMO. The present findings suggest that LUS may be useful for the detection of P-SILI. However, further prospective studies are needed to test this hypothesis.
Declaration of competing interest
The authors have no conflicts of interest directly relevant to the content of this article.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101383. | 500 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33717868 | 19,854,293 | 2021 |
What was the dosage of drug 'CEFTRIAXONE'? | Usefulness of serial lung ultrasound for a severe COVID-19 patient on extracorporeal membrane oxygenation.
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO). Notably, lung ultrasound (LUS) is a favored alternative imaging modality due to its ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost. We demonstrated that serial LUS compares favorably with other imaging modalities in terms of usefulness for evaluating lung aeration and recovery in an ECMO-managed COVID-19 patient.
1 Introduction
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis [1,2]. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO) [3,4]. Notably, lung ultrasound (LUS) is an alternative favored imaging modality due to its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 patients in whom lung pathology is a key characteristic5.6. LUS also has other advantages, including ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost [5,6].
2 Case presentation
A 57-year-old male office worker presented to his local hospital with a 3-day history of malaise and fever. He later developed shortness of breath that led to his hospitalization. Furthermore, a polymerase chain reaction–based test for severe acute respiratory syndrome coronavirus 2 in a nasopharyngeal swab sample returned positive results (Cobas SARS-CoV-2 Test; Roche Diagnostics, Rotkreuz, Switzerland). The patient was a heavy smoker, and his medical history included diabetes (HbA1c, 6.6; on insulin). After two days in the local hospital, he was transported to our emergency room (ER) due to worsening symptoms.
Upon admission to the ER, his vital signs were as follows: respiratory rate, 30 breaths/min; oxygen saturation, 97% on an oxygen mask at 6 L/min; heart rate, 135 beats/min; and blood pressure, 153/103 mmHg. A physical examination showed an alert man with no rashes or swelling. On auscultation, he had significant bilateral wheezing. He was therefore intubated and ventilated in the intensive care unit. After intubation, static lung compliance and airway occlusion pressure at 100 ms (P0.1) were measured (Table 1) [7].Table 1 Clinical parameters.
Table 1Measure Day 1 Day 3 Day 5 Day 7 Day 9 Day 13 Day 14 Day 26
Laboratory findings During ECMO management
White blood cell count (/μL) 7,900 3,200 6,400 4,600 7,000 7,200 11,000 6,200
Absolute lymphocyte count (/μL) 979 714 761 961 1,379 1,044
C-reactive protein (mg/dL) 7.09 15.8 31.5 17.8 20.4 8.25 4.2 4.4
Lactate Dehydrogenase (U/L) 500 820 845 705 634 533 407 294
Krebs von den Lungen‐6 (ng/mL) 287 – 1,070 842 792 588 – 672
Respiratory parameter
Respiratory rate (/min) 24 26 6 6 6 15 16 12
Minute volume (L/min) 10.5 13.3 1.9 1.9 1.9 3.6 8.5 6.2
PaO2/FIO2 ratio 224 118 69 223 170 242 285 280
P0.1 (cmH2O) 0.8 6.4 – 0.6 0.8 1.6 0.8 0.8
Static Lung Compliance (mL/cmH2O) 60 50 46 – – 68 – –
Lung Ultrasound Score 9 21 25 25 23 18 13 15
FiO2, fraction of inspired oxygen; P0.1, airway occlusion pressure at 100 ms; PaO2, partial pressure of oxygen.
The laboratory finding on admission are shown in Table 1. Chest radiography and CT findings showed pale, bilateral, ground-glass opacities (day 1; Fig. 1). LUS was performed at 6 points per hemithorax (superior and inferior regions anteriorly, laterally, and posteriorly) bilaterally (day 1; Fig. 1) [8]. A linear probe was placed in the intercostal muscles to evaluate the lungs. LUS was performed and graded by three emergency physicians who were experienced in performing LUS. The LUS Score (LUSS) was evaluated at the bedside as previously described [9]. Briefly, 0–3 points were allocated for each of the 12 pre-determined anatomical regions according to the ultrasound pattern: normal = 0, well-defined B-lines = 1, coalescent B-lines = 2, and consolidation = 3 (total score ranges from 0 to 36). Lung consolidations (scoring 3) were noted only when the thickness (measured perpendicular from the pleura) was greater than 15 mm. Sub-pleural thickening and sub-pleural consolidations (thickness: 15 mm or thinner) were graded as a score of 2. Each score with the detail of each zone was recorded day by day in a table and kept in the patient medical record.Fig. 1 Chest X-ray, CT, and LUS findings on days 1 and 3.
Day 1: Chest radiography and CT scan: pale bilateral ground-glass opacities.
LUSS: total 9 points. A-lines or <3 B-lines appeared in the bilateral upper lobes, and multiple B-lines appeared in the bilateral lower lobes.
Day 3: Chest radiography and CT scan: pulmonary consolidation appeared in the bilateral lower lobes, and bilateral ground-glass opacities were prominent in the right upper lobe.
LUSS: total 21 points. Multiple B-lines appeared in the upper bilateral lobes, and coalescent B-lines appeared in the bilateral lower lobes.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 1
After admission, bacterial pneumonia was considered; hence, ceftriaxone (1 g) and azithromycin (500 mg) were administered. To treat COVID-19, favipiravir (1,200 mg) and ciclesonide (800 μg) were also administered (Fig. 2). On day 2, although his C-reactive protein level had increased and his chest radiography findings remained unchange, his oxygenation improved (P/F ratio > 300 mmHg). Therefore, the ventilator settings were changed from pressure control ventilation (PCV; driving pressure).Fig. 2 Time course of physical conditions, therapeutic interventions, and ECMO status of this patient.
ECMO: extracorporeal membrane oxygenation; PCV: pressure control ventilation; PSV: pressure support ventilation; PEEP: positive end-expiratory pressure; VV-ECMO: veno-venous ECMO.
Fig. 2
10 cmH2O; positive end-expiratory pressure [PEEP], 10 cmH2O) to pressure support ventilation (PSV; fraction of inspired oxygen, 30%; PEEP, 5 cmH2O; pressure support, 5 cmH2O).
On day 3, his breathing pattern worsened, and he was in distress (Additional file 1). We evaluated the patient with a P0.1 measurement and an LUSS-based evaluation. His P0.1 was high at 6.4 cmH2O (Table 1), and the LUSS results had worsened (day 3; Fig. 1) [10]. The P/F ratio and chest radiography findings continued to worsen; thus, the ventilator setting was changed back from PSV to PCV because a higher PEEP and driving pressure were needed to maintain oxygenation. We then performed a CT scan to evaluate his lungs (day 3; Fig. 1). Patient self-inflicted lung injury (P-SILI) was diagnosed because the CT images showed acute respiratory distress syndrome (ARDS) [11]. Accordingly, continuous infusion of muscle relaxants was administered to prevent excessive spontaneous breathing.
On day 5, all parameters worsened (Table 1 and Fig. 3). Therefore, we decided to initiate veno-venous extracorporeal membrane oxygenation (VV-ECMO). The right internal jugular vein was cannulated with a 25-Fr heparin-coated cannula for blood access, and the right femoral vein was cannulated with a 21-Fr heparin-coated cannula for blood return. The procedure was performed safely, and no complications occurred.Fig. 3 Chest X-ray, CT, and LUS findings on days 5 and 14.
Day 5: Chest radiography and CT: pulmonary consolidation worsened in the bilateral lower lobes, and bilateral ground-glass opacities also worsened in the bilateral upper lobes.
LUSS: total 25 points. Coalescent B-lines were prominent in the bilateral anterior and lateral lobes. Subpleural consolidation appeared in the bilateral posterior lobe.
Day 14: Chest radiography and CT: pulmonary consolidation improved in the bilateral lower lobes, and bilateral ground-glass opacities decreased in the bilateral upper lobes.
LUSS: total 13 points. Multiple B-lines and subpleural consolidation decreased, and A-lines reemerged in the anterior lobe.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 3
After the initiation of VV-ECMO, the patient's breathing pattern stabilized. The continuous infusion of muscle relaxants was stopped, and his lung function was reevaluated every day (P0.1 measurement, physical assessment, LUSS, chest radiography, and laboratory testing; Table 1). We performed a tracheostomy on day 7. Remdesivir (200 mg on the first day, 100 mg/day thereafter) was administered as a replacement for favipiravir on day 9. On day 13, his chest radiography findings, static lung compliance, and LUSS improved. VV-ECMO was eventually discontinued on day 14 (Fig. 3). The chest radiography and CT findings after weaning of VV-ECMO showed consistent daily improvements. On day 26, he was transferred to the hospital where he was previously admitted. Two months later, he was discharged home.
3 Discussion
3.1 Strategy for managing patients with severe COVID-19
Currently, VV-ECMO has been established as a standard step in managing ARDS when other treatments fail [12]. Although an effective treatment for COVID-19 has not been established, VV-ECMO has been used as the ultimate symptomatic treatment for COVID-19 [[13], [14], [15]]. Gattinoni et al. reported variations in the respiratory mechanics profiles of invasively ventilated patients with COVID-19 pneumonitis [16], and the following two clinical phenotypes were identified: (1) type L, which was characterized by low elastance, a low ventilation-to-perfusion ratio, a low lung weight, and low recruitability, and (2) type H, which was characterized by high elastance, a pronounced right-to-left shunt, high lung weight, and high recruitability. The transition from Type L to Type H may be due to the worsening of COVID-19 severity or due to an injury caused by high-stress ventilation.
Besides the severity of the disease itself, the depth of negative intrathoracic pressure may also play a possible key role in the phenotype shift from Type L to Type H [17]. Transpulmonary pressure (TPP), which is the distending force applied to the lungs, is the difference between the alveolar and intrathoracic pressures. TPP will increase with strong spontaneous breathing. Higher TPP and lung permeability due to inflammation result in interstitial lung edema. This phenomenon has recently been recognized as P-SILI [11].
Effective treatment for severe COVID-19 pneumonitis may prevent the occurrence of P-SILI and its progression from Type L to Type H. Systemic steroid administration, which was not used in this study, has been thought to reduce inflammation, thereby suppressing strong spontaneous breathing and improving the prognosis of patients on mechanical ventilation [18]. However, if the lungs are severely damaged, ECMO is the only way to gain time with lung-protective ventilation until recovery. In fact, we have previously reported successful treatment of a COVID-19 pneumonitis patient with VV-ECMO in 7 days [14].
3.2 Evaluation of lung condition during ECMO
Although VV-ECMO is one way to save lives, it is risky and associated with some complications, primarily including bleeding and infection [1]. Therefore, clinicians perform daily lung evaluations to determine when VV-ECMO should be induced and when a patient should be weaned off it.
It has been reported that CT scans provide the most reliable assessment of lung condition in COVID-19 pneumonitis patients [1,20]. However, during a pandemic, the transportation of critically ill ventilated patients to radiology facilities is challenging, especially for ECMO-managed patients3,4. Although increased levels of D-dimer, C-reactive protein, ferritin, and lactate dehydrogenase have also been reported as markers of severity for COVID-19, they are not specific to the lungs [21]. The serum Krebs von den Lungen‐6 (KL‐6) concentration is a lung-specific biomarker, and its usefulness in COVID-19 has been reported [22]. However, the measurement of KL-6 levels is time-consuming and cannot be done at all facilities. Notably, LUS is the preferred imaging modality because of its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 pneumonitis cases where lung pathology is a characteristic feature [5,6]. LUS provides results that are similar to chest CT findings, and it is superior to chest radiography for the evaluation of COVID-19 [[23], [24], [25]]. However, the existing literature contains only a few case reports supporting the usefulness of serial LUS in ECMO-managed severe COVID-19 patients [26].
3.3 Usefulness of serial LUS in an ECMO-managed patient with severe COVID-19
We believe that serial LUS was very useful in our patient's case. First, the LUSS was associated with the progression and improvement of the patient's lung condition, as observed in CT images (Fig. 1, Fig. 3) and laboratory findings (Table 1). The longer the ECMO management, the more complications patients have [19]. However, it is uncertain how long we should protect the lungs with ECMO. Because the condition of the lungs varies from case to case, laboratory findings like P/F ratios do not directly correlate with the improvement of lung condition during ECMO. LUS can be evaluated individually and specifically for the lungs, and the reemergence of A-lines suggests an improvement in lung condition [[3], [4], [5], [6],8]. Although serial LUS evaluation is also considered appropriate for patients on ECMO, few studies have examined its appropriateness for COVID-19 patients [27].
Second, LUS can be performed quickly by one clinician without displacing the patient or requiring radiation exposure [22]. Accordingly, LUS is faster, easier, and safer than other imaging modalities, with significant advantages during a pandemic [5,6].
Third, in this case, the LUSS increased sharply from day 1 to day 3 (score: from 9 to 21). We believe that P-SILI occurred on day 3 because the patient's P0.1 value increased and his respiratory patterns appeared distressed (Additional file 1). Given that there was an improvement in oxygenation, but not yet in inflammation, changing the ventilator setting from PCV to PSV probably led to increased respiratory efforts, increased transpulmonary pressure, and P-SILI. It has been reported that P-SILI increases transmural pulmonary vascular pressure, thereby resulting in increased vascular permeability and pulmonary edema [11]. Therefore, we suspect that the appearance of multiple B-lines, especially those in the lateral and posterior regions, might have been due to negative intrathoracic pressure generated by strong spontaneous breathing. Although no studies have demonstrated a relationship between P-SILI and LUS, we thought that the rapid increase of the LUSS suggested the occurrence of P-SILI.
This case study has several limitations. One limitation is that the inter-rater reliability was not evaluated, although three experienced emergency physicians performed LUS. The other limitation is that the pandemic is ongoing, and the existing knowledge about COVID-19 might be modified by future findings.
4 Conclusion
This case report demonstrated that serial LUS was useful for evaluating lung condition in a COVID-19 patient requiring ECMO. The present findings suggest that LUS may be useful for the detection of P-SILI. However, further prospective studies are needed to test this hypothesis.
Declaration of competing interest
The authors have no conflicts of interest directly relevant to the content of this article.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101383. | 1 g (grams). | DrugDosage | CC BY-NC-ND | 33717868 | 19,854,293 | 2021 |
What was the dosage of drug 'CICLESONIDE'? | Usefulness of serial lung ultrasound for a severe COVID-19 patient on extracorporeal membrane oxygenation.
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO). Notably, lung ultrasound (LUS) is a favored alternative imaging modality due to its ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost. We demonstrated that serial LUS compares favorably with other imaging modalities in terms of usefulness for evaluating lung aeration and recovery in an ECMO-managed COVID-19 patient.
1 Introduction
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis [1,2]. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO) [3,4]. Notably, lung ultrasound (LUS) is an alternative favored imaging modality due to its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 patients in whom lung pathology is a key characteristic5.6. LUS also has other advantages, including ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost [5,6].
2 Case presentation
A 57-year-old male office worker presented to his local hospital with a 3-day history of malaise and fever. He later developed shortness of breath that led to his hospitalization. Furthermore, a polymerase chain reaction–based test for severe acute respiratory syndrome coronavirus 2 in a nasopharyngeal swab sample returned positive results (Cobas SARS-CoV-2 Test; Roche Diagnostics, Rotkreuz, Switzerland). The patient was a heavy smoker, and his medical history included diabetes (HbA1c, 6.6; on insulin). After two days in the local hospital, he was transported to our emergency room (ER) due to worsening symptoms.
Upon admission to the ER, his vital signs were as follows: respiratory rate, 30 breaths/min; oxygen saturation, 97% on an oxygen mask at 6 L/min; heart rate, 135 beats/min; and blood pressure, 153/103 mmHg. A physical examination showed an alert man with no rashes or swelling. On auscultation, he had significant bilateral wheezing. He was therefore intubated and ventilated in the intensive care unit. After intubation, static lung compliance and airway occlusion pressure at 100 ms (P0.1) were measured (Table 1) [7].Table 1 Clinical parameters.
Table 1Measure Day 1 Day 3 Day 5 Day 7 Day 9 Day 13 Day 14 Day 26
Laboratory findings During ECMO management
White blood cell count (/μL) 7,900 3,200 6,400 4,600 7,000 7,200 11,000 6,200
Absolute lymphocyte count (/μL) 979 714 761 961 1,379 1,044
C-reactive protein (mg/dL) 7.09 15.8 31.5 17.8 20.4 8.25 4.2 4.4
Lactate Dehydrogenase (U/L) 500 820 845 705 634 533 407 294
Krebs von den Lungen‐6 (ng/mL) 287 – 1,070 842 792 588 – 672
Respiratory parameter
Respiratory rate (/min) 24 26 6 6 6 15 16 12
Minute volume (L/min) 10.5 13.3 1.9 1.9 1.9 3.6 8.5 6.2
PaO2/FIO2 ratio 224 118 69 223 170 242 285 280
P0.1 (cmH2O) 0.8 6.4 – 0.6 0.8 1.6 0.8 0.8
Static Lung Compliance (mL/cmH2O) 60 50 46 – – 68 – –
Lung Ultrasound Score 9 21 25 25 23 18 13 15
FiO2, fraction of inspired oxygen; P0.1, airway occlusion pressure at 100 ms; PaO2, partial pressure of oxygen.
The laboratory finding on admission are shown in Table 1. Chest radiography and CT findings showed pale, bilateral, ground-glass opacities (day 1; Fig. 1). LUS was performed at 6 points per hemithorax (superior and inferior regions anteriorly, laterally, and posteriorly) bilaterally (day 1; Fig. 1) [8]. A linear probe was placed in the intercostal muscles to evaluate the lungs. LUS was performed and graded by three emergency physicians who were experienced in performing LUS. The LUS Score (LUSS) was evaluated at the bedside as previously described [9]. Briefly, 0–3 points were allocated for each of the 12 pre-determined anatomical regions according to the ultrasound pattern: normal = 0, well-defined B-lines = 1, coalescent B-lines = 2, and consolidation = 3 (total score ranges from 0 to 36). Lung consolidations (scoring 3) were noted only when the thickness (measured perpendicular from the pleura) was greater than 15 mm. Sub-pleural thickening and sub-pleural consolidations (thickness: 15 mm or thinner) were graded as a score of 2. Each score with the detail of each zone was recorded day by day in a table and kept in the patient medical record.Fig. 1 Chest X-ray, CT, and LUS findings on days 1 and 3.
Day 1: Chest radiography and CT scan: pale bilateral ground-glass opacities.
LUSS: total 9 points. A-lines or <3 B-lines appeared in the bilateral upper lobes, and multiple B-lines appeared in the bilateral lower lobes.
Day 3: Chest radiography and CT scan: pulmonary consolidation appeared in the bilateral lower lobes, and bilateral ground-glass opacities were prominent in the right upper lobe.
LUSS: total 21 points. Multiple B-lines appeared in the upper bilateral lobes, and coalescent B-lines appeared in the bilateral lower lobes.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 1
After admission, bacterial pneumonia was considered; hence, ceftriaxone (1 g) and azithromycin (500 mg) were administered. To treat COVID-19, favipiravir (1,200 mg) and ciclesonide (800 μg) were also administered (Fig. 2). On day 2, although his C-reactive protein level had increased and his chest radiography findings remained unchange, his oxygenation improved (P/F ratio > 300 mmHg). Therefore, the ventilator settings were changed from pressure control ventilation (PCV; driving pressure).Fig. 2 Time course of physical conditions, therapeutic interventions, and ECMO status of this patient.
ECMO: extracorporeal membrane oxygenation; PCV: pressure control ventilation; PSV: pressure support ventilation; PEEP: positive end-expiratory pressure; VV-ECMO: veno-venous ECMO.
Fig. 2
10 cmH2O; positive end-expiratory pressure [PEEP], 10 cmH2O) to pressure support ventilation (PSV; fraction of inspired oxygen, 30%; PEEP, 5 cmH2O; pressure support, 5 cmH2O).
On day 3, his breathing pattern worsened, and he was in distress (Additional file 1). We evaluated the patient with a P0.1 measurement and an LUSS-based evaluation. His P0.1 was high at 6.4 cmH2O (Table 1), and the LUSS results had worsened (day 3; Fig. 1) [10]. The P/F ratio and chest radiography findings continued to worsen; thus, the ventilator setting was changed back from PSV to PCV because a higher PEEP and driving pressure were needed to maintain oxygenation. We then performed a CT scan to evaluate his lungs (day 3; Fig. 1). Patient self-inflicted lung injury (P-SILI) was diagnosed because the CT images showed acute respiratory distress syndrome (ARDS) [11]. Accordingly, continuous infusion of muscle relaxants was administered to prevent excessive spontaneous breathing.
On day 5, all parameters worsened (Table 1 and Fig. 3). Therefore, we decided to initiate veno-venous extracorporeal membrane oxygenation (VV-ECMO). The right internal jugular vein was cannulated with a 25-Fr heparin-coated cannula for blood access, and the right femoral vein was cannulated with a 21-Fr heparin-coated cannula for blood return. The procedure was performed safely, and no complications occurred.Fig. 3 Chest X-ray, CT, and LUS findings on days 5 and 14.
Day 5: Chest radiography and CT: pulmonary consolidation worsened in the bilateral lower lobes, and bilateral ground-glass opacities also worsened in the bilateral upper lobes.
LUSS: total 25 points. Coalescent B-lines were prominent in the bilateral anterior and lateral lobes. Subpleural consolidation appeared in the bilateral posterior lobe.
Day 14: Chest radiography and CT: pulmonary consolidation improved in the bilateral lower lobes, and bilateral ground-glass opacities decreased in the bilateral upper lobes.
LUSS: total 13 points. Multiple B-lines and subpleural consolidation decreased, and A-lines reemerged in the anterior lobe.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 3
After the initiation of VV-ECMO, the patient's breathing pattern stabilized. The continuous infusion of muscle relaxants was stopped, and his lung function was reevaluated every day (P0.1 measurement, physical assessment, LUSS, chest radiography, and laboratory testing; Table 1). We performed a tracheostomy on day 7. Remdesivir (200 mg on the first day, 100 mg/day thereafter) was administered as a replacement for favipiravir on day 9. On day 13, his chest radiography findings, static lung compliance, and LUSS improved. VV-ECMO was eventually discontinued on day 14 (Fig. 3). The chest radiography and CT findings after weaning of VV-ECMO showed consistent daily improvements. On day 26, he was transferred to the hospital where he was previously admitted. Two months later, he was discharged home.
3 Discussion
3.1 Strategy for managing patients with severe COVID-19
Currently, VV-ECMO has been established as a standard step in managing ARDS when other treatments fail [12]. Although an effective treatment for COVID-19 has not been established, VV-ECMO has been used as the ultimate symptomatic treatment for COVID-19 [[13], [14], [15]]. Gattinoni et al. reported variations in the respiratory mechanics profiles of invasively ventilated patients with COVID-19 pneumonitis [16], and the following two clinical phenotypes were identified: (1) type L, which was characterized by low elastance, a low ventilation-to-perfusion ratio, a low lung weight, and low recruitability, and (2) type H, which was characterized by high elastance, a pronounced right-to-left shunt, high lung weight, and high recruitability. The transition from Type L to Type H may be due to the worsening of COVID-19 severity or due to an injury caused by high-stress ventilation.
Besides the severity of the disease itself, the depth of negative intrathoracic pressure may also play a possible key role in the phenotype shift from Type L to Type H [17]. Transpulmonary pressure (TPP), which is the distending force applied to the lungs, is the difference between the alveolar and intrathoracic pressures. TPP will increase with strong spontaneous breathing. Higher TPP and lung permeability due to inflammation result in interstitial lung edema. This phenomenon has recently been recognized as P-SILI [11].
Effective treatment for severe COVID-19 pneumonitis may prevent the occurrence of P-SILI and its progression from Type L to Type H. Systemic steroid administration, which was not used in this study, has been thought to reduce inflammation, thereby suppressing strong spontaneous breathing and improving the prognosis of patients on mechanical ventilation [18]. However, if the lungs are severely damaged, ECMO is the only way to gain time with lung-protective ventilation until recovery. In fact, we have previously reported successful treatment of a COVID-19 pneumonitis patient with VV-ECMO in 7 days [14].
3.2 Evaluation of lung condition during ECMO
Although VV-ECMO is one way to save lives, it is risky and associated with some complications, primarily including bleeding and infection [1]. Therefore, clinicians perform daily lung evaluations to determine when VV-ECMO should be induced and when a patient should be weaned off it.
It has been reported that CT scans provide the most reliable assessment of lung condition in COVID-19 pneumonitis patients [1,20]. However, during a pandemic, the transportation of critically ill ventilated patients to radiology facilities is challenging, especially for ECMO-managed patients3,4. Although increased levels of D-dimer, C-reactive protein, ferritin, and lactate dehydrogenase have also been reported as markers of severity for COVID-19, they are not specific to the lungs [21]. The serum Krebs von den Lungen‐6 (KL‐6) concentration is a lung-specific biomarker, and its usefulness in COVID-19 has been reported [22]. However, the measurement of KL-6 levels is time-consuming and cannot be done at all facilities. Notably, LUS is the preferred imaging modality because of its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 pneumonitis cases where lung pathology is a characteristic feature [5,6]. LUS provides results that are similar to chest CT findings, and it is superior to chest radiography for the evaluation of COVID-19 [[23], [24], [25]]. However, the existing literature contains only a few case reports supporting the usefulness of serial LUS in ECMO-managed severe COVID-19 patients [26].
3.3 Usefulness of serial LUS in an ECMO-managed patient with severe COVID-19
We believe that serial LUS was very useful in our patient's case. First, the LUSS was associated with the progression and improvement of the patient's lung condition, as observed in CT images (Fig. 1, Fig. 3) and laboratory findings (Table 1). The longer the ECMO management, the more complications patients have [19]. However, it is uncertain how long we should protect the lungs with ECMO. Because the condition of the lungs varies from case to case, laboratory findings like P/F ratios do not directly correlate with the improvement of lung condition during ECMO. LUS can be evaluated individually and specifically for the lungs, and the reemergence of A-lines suggests an improvement in lung condition [[3], [4], [5], [6],8]. Although serial LUS evaluation is also considered appropriate for patients on ECMO, few studies have examined its appropriateness for COVID-19 patients [27].
Second, LUS can be performed quickly by one clinician without displacing the patient or requiring radiation exposure [22]. Accordingly, LUS is faster, easier, and safer than other imaging modalities, with significant advantages during a pandemic [5,6].
Third, in this case, the LUSS increased sharply from day 1 to day 3 (score: from 9 to 21). We believe that P-SILI occurred on day 3 because the patient's P0.1 value increased and his respiratory patterns appeared distressed (Additional file 1). Given that there was an improvement in oxygenation, but not yet in inflammation, changing the ventilator setting from PCV to PSV probably led to increased respiratory efforts, increased transpulmonary pressure, and P-SILI. It has been reported that P-SILI increases transmural pulmonary vascular pressure, thereby resulting in increased vascular permeability and pulmonary edema [11]. Therefore, we suspect that the appearance of multiple B-lines, especially those in the lateral and posterior regions, might have been due to negative intrathoracic pressure generated by strong spontaneous breathing. Although no studies have demonstrated a relationship between P-SILI and LUS, we thought that the rapid increase of the LUSS suggested the occurrence of P-SILI.
This case study has several limitations. One limitation is that the inter-rater reliability was not evaluated, although three experienced emergency physicians performed LUS. The other limitation is that the pandemic is ongoing, and the existing knowledge about COVID-19 might be modified by future findings.
4 Conclusion
This case report demonstrated that serial LUS was useful for evaluating lung condition in a COVID-19 patient requiring ECMO. The present findings suggest that LUS may be useful for the detection of P-SILI. However, further prospective studies are needed to test this hypothesis.
Declaration of competing interest
The authors have no conflicts of interest directly relevant to the content of this article.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101383. | 800 µg (micrograms). | DrugDosage | CC BY-NC-ND | 33717868 | 19,854,293 | 2021 |
What was the dosage of drug 'FAVIPIRAVIR'? | Usefulness of serial lung ultrasound for a severe COVID-19 patient on extracorporeal membrane oxygenation.
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO). Notably, lung ultrasound (LUS) is a favored alternative imaging modality due to its ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost. We demonstrated that serial LUS compares favorably with other imaging modalities in terms of usefulness for evaluating lung aeration and recovery in an ECMO-managed COVID-19 patient.
1 Introduction
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis [1,2]. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO) [3,4]. Notably, lung ultrasound (LUS) is an alternative favored imaging modality due to its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 patients in whom lung pathology is a key characteristic5.6. LUS also has other advantages, including ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost [5,6].
2 Case presentation
A 57-year-old male office worker presented to his local hospital with a 3-day history of malaise and fever. He later developed shortness of breath that led to his hospitalization. Furthermore, a polymerase chain reaction–based test for severe acute respiratory syndrome coronavirus 2 in a nasopharyngeal swab sample returned positive results (Cobas SARS-CoV-2 Test; Roche Diagnostics, Rotkreuz, Switzerland). The patient was a heavy smoker, and his medical history included diabetes (HbA1c, 6.6; on insulin). After two days in the local hospital, he was transported to our emergency room (ER) due to worsening symptoms.
Upon admission to the ER, his vital signs were as follows: respiratory rate, 30 breaths/min; oxygen saturation, 97% on an oxygen mask at 6 L/min; heart rate, 135 beats/min; and blood pressure, 153/103 mmHg. A physical examination showed an alert man with no rashes or swelling. On auscultation, he had significant bilateral wheezing. He was therefore intubated and ventilated in the intensive care unit. After intubation, static lung compliance and airway occlusion pressure at 100 ms (P0.1) were measured (Table 1) [7].Table 1 Clinical parameters.
Table 1Measure Day 1 Day 3 Day 5 Day 7 Day 9 Day 13 Day 14 Day 26
Laboratory findings During ECMO management
White blood cell count (/μL) 7,900 3,200 6,400 4,600 7,000 7,200 11,000 6,200
Absolute lymphocyte count (/μL) 979 714 761 961 1,379 1,044
C-reactive protein (mg/dL) 7.09 15.8 31.5 17.8 20.4 8.25 4.2 4.4
Lactate Dehydrogenase (U/L) 500 820 845 705 634 533 407 294
Krebs von den Lungen‐6 (ng/mL) 287 – 1,070 842 792 588 – 672
Respiratory parameter
Respiratory rate (/min) 24 26 6 6 6 15 16 12
Minute volume (L/min) 10.5 13.3 1.9 1.9 1.9 3.6 8.5 6.2
PaO2/FIO2 ratio 224 118 69 223 170 242 285 280
P0.1 (cmH2O) 0.8 6.4 – 0.6 0.8 1.6 0.8 0.8
Static Lung Compliance (mL/cmH2O) 60 50 46 – – 68 – –
Lung Ultrasound Score 9 21 25 25 23 18 13 15
FiO2, fraction of inspired oxygen; P0.1, airway occlusion pressure at 100 ms; PaO2, partial pressure of oxygen.
The laboratory finding on admission are shown in Table 1. Chest radiography and CT findings showed pale, bilateral, ground-glass opacities (day 1; Fig. 1). LUS was performed at 6 points per hemithorax (superior and inferior regions anteriorly, laterally, and posteriorly) bilaterally (day 1; Fig. 1) [8]. A linear probe was placed in the intercostal muscles to evaluate the lungs. LUS was performed and graded by three emergency physicians who were experienced in performing LUS. The LUS Score (LUSS) was evaluated at the bedside as previously described [9]. Briefly, 0–3 points were allocated for each of the 12 pre-determined anatomical regions according to the ultrasound pattern: normal = 0, well-defined B-lines = 1, coalescent B-lines = 2, and consolidation = 3 (total score ranges from 0 to 36). Lung consolidations (scoring 3) were noted only when the thickness (measured perpendicular from the pleura) was greater than 15 mm. Sub-pleural thickening and sub-pleural consolidations (thickness: 15 mm or thinner) were graded as a score of 2. Each score with the detail of each zone was recorded day by day in a table and kept in the patient medical record.Fig. 1 Chest X-ray, CT, and LUS findings on days 1 and 3.
Day 1: Chest radiography and CT scan: pale bilateral ground-glass opacities.
LUSS: total 9 points. A-lines or <3 B-lines appeared in the bilateral upper lobes, and multiple B-lines appeared in the bilateral lower lobes.
Day 3: Chest radiography and CT scan: pulmonary consolidation appeared in the bilateral lower lobes, and bilateral ground-glass opacities were prominent in the right upper lobe.
LUSS: total 21 points. Multiple B-lines appeared in the upper bilateral lobes, and coalescent B-lines appeared in the bilateral lower lobes.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 1
After admission, bacterial pneumonia was considered; hence, ceftriaxone (1 g) and azithromycin (500 mg) were administered. To treat COVID-19, favipiravir (1,200 mg) and ciclesonide (800 μg) were also administered (Fig. 2). On day 2, although his C-reactive protein level had increased and his chest radiography findings remained unchange, his oxygenation improved (P/F ratio > 300 mmHg). Therefore, the ventilator settings were changed from pressure control ventilation (PCV; driving pressure).Fig. 2 Time course of physical conditions, therapeutic interventions, and ECMO status of this patient.
ECMO: extracorporeal membrane oxygenation; PCV: pressure control ventilation; PSV: pressure support ventilation; PEEP: positive end-expiratory pressure; VV-ECMO: veno-venous ECMO.
Fig. 2
10 cmH2O; positive end-expiratory pressure [PEEP], 10 cmH2O) to pressure support ventilation (PSV; fraction of inspired oxygen, 30%; PEEP, 5 cmH2O; pressure support, 5 cmH2O).
On day 3, his breathing pattern worsened, and he was in distress (Additional file 1). We evaluated the patient with a P0.1 measurement and an LUSS-based evaluation. His P0.1 was high at 6.4 cmH2O (Table 1), and the LUSS results had worsened (day 3; Fig. 1) [10]. The P/F ratio and chest radiography findings continued to worsen; thus, the ventilator setting was changed back from PSV to PCV because a higher PEEP and driving pressure were needed to maintain oxygenation. We then performed a CT scan to evaluate his lungs (day 3; Fig. 1). Patient self-inflicted lung injury (P-SILI) was diagnosed because the CT images showed acute respiratory distress syndrome (ARDS) [11]. Accordingly, continuous infusion of muscle relaxants was administered to prevent excessive spontaneous breathing.
On day 5, all parameters worsened (Table 1 and Fig. 3). Therefore, we decided to initiate veno-venous extracorporeal membrane oxygenation (VV-ECMO). The right internal jugular vein was cannulated with a 25-Fr heparin-coated cannula for blood access, and the right femoral vein was cannulated with a 21-Fr heparin-coated cannula for blood return. The procedure was performed safely, and no complications occurred.Fig. 3 Chest X-ray, CT, and LUS findings on days 5 and 14.
Day 5: Chest radiography and CT: pulmonary consolidation worsened in the bilateral lower lobes, and bilateral ground-glass opacities also worsened in the bilateral upper lobes.
LUSS: total 25 points. Coalescent B-lines were prominent in the bilateral anterior and lateral lobes. Subpleural consolidation appeared in the bilateral posterior lobe.
Day 14: Chest radiography and CT: pulmonary consolidation improved in the bilateral lower lobes, and bilateral ground-glass opacities decreased in the bilateral upper lobes.
LUSS: total 13 points. Multiple B-lines and subpleural consolidation decreased, and A-lines reemerged in the anterior lobe.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 3
After the initiation of VV-ECMO, the patient's breathing pattern stabilized. The continuous infusion of muscle relaxants was stopped, and his lung function was reevaluated every day (P0.1 measurement, physical assessment, LUSS, chest radiography, and laboratory testing; Table 1). We performed a tracheostomy on day 7. Remdesivir (200 mg on the first day, 100 mg/day thereafter) was administered as a replacement for favipiravir on day 9. On day 13, his chest radiography findings, static lung compliance, and LUSS improved. VV-ECMO was eventually discontinued on day 14 (Fig. 3). The chest radiography and CT findings after weaning of VV-ECMO showed consistent daily improvements. On day 26, he was transferred to the hospital where he was previously admitted. Two months later, he was discharged home.
3 Discussion
3.1 Strategy for managing patients with severe COVID-19
Currently, VV-ECMO has been established as a standard step in managing ARDS when other treatments fail [12]. Although an effective treatment for COVID-19 has not been established, VV-ECMO has been used as the ultimate symptomatic treatment for COVID-19 [[13], [14], [15]]. Gattinoni et al. reported variations in the respiratory mechanics profiles of invasively ventilated patients with COVID-19 pneumonitis [16], and the following two clinical phenotypes were identified: (1) type L, which was characterized by low elastance, a low ventilation-to-perfusion ratio, a low lung weight, and low recruitability, and (2) type H, which was characterized by high elastance, a pronounced right-to-left shunt, high lung weight, and high recruitability. The transition from Type L to Type H may be due to the worsening of COVID-19 severity or due to an injury caused by high-stress ventilation.
Besides the severity of the disease itself, the depth of negative intrathoracic pressure may also play a possible key role in the phenotype shift from Type L to Type H [17]. Transpulmonary pressure (TPP), which is the distending force applied to the lungs, is the difference between the alveolar and intrathoracic pressures. TPP will increase with strong spontaneous breathing. Higher TPP and lung permeability due to inflammation result in interstitial lung edema. This phenomenon has recently been recognized as P-SILI [11].
Effective treatment for severe COVID-19 pneumonitis may prevent the occurrence of P-SILI and its progression from Type L to Type H. Systemic steroid administration, which was not used in this study, has been thought to reduce inflammation, thereby suppressing strong spontaneous breathing and improving the prognosis of patients on mechanical ventilation [18]. However, if the lungs are severely damaged, ECMO is the only way to gain time with lung-protective ventilation until recovery. In fact, we have previously reported successful treatment of a COVID-19 pneumonitis patient with VV-ECMO in 7 days [14].
3.2 Evaluation of lung condition during ECMO
Although VV-ECMO is one way to save lives, it is risky and associated with some complications, primarily including bleeding and infection [1]. Therefore, clinicians perform daily lung evaluations to determine when VV-ECMO should be induced and when a patient should be weaned off it.
It has been reported that CT scans provide the most reliable assessment of lung condition in COVID-19 pneumonitis patients [1,20]. However, during a pandemic, the transportation of critically ill ventilated patients to radiology facilities is challenging, especially for ECMO-managed patients3,4. Although increased levels of D-dimer, C-reactive protein, ferritin, and lactate dehydrogenase have also been reported as markers of severity for COVID-19, they are not specific to the lungs [21]. The serum Krebs von den Lungen‐6 (KL‐6) concentration is a lung-specific biomarker, and its usefulness in COVID-19 has been reported [22]. However, the measurement of KL-6 levels is time-consuming and cannot be done at all facilities. Notably, LUS is the preferred imaging modality because of its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 pneumonitis cases where lung pathology is a characteristic feature [5,6]. LUS provides results that are similar to chest CT findings, and it is superior to chest radiography for the evaluation of COVID-19 [[23], [24], [25]]. However, the existing literature contains only a few case reports supporting the usefulness of serial LUS in ECMO-managed severe COVID-19 patients [26].
3.3 Usefulness of serial LUS in an ECMO-managed patient with severe COVID-19
We believe that serial LUS was very useful in our patient's case. First, the LUSS was associated with the progression and improvement of the patient's lung condition, as observed in CT images (Fig. 1, Fig. 3) and laboratory findings (Table 1). The longer the ECMO management, the more complications patients have [19]. However, it is uncertain how long we should protect the lungs with ECMO. Because the condition of the lungs varies from case to case, laboratory findings like P/F ratios do not directly correlate with the improvement of lung condition during ECMO. LUS can be evaluated individually and specifically for the lungs, and the reemergence of A-lines suggests an improvement in lung condition [[3], [4], [5], [6],8]. Although serial LUS evaluation is also considered appropriate for patients on ECMO, few studies have examined its appropriateness for COVID-19 patients [27].
Second, LUS can be performed quickly by one clinician without displacing the patient or requiring radiation exposure [22]. Accordingly, LUS is faster, easier, and safer than other imaging modalities, with significant advantages during a pandemic [5,6].
Third, in this case, the LUSS increased sharply from day 1 to day 3 (score: from 9 to 21). We believe that P-SILI occurred on day 3 because the patient's P0.1 value increased and his respiratory patterns appeared distressed (Additional file 1). Given that there was an improvement in oxygenation, but not yet in inflammation, changing the ventilator setting from PCV to PSV probably led to increased respiratory efforts, increased transpulmonary pressure, and P-SILI. It has been reported that P-SILI increases transmural pulmonary vascular pressure, thereby resulting in increased vascular permeability and pulmonary edema [11]. Therefore, we suspect that the appearance of multiple B-lines, especially those in the lateral and posterior regions, might have been due to negative intrathoracic pressure generated by strong spontaneous breathing. Although no studies have demonstrated a relationship between P-SILI and LUS, we thought that the rapid increase of the LUSS suggested the occurrence of P-SILI.
This case study has several limitations. One limitation is that the inter-rater reliability was not evaluated, although three experienced emergency physicians performed LUS. The other limitation is that the pandemic is ongoing, and the existing knowledge about COVID-19 might be modified by future findings.
4 Conclusion
This case report demonstrated that serial LUS was useful for evaluating lung condition in a COVID-19 patient requiring ECMO. The present findings suggest that LUS may be useful for the detection of P-SILI. However, further prospective studies are needed to test this hypothesis.
Declaration of competing interest
The authors have no conflicts of interest directly relevant to the content of this article.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101383. | 1200 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33717868 | 19,854,293 | 2021 |
What was the dosage of drug 'REMDESIVIR'? | Usefulness of serial lung ultrasound for a severe COVID-19 patient on extracorporeal membrane oxygenation.
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO). Notably, lung ultrasound (LUS) is a favored alternative imaging modality due to its ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost. We demonstrated that serial LUS compares favorably with other imaging modalities in terms of usefulness for evaluating lung aeration and recovery in an ECMO-managed COVID-19 patient.
1 Introduction
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis [1,2]. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO) [3,4]. Notably, lung ultrasound (LUS) is an alternative favored imaging modality due to its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 patients in whom lung pathology is a key characteristic5.6. LUS also has other advantages, including ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost [5,6].
2 Case presentation
A 57-year-old male office worker presented to his local hospital with a 3-day history of malaise and fever. He later developed shortness of breath that led to his hospitalization. Furthermore, a polymerase chain reaction–based test for severe acute respiratory syndrome coronavirus 2 in a nasopharyngeal swab sample returned positive results (Cobas SARS-CoV-2 Test; Roche Diagnostics, Rotkreuz, Switzerland). The patient was a heavy smoker, and his medical history included diabetes (HbA1c, 6.6; on insulin). After two days in the local hospital, he was transported to our emergency room (ER) due to worsening symptoms.
Upon admission to the ER, his vital signs were as follows: respiratory rate, 30 breaths/min; oxygen saturation, 97% on an oxygen mask at 6 L/min; heart rate, 135 beats/min; and blood pressure, 153/103 mmHg. A physical examination showed an alert man with no rashes or swelling. On auscultation, he had significant bilateral wheezing. He was therefore intubated and ventilated in the intensive care unit. After intubation, static lung compliance and airway occlusion pressure at 100 ms (P0.1) were measured (Table 1) [7].Table 1 Clinical parameters.
Table 1Measure Day 1 Day 3 Day 5 Day 7 Day 9 Day 13 Day 14 Day 26
Laboratory findings During ECMO management
White blood cell count (/μL) 7,900 3,200 6,400 4,600 7,000 7,200 11,000 6,200
Absolute lymphocyte count (/μL) 979 714 761 961 1,379 1,044
C-reactive protein (mg/dL) 7.09 15.8 31.5 17.8 20.4 8.25 4.2 4.4
Lactate Dehydrogenase (U/L) 500 820 845 705 634 533 407 294
Krebs von den Lungen‐6 (ng/mL) 287 – 1,070 842 792 588 – 672
Respiratory parameter
Respiratory rate (/min) 24 26 6 6 6 15 16 12
Minute volume (L/min) 10.5 13.3 1.9 1.9 1.9 3.6 8.5 6.2
PaO2/FIO2 ratio 224 118 69 223 170 242 285 280
P0.1 (cmH2O) 0.8 6.4 – 0.6 0.8 1.6 0.8 0.8
Static Lung Compliance (mL/cmH2O) 60 50 46 – – 68 – –
Lung Ultrasound Score 9 21 25 25 23 18 13 15
FiO2, fraction of inspired oxygen; P0.1, airway occlusion pressure at 100 ms; PaO2, partial pressure of oxygen.
The laboratory finding on admission are shown in Table 1. Chest radiography and CT findings showed pale, bilateral, ground-glass opacities (day 1; Fig. 1). LUS was performed at 6 points per hemithorax (superior and inferior regions anteriorly, laterally, and posteriorly) bilaterally (day 1; Fig. 1) [8]. A linear probe was placed in the intercostal muscles to evaluate the lungs. LUS was performed and graded by three emergency physicians who were experienced in performing LUS. The LUS Score (LUSS) was evaluated at the bedside as previously described [9]. Briefly, 0–3 points were allocated for each of the 12 pre-determined anatomical regions according to the ultrasound pattern: normal = 0, well-defined B-lines = 1, coalescent B-lines = 2, and consolidation = 3 (total score ranges from 0 to 36). Lung consolidations (scoring 3) were noted only when the thickness (measured perpendicular from the pleura) was greater than 15 mm. Sub-pleural thickening and sub-pleural consolidations (thickness: 15 mm or thinner) were graded as a score of 2. Each score with the detail of each zone was recorded day by day in a table and kept in the patient medical record.Fig. 1 Chest X-ray, CT, and LUS findings on days 1 and 3.
Day 1: Chest radiography and CT scan: pale bilateral ground-glass opacities.
LUSS: total 9 points. A-lines or <3 B-lines appeared in the bilateral upper lobes, and multiple B-lines appeared in the bilateral lower lobes.
Day 3: Chest radiography and CT scan: pulmonary consolidation appeared in the bilateral lower lobes, and bilateral ground-glass opacities were prominent in the right upper lobe.
LUSS: total 21 points. Multiple B-lines appeared in the upper bilateral lobes, and coalescent B-lines appeared in the bilateral lower lobes.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 1
After admission, bacterial pneumonia was considered; hence, ceftriaxone (1 g) and azithromycin (500 mg) were administered. To treat COVID-19, favipiravir (1,200 mg) and ciclesonide (800 μg) were also administered (Fig. 2). On day 2, although his C-reactive protein level had increased and his chest radiography findings remained unchange, his oxygenation improved (P/F ratio > 300 mmHg). Therefore, the ventilator settings were changed from pressure control ventilation (PCV; driving pressure).Fig. 2 Time course of physical conditions, therapeutic interventions, and ECMO status of this patient.
ECMO: extracorporeal membrane oxygenation; PCV: pressure control ventilation; PSV: pressure support ventilation; PEEP: positive end-expiratory pressure; VV-ECMO: veno-venous ECMO.
Fig. 2
10 cmH2O; positive end-expiratory pressure [PEEP], 10 cmH2O) to pressure support ventilation (PSV; fraction of inspired oxygen, 30%; PEEP, 5 cmH2O; pressure support, 5 cmH2O).
On day 3, his breathing pattern worsened, and he was in distress (Additional file 1). We evaluated the patient with a P0.1 measurement and an LUSS-based evaluation. His P0.1 was high at 6.4 cmH2O (Table 1), and the LUSS results had worsened (day 3; Fig. 1) [10]. The P/F ratio and chest radiography findings continued to worsen; thus, the ventilator setting was changed back from PSV to PCV because a higher PEEP and driving pressure were needed to maintain oxygenation. We then performed a CT scan to evaluate his lungs (day 3; Fig. 1). Patient self-inflicted lung injury (P-SILI) was diagnosed because the CT images showed acute respiratory distress syndrome (ARDS) [11]. Accordingly, continuous infusion of muscle relaxants was administered to prevent excessive spontaneous breathing.
On day 5, all parameters worsened (Table 1 and Fig. 3). Therefore, we decided to initiate veno-venous extracorporeal membrane oxygenation (VV-ECMO). The right internal jugular vein was cannulated with a 25-Fr heparin-coated cannula for blood access, and the right femoral vein was cannulated with a 21-Fr heparin-coated cannula for blood return. The procedure was performed safely, and no complications occurred.Fig. 3 Chest X-ray, CT, and LUS findings on days 5 and 14.
Day 5: Chest radiography and CT: pulmonary consolidation worsened in the bilateral lower lobes, and bilateral ground-glass opacities also worsened in the bilateral upper lobes.
LUSS: total 25 points. Coalescent B-lines were prominent in the bilateral anterior and lateral lobes. Subpleural consolidation appeared in the bilateral posterior lobe.
Day 14: Chest radiography and CT: pulmonary consolidation improved in the bilateral lower lobes, and bilateral ground-glass opacities decreased in the bilateral upper lobes.
LUSS: total 13 points. Multiple B-lines and subpleural consolidation decreased, and A-lines reemerged in the anterior lobe.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 3
After the initiation of VV-ECMO, the patient's breathing pattern stabilized. The continuous infusion of muscle relaxants was stopped, and his lung function was reevaluated every day (P0.1 measurement, physical assessment, LUSS, chest radiography, and laboratory testing; Table 1). We performed a tracheostomy on day 7. Remdesivir (200 mg on the first day, 100 mg/day thereafter) was administered as a replacement for favipiravir on day 9. On day 13, his chest radiography findings, static lung compliance, and LUSS improved. VV-ECMO was eventually discontinued on day 14 (Fig. 3). The chest radiography and CT findings after weaning of VV-ECMO showed consistent daily improvements. On day 26, he was transferred to the hospital where he was previously admitted. Two months later, he was discharged home.
3 Discussion
3.1 Strategy for managing patients with severe COVID-19
Currently, VV-ECMO has been established as a standard step in managing ARDS when other treatments fail [12]. Although an effective treatment for COVID-19 has not been established, VV-ECMO has been used as the ultimate symptomatic treatment for COVID-19 [[13], [14], [15]]. Gattinoni et al. reported variations in the respiratory mechanics profiles of invasively ventilated patients with COVID-19 pneumonitis [16], and the following two clinical phenotypes were identified: (1) type L, which was characterized by low elastance, a low ventilation-to-perfusion ratio, a low lung weight, and low recruitability, and (2) type H, which was characterized by high elastance, a pronounced right-to-left shunt, high lung weight, and high recruitability. The transition from Type L to Type H may be due to the worsening of COVID-19 severity or due to an injury caused by high-stress ventilation.
Besides the severity of the disease itself, the depth of negative intrathoracic pressure may also play a possible key role in the phenotype shift from Type L to Type H [17]. Transpulmonary pressure (TPP), which is the distending force applied to the lungs, is the difference between the alveolar and intrathoracic pressures. TPP will increase with strong spontaneous breathing. Higher TPP and lung permeability due to inflammation result in interstitial lung edema. This phenomenon has recently been recognized as P-SILI [11].
Effective treatment for severe COVID-19 pneumonitis may prevent the occurrence of P-SILI and its progression from Type L to Type H. Systemic steroid administration, which was not used in this study, has been thought to reduce inflammation, thereby suppressing strong spontaneous breathing and improving the prognosis of patients on mechanical ventilation [18]. However, if the lungs are severely damaged, ECMO is the only way to gain time with lung-protective ventilation until recovery. In fact, we have previously reported successful treatment of a COVID-19 pneumonitis patient with VV-ECMO in 7 days [14].
3.2 Evaluation of lung condition during ECMO
Although VV-ECMO is one way to save lives, it is risky and associated with some complications, primarily including bleeding and infection [1]. Therefore, clinicians perform daily lung evaluations to determine when VV-ECMO should be induced and when a patient should be weaned off it.
It has been reported that CT scans provide the most reliable assessment of lung condition in COVID-19 pneumonitis patients [1,20]. However, during a pandemic, the transportation of critically ill ventilated patients to radiology facilities is challenging, especially for ECMO-managed patients3,4. Although increased levels of D-dimer, C-reactive protein, ferritin, and lactate dehydrogenase have also been reported as markers of severity for COVID-19, they are not specific to the lungs [21]. The serum Krebs von den Lungen‐6 (KL‐6) concentration is a lung-specific biomarker, and its usefulness in COVID-19 has been reported [22]. However, the measurement of KL-6 levels is time-consuming and cannot be done at all facilities. Notably, LUS is the preferred imaging modality because of its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 pneumonitis cases where lung pathology is a characteristic feature [5,6]. LUS provides results that are similar to chest CT findings, and it is superior to chest radiography for the evaluation of COVID-19 [[23], [24], [25]]. However, the existing literature contains only a few case reports supporting the usefulness of serial LUS in ECMO-managed severe COVID-19 patients [26].
3.3 Usefulness of serial LUS in an ECMO-managed patient with severe COVID-19
We believe that serial LUS was very useful in our patient's case. First, the LUSS was associated with the progression and improvement of the patient's lung condition, as observed in CT images (Fig. 1, Fig. 3) and laboratory findings (Table 1). The longer the ECMO management, the more complications patients have [19]. However, it is uncertain how long we should protect the lungs with ECMO. Because the condition of the lungs varies from case to case, laboratory findings like P/F ratios do not directly correlate with the improvement of lung condition during ECMO. LUS can be evaluated individually and specifically for the lungs, and the reemergence of A-lines suggests an improvement in lung condition [[3], [4], [5], [6],8]. Although serial LUS evaluation is also considered appropriate for patients on ECMO, few studies have examined its appropriateness for COVID-19 patients [27].
Second, LUS can be performed quickly by one clinician without displacing the patient or requiring radiation exposure [22]. Accordingly, LUS is faster, easier, and safer than other imaging modalities, with significant advantages during a pandemic [5,6].
Third, in this case, the LUSS increased sharply from day 1 to day 3 (score: from 9 to 21). We believe that P-SILI occurred on day 3 because the patient's P0.1 value increased and his respiratory patterns appeared distressed (Additional file 1). Given that there was an improvement in oxygenation, but not yet in inflammation, changing the ventilator setting from PCV to PSV probably led to increased respiratory efforts, increased transpulmonary pressure, and P-SILI. It has been reported that P-SILI increases transmural pulmonary vascular pressure, thereby resulting in increased vascular permeability and pulmonary edema [11]. Therefore, we suspect that the appearance of multiple B-lines, especially those in the lateral and posterior regions, might have been due to negative intrathoracic pressure generated by strong spontaneous breathing. Although no studies have demonstrated a relationship between P-SILI and LUS, we thought that the rapid increase of the LUSS suggested the occurrence of P-SILI.
This case study has several limitations. One limitation is that the inter-rater reliability was not evaluated, although three experienced emergency physicians performed LUS. The other limitation is that the pandemic is ongoing, and the existing knowledge about COVID-19 might be modified by future findings.
4 Conclusion
This case report demonstrated that serial LUS was useful for evaluating lung condition in a COVID-19 patient requiring ECMO. The present findings suggest that LUS may be useful for the detection of P-SILI. However, further prospective studies are needed to test this hypothesis.
Declaration of competing interest
The authors have no conflicts of interest directly relevant to the content of this article.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101383. | 200 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33717868 | 19,854,293 | 2021 |
What was the outcome of reaction 'Acute respiratory distress syndrome'? | Usefulness of serial lung ultrasound for a severe COVID-19 patient on extracorporeal membrane oxygenation.
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO). Notably, lung ultrasound (LUS) is a favored alternative imaging modality due to its ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost. We demonstrated that serial LUS compares favorably with other imaging modalities in terms of usefulness for evaluating lung aeration and recovery in an ECMO-managed COVID-19 patient.
1 Introduction
Computed tomography (CT) is the most reliable method to evaluate the progression of COVID-19 pneumonitis [1,2]. However, in a pandemic, transportation of critically ill invasively ventilated patients to radiology facilities is challenging, especially for those on extracorporeal membrane oxygenation (ECMO) [3,4]. Notably, lung ultrasound (LUS) is an alternative favored imaging modality due to its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 patients in whom lung pathology is a key characteristic5.6. LUS also has other advantages, including ease of use at the point of care, which reduces the infectious risk of exposure and transmission; repeatability; absence of radiation exposure; and low cost [5,6].
2 Case presentation
A 57-year-old male office worker presented to his local hospital with a 3-day history of malaise and fever. He later developed shortness of breath that led to his hospitalization. Furthermore, a polymerase chain reaction–based test for severe acute respiratory syndrome coronavirus 2 in a nasopharyngeal swab sample returned positive results (Cobas SARS-CoV-2 Test; Roche Diagnostics, Rotkreuz, Switzerland). The patient was a heavy smoker, and his medical history included diabetes (HbA1c, 6.6; on insulin). After two days in the local hospital, he was transported to our emergency room (ER) due to worsening symptoms.
Upon admission to the ER, his vital signs were as follows: respiratory rate, 30 breaths/min; oxygen saturation, 97% on an oxygen mask at 6 L/min; heart rate, 135 beats/min; and blood pressure, 153/103 mmHg. A physical examination showed an alert man with no rashes or swelling. On auscultation, he had significant bilateral wheezing. He was therefore intubated and ventilated in the intensive care unit. After intubation, static lung compliance and airway occlusion pressure at 100 ms (P0.1) were measured (Table 1) [7].Table 1 Clinical parameters.
Table 1Measure Day 1 Day 3 Day 5 Day 7 Day 9 Day 13 Day 14 Day 26
Laboratory findings During ECMO management
White blood cell count (/μL) 7,900 3,200 6,400 4,600 7,000 7,200 11,000 6,200
Absolute lymphocyte count (/μL) 979 714 761 961 1,379 1,044
C-reactive protein (mg/dL) 7.09 15.8 31.5 17.8 20.4 8.25 4.2 4.4
Lactate Dehydrogenase (U/L) 500 820 845 705 634 533 407 294
Krebs von den Lungen‐6 (ng/mL) 287 – 1,070 842 792 588 – 672
Respiratory parameter
Respiratory rate (/min) 24 26 6 6 6 15 16 12
Minute volume (L/min) 10.5 13.3 1.9 1.9 1.9 3.6 8.5 6.2
PaO2/FIO2 ratio 224 118 69 223 170 242 285 280
P0.1 (cmH2O) 0.8 6.4 – 0.6 0.8 1.6 0.8 0.8
Static Lung Compliance (mL/cmH2O) 60 50 46 – – 68 – –
Lung Ultrasound Score 9 21 25 25 23 18 13 15
FiO2, fraction of inspired oxygen; P0.1, airway occlusion pressure at 100 ms; PaO2, partial pressure of oxygen.
The laboratory finding on admission are shown in Table 1. Chest radiography and CT findings showed pale, bilateral, ground-glass opacities (day 1; Fig. 1). LUS was performed at 6 points per hemithorax (superior and inferior regions anteriorly, laterally, and posteriorly) bilaterally (day 1; Fig. 1) [8]. A linear probe was placed in the intercostal muscles to evaluate the lungs. LUS was performed and graded by three emergency physicians who were experienced in performing LUS. The LUS Score (LUSS) was evaluated at the bedside as previously described [9]. Briefly, 0–3 points were allocated for each of the 12 pre-determined anatomical regions according to the ultrasound pattern: normal = 0, well-defined B-lines = 1, coalescent B-lines = 2, and consolidation = 3 (total score ranges from 0 to 36). Lung consolidations (scoring 3) were noted only when the thickness (measured perpendicular from the pleura) was greater than 15 mm. Sub-pleural thickening and sub-pleural consolidations (thickness: 15 mm or thinner) were graded as a score of 2. Each score with the detail of each zone was recorded day by day in a table and kept in the patient medical record.Fig. 1 Chest X-ray, CT, and LUS findings on days 1 and 3.
Day 1: Chest radiography and CT scan: pale bilateral ground-glass opacities.
LUSS: total 9 points. A-lines or <3 B-lines appeared in the bilateral upper lobes, and multiple B-lines appeared in the bilateral lower lobes.
Day 3: Chest radiography and CT scan: pulmonary consolidation appeared in the bilateral lower lobes, and bilateral ground-glass opacities were prominent in the right upper lobe.
LUSS: total 21 points. Multiple B-lines appeared in the upper bilateral lobes, and coalescent B-lines appeared in the bilateral lower lobes.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 1
After admission, bacterial pneumonia was considered; hence, ceftriaxone (1 g) and azithromycin (500 mg) were administered. To treat COVID-19, favipiravir (1,200 mg) and ciclesonide (800 μg) were also administered (Fig. 2). On day 2, although his C-reactive protein level had increased and his chest radiography findings remained unchange, his oxygenation improved (P/F ratio > 300 mmHg). Therefore, the ventilator settings were changed from pressure control ventilation (PCV; driving pressure).Fig. 2 Time course of physical conditions, therapeutic interventions, and ECMO status of this patient.
ECMO: extracorporeal membrane oxygenation; PCV: pressure control ventilation; PSV: pressure support ventilation; PEEP: positive end-expiratory pressure; VV-ECMO: veno-venous ECMO.
Fig. 2
10 cmH2O; positive end-expiratory pressure [PEEP], 10 cmH2O) to pressure support ventilation (PSV; fraction of inspired oxygen, 30%; PEEP, 5 cmH2O; pressure support, 5 cmH2O).
On day 3, his breathing pattern worsened, and he was in distress (Additional file 1). We evaluated the patient with a P0.1 measurement and an LUSS-based evaluation. His P0.1 was high at 6.4 cmH2O (Table 1), and the LUSS results had worsened (day 3; Fig. 1) [10]. The P/F ratio and chest radiography findings continued to worsen; thus, the ventilator setting was changed back from PSV to PCV because a higher PEEP and driving pressure were needed to maintain oxygenation. We then performed a CT scan to evaluate his lungs (day 3; Fig. 1). Patient self-inflicted lung injury (P-SILI) was diagnosed because the CT images showed acute respiratory distress syndrome (ARDS) [11]. Accordingly, continuous infusion of muscle relaxants was administered to prevent excessive spontaneous breathing.
On day 5, all parameters worsened (Table 1 and Fig. 3). Therefore, we decided to initiate veno-venous extracorporeal membrane oxygenation (VV-ECMO). The right internal jugular vein was cannulated with a 25-Fr heparin-coated cannula for blood access, and the right femoral vein was cannulated with a 21-Fr heparin-coated cannula for blood return. The procedure was performed safely, and no complications occurred.Fig. 3 Chest X-ray, CT, and LUS findings on days 5 and 14.
Day 5: Chest radiography and CT: pulmonary consolidation worsened in the bilateral lower lobes, and bilateral ground-glass opacities also worsened in the bilateral upper lobes.
LUSS: total 25 points. Coalescent B-lines were prominent in the bilateral anterior and lateral lobes. Subpleural consolidation appeared in the bilateral posterior lobe.
Day 14: Chest radiography and CT: pulmonary consolidation improved in the bilateral lower lobes, and bilateral ground-glass opacities decreased in the bilateral upper lobes.
LUSS: total 13 points. Multiple B-lines and subpleural consolidation decreased, and A-lines reemerged in the anterior lobe.
CT: computed tomography; LUS, lung ultrasound; LUSS: Lung ultrasound Score.
Fig. 3
After the initiation of VV-ECMO, the patient's breathing pattern stabilized. The continuous infusion of muscle relaxants was stopped, and his lung function was reevaluated every day (P0.1 measurement, physical assessment, LUSS, chest radiography, and laboratory testing; Table 1). We performed a tracheostomy on day 7. Remdesivir (200 mg on the first day, 100 mg/day thereafter) was administered as a replacement for favipiravir on day 9. On day 13, his chest radiography findings, static lung compliance, and LUSS improved. VV-ECMO was eventually discontinued on day 14 (Fig. 3). The chest radiography and CT findings after weaning of VV-ECMO showed consistent daily improvements. On day 26, he was transferred to the hospital where he was previously admitted. Two months later, he was discharged home.
3 Discussion
3.1 Strategy for managing patients with severe COVID-19
Currently, VV-ECMO has been established as a standard step in managing ARDS when other treatments fail [12]. Although an effective treatment for COVID-19 has not been established, VV-ECMO has been used as the ultimate symptomatic treatment for COVID-19 [[13], [14], [15]]. Gattinoni et al. reported variations in the respiratory mechanics profiles of invasively ventilated patients with COVID-19 pneumonitis [16], and the following two clinical phenotypes were identified: (1) type L, which was characterized by low elastance, a low ventilation-to-perfusion ratio, a low lung weight, and low recruitability, and (2) type H, which was characterized by high elastance, a pronounced right-to-left shunt, high lung weight, and high recruitability. The transition from Type L to Type H may be due to the worsening of COVID-19 severity or due to an injury caused by high-stress ventilation.
Besides the severity of the disease itself, the depth of negative intrathoracic pressure may also play a possible key role in the phenotype shift from Type L to Type H [17]. Transpulmonary pressure (TPP), which is the distending force applied to the lungs, is the difference between the alveolar and intrathoracic pressures. TPP will increase with strong spontaneous breathing. Higher TPP and lung permeability due to inflammation result in interstitial lung edema. This phenomenon has recently been recognized as P-SILI [11].
Effective treatment for severe COVID-19 pneumonitis may prevent the occurrence of P-SILI and its progression from Type L to Type H. Systemic steroid administration, which was not used in this study, has been thought to reduce inflammation, thereby suppressing strong spontaneous breathing and improving the prognosis of patients on mechanical ventilation [18]. However, if the lungs are severely damaged, ECMO is the only way to gain time with lung-protective ventilation until recovery. In fact, we have previously reported successful treatment of a COVID-19 pneumonitis patient with VV-ECMO in 7 days [14].
3.2 Evaluation of lung condition during ECMO
Although VV-ECMO is one way to save lives, it is risky and associated with some complications, primarily including bleeding and infection [1]. Therefore, clinicians perform daily lung evaluations to determine when VV-ECMO should be induced and when a patient should be weaned off it.
It has been reported that CT scans provide the most reliable assessment of lung condition in COVID-19 pneumonitis patients [1,20]. However, during a pandemic, the transportation of critically ill ventilated patients to radiology facilities is challenging, especially for ECMO-managed patients3,4. Although increased levels of D-dimer, C-reactive protein, ferritin, and lactate dehydrogenase have also been reported as markers of severity for COVID-19, they are not specific to the lungs [21]. The serum Krebs von den Lungen‐6 (KL‐6) concentration is a lung-specific biomarker, and its usefulness in COVID-19 has been reported [22]. However, the measurement of KL-6 levels is time-consuming and cannot be done at all facilities. Notably, LUS is the preferred imaging modality because of its utility for identifying and evaluating the serial progression of lung pathology, especially in COVID-19 pneumonitis cases where lung pathology is a characteristic feature [5,6]. LUS provides results that are similar to chest CT findings, and it is superior to chest radiography for the evaluation of COVID-19 [[23], [24], [25]]. However, the existing literature contains only a few case reports supporting the usefulness of serial LUS in ECMO-managed severe COVID-19 patients [26].
3.3 Usefulness of serial LUS in an ECMO-managed patient with severe COVID-19
We believe that serial LUS was very useful in our patient's case. First, the LUSS was associated with the progression and improvement of the patient's lung condition, as observed in CT images (Fig. 1, Fig. 3) and laboratory findings (Table 1). The longer the ECMO management, the more complications patients have [19]. However, it is uncertain how long we should protect the lungs with ECMO. Because the condition of the lungs varies from case to case, laboratory findings like P/F ratios do not directly correlate with the improvement of lung condition during ECMO. LUS can be evaluated individually and specifically for the lungs, and the reemergence of A-lines suggests an improvement in lung condition [[3], [4], [5], [6],8]. Although serial LUS evaluation is also considered appropriate for patients on ECMO, few studies have examined its appropriateness for COVID-19 patients [27].
Second, LUS can be performed quickly by one clinician without displacing the patient or requiring radiation exposure [22]. Accordingly, LUS is faster, easier, and safer than other imaging modalities, with significant advantages during a pandemic [5,6].
Third, in this case, the LUSS increased sharply from day 1 to day 3 (score: from 9 to 21). We believe that P-SILI occurred on day 3 because the patient's P0.1 value increased and his respiratory patterns appeared distressed (Additional file 1). Given that there was an improvement in oxygenation, but not yet in inflammation, changing the ventilator setting from PCV to PSV probably led to increased respiratory efforts, increased transpulmonary pressure, and P-SILI. It has been reported that P-SILI increases transmural pulmonary vascular pressure, thereby resulting in increased vascular permeability and pulmonary edema [11]. Therefore, we suspect that the appearance of multiple B-lines, especially those in the lateral and posterior regions, might have been due to negative intrathoracic pressure generated by strong spontaneous breathing. Although no studies have demonstrated a relationship between P-SILI and LUS, we thought that the rapid increase of the LUSS suggested the occurrence of P-SILI.
This case study has several limitations. One limitation is that the inter-rater reliability was not evaluated, although three experienced emergency physicians performed LUS. The other limitation is that the pandemic is ongoing, and the existing knowledge about COVID-19 might be modified by future findings.
4 Conclusion
This case report demonstrated that serial LUS was useful for evaluating lung condition in a COVID-19 patient requiring ECMO. The present findings suggest that LUS may be useful for the detection of P-SILI. However, further prospective studies are needed to test this hypothesis.
Declaration of competing interest
The authors have no conflicts of interest directly relevant to the content of this article.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101383. | Recovered | ReactionOutcome | CC BY-NC-ND | 33717868 | 19,854,293 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperglycaemia'. | Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable non-small cell lung cancer: an open-label, multicenter, single-arm study.
Neoadjuvant therapy has significantly improved the 5-year overall survival (OS) of patients with resectable non-small cell lung cancer (NSCLC). The CheckMate 159 trial showed that neoadjuvant therapy with a single-drug programmed cell death protein 1 (PD-1) inhibitor (nivolumab) achieved major pathological response (MPR) and pathological complete response (pCR) in 45% and 15%of participants, respectively. We conducted an open-label single-arm study to evaluate the safety and efficacy of neoadjuvant PD-1 inhibitors in combination with chemotherapy in the treatment of resectable NSCLC.
This study was conducted in a total of 2 hospitals in the Chinese cities of Xi'an and Chongqing, and included eligible patients over 18 years of age with clinically staged IIA-IIIB NSCLC. All patients were scheduled to receive surgery within 4-6 weeks after neoadjuvant treatment (3-4 cycles) consisting of PD-1 inhibitors combined with a conventional chemotherapy regimen on day 1 of each 21-day cycle.
Twenty-three patients, 22 males, and 1 female with just one of them with no smoking habits) were diagnosed with NSCL C in a stage IIA (3 cases), IIB (3 cases), IIIA (8 cases), and IIIB (9cases) and no druggable driver mutations/translocations were addressed to receive neoadjuvant treatment between June 2018 and June 2020. The treatment was well tolerated with just 3 typical immune-related adverse events (hyperthyroidism, hyperglycemia, and rash) recorded. There was a partial response (PR) and stable disease (SD) in 17 (73.9%) and 6 (26.1%) patients, with an overall response rate (ORR) of 73.9% according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). Six of these patients resulted in pCR (30%) while ten of them showed a MPR (50%). Twenty patients underwent surgical resection after treatment, while further 3 refused surgery. Surgical procedure included video-assisted thoracoscopic resection (10 cases), Vinci Robot surgery (4 cases), and thoracotomy in 4 cases while there were secondary compliance-related thoracotomy in two cases. The pathology analysis revealed a R0 in 19 cases (19/20, 95%).
Our results suggest that the neoadjuvant approach with chemotherapy and PD-1 blocking mAbs is safe and active in patients with resectable NSCLC where is associated with a promising high ORR, MPR and pCR.
pmcIntroduction
Neoadjuvant therapy is a promising treatment strategy for patients with resectable non-small cell lung cancer (NSCLC). This kind of treatment for many years has included chemotherapy, tyrosine kinase inhibitors (TKIs), radiotherapy, alone or in multiple combinations (1). A meta-analysis of data from NSCLC patients treated with neoadjuvant chemotherapy showed an absolute improvement in 5-year overall survival (OS) of 5% (40–45%) (2). The mortality risk was significantly reduced in patients who achieved a major pathological response (MPR) after neoadjuvant therapy. Similarly, the results of various clinical trials in patients with bladder, breast, and gastroesophageal cancer showed an improved OS in those who achieved a pathological complete response (pCR) after neoadjuvant therapies (3). In this context further exploration concerning innovative neoadjuvant strategies in resectable NSCLC patients is strongly required.
In more recent years, immunocheckpoint blockade with mAbs to PD-1/PD-L1 alone or in combination with platinum doublets has been shown to significant efficacy in lung cancer patients. The KEYNOTE189 trial in particular, reported the efficacy of an anti-PD-1 mA, pembrolizumab, in combination with chemotherapy in patients with advanced Lung adenocarcinoma. In particular, this trial showed a 12-month OS of 69.2% in the experimental group compared with a 49.4% reported in the group of patients who received the chemotherapy alone (4). Furthermore, in the KEYNOTE407 trial, the OS reached 15.9 months for patients with advanced squamous cell carcinoma in the chemo-immunotherapy arm, compared with 11.3 months recorded in the group addressed to chemotherapy alone (5). The above-mentioned trials have established the role of PD-1 blockade and chemotherapy in the treatment of NSCLC. In line with these results a recent meta-analysis showed that NSCLC patients over-expressing with the programmed death ligand 1 (PD-L1) (PD-L1 score >50%) receiving pembrolizumab-chemotherapy combination showed a much greater ORR, and progression-free survival (PFS) compared with the groups of patients receiving chemotherapy- or pembrolizumab-alone (6). Finally, the CheckMate159 trial reported an MPR rate of 45% in NSCLC patients receiving neoadjuvant therapy with nivolumab, which was much higher than that achieved by any previously tested chemotherapy regimens in neoadjuvant setting (7). The trial therefore suggested that PD-1 blockade is effective and may have definite advantages in patients with resectable NSCLC. Therefore, the present study was conducted to evaluate the anti-tumor activity and safety of neoadjuvant PD-1 blocking mAbs used in combination with standard chemotherapy for potentially resectable (clinical stage IIA–IIIB) NSCLC patients for only Asian performed setting in two different oncology centers in China (Xi’an and Chongqing). We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/tlcr-21-130).
Methods
This study is a multinstitutional single-arm observational study, including 23 patients who received the neoadjuvant treatment in two different Chinese center study. Clinical stages IIA–IIIB NSCLC patients over the age of 18 years with were eligible for inclusion. All of the enrolled patients were scheduled to receive surgery within 4–6 weeks after neoadjuvant therapy that consisted in 3–4 cycles of a conventional chemotherapy regimen with PD-1 inhibitors on day 1 of each cycle according to the international consensus. The specific chemoimmunotherapy regimens are detailed in the Table 1. Additional inclusion criteria included eligibility for surgery, as indicated by auxiliary examination including lung function and blood gas analysis; no distant metastasis; and no contraindications for PD-1 inhibitor therapy. The patients’ clinical staging was reviewed by 3 senior physicians and was confirmed if at least 2 of them agreed. Positron emission tomography/computed tomography (PET/CT) and immunohistochemicalPD-L1 detection were not necessary for inclusion. Patients with adenocarcinoma who had epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement were excluded. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tangdu Hospital of the Fourth Military Medical University (202012-12-KY-02-XW-01) and informed consent was taken from all individual participants.
Table 1 Specific chemoimmunotherapy regimens received by each patient
Patient no. Chemoimmunotherapy Cycles Pathological type Response as per RECIST v.1.1 pCR/MPR PD-L1 (TPS)
P1 Pemetrexed disodium (500 mg/m2, D1) + cisplatin (75 mg/m2, D1) + nivolumab (360 mg, D1) 3 Adenocarcinoma PR pCR N
P2 Nab-paclitaxel (260 mg/m2, D1) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P3 Gemcitabine (1000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma PR 70%
P4 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 3 Squamous carcinoma PR MPR N
P5 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 3 Squamous carcinoma PR MPR N
P6 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma SD <1%
P7 Gemcitabine (1,000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 1 Squamous carcinoma SD MPR N
P8 Gemcitabine (1,000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 2 Squamous carcinoma PR MPR N
P9 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 4 Squamous carcinoma PR pCR N
P10 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P11 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P12 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR pCR N
P13 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma PR 10%
P14 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Adenocarcinoma SD pCR 70%
P15 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 4 Squamous carcinoma PR 1%
P16 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma SD 15%
P17 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma SD <1%
P18 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 4 Adenocarcinoma PR pCR 15.4%
P19 Pemetrexed disodium (500 mg/m2, D1) + cisplatin (75 mg/m2, D1) + sintilimab (200 mg, D1) 3 Adenocarcinoma SD <1%
P20 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR pCR N
P21 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR N
P22 Paclitaxel (175 mg/m2, D1) + carboplatin (AUC=5, D1) + nivolumab (360 mg, D1) 2 Squamous carcinoma PR N
P23 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma PR N
pCR, pathological complete response; MPR, major pathological response; PR, partial response; SD, stable disease; N, none detected; AUC, area under the curve.
Study endpoints
The primary endpoints of the study were the safety and efficacy of neoadjuvant chemotherapy combined with PD-1 inhibitors. The safety-related endpoints included adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE, v.4.0). The efficacy-related endpoints included ORR according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1), and postoperative pathological down-staging according to the eighth edition of the National Comprehensive Cancer Network (NCCN) guidelines for tumor-node-metastasis (TNM) staging of NSCLC.
The secondary study endpoints were pCR, which was defined as the complete absence of tumor cells, and MPR, which was defined as <10% residual viable tumor (RVT).
Statistical analysis
Adverse events and feasibility were continuously monitored. Continuous variables are presented as means with standard deviation, while categorical variables are presented as frequencies.
Results
Patient characteristics
Twenty-three eligible candidates were recruited for this study. There were 22 men and one woman with just one of them with no smoking habits. A squamous histology and an adenocarcinoma were respectively, recorded in 19 and 4 of these patients with no driver mutations/translocation (EGFR or ALK etc.). Three cases were in IIA stage, 3 cases in IIB, 8 cases in IIIA, and 9 cases of IIIB stage (Table 2). Twenty patients underwent surgical resection Fourteen of them completed 3–4 cycles of chemo-immunotherapy as described elsewhere (method section) prior surgery; five further patients experienced grade 1 or 2 irAEs and where addressed to surgery after two treatment cycles while one last patient presented a lung abscess and underwent surgery after just one neo-adjuvant treatment cycle. All data on specific chemo-immunotherapy regimens are shown in Table 1. Three patients did not receive; in fact, two of them who completed the neoadjuvant program refused the risk of the surgery (Patients #21 and #23, Table 2) while another one (#22) refused to complete the neoadjuvant program after he developed a severe (grade 3) hyperglycemia during the second chemotherapy cycle.
Table 2 Baseline characteristics of the intention-to-treat population (N=23)
Characteristics Value Surgery Rejected surgery
Age, years
Median (range) 61.83
≥60 years 20 17 3
<60 years 3 3 0
Sex
Male 22 19 3
Female 1 1 0
BMI, kg/m2 (mean) 24.38
History of smoking
Current/ex-smoker 22 19 3
Never-smoker 1 1 0
KPS
90 21 19 2
100 2 1 1
Pathological type
Squamous carcinoma 19 16 3
Adenocarcinoma 4 4 0
Clinical T stage
T1 2 2 0
T2 4 4 0
T3 11 8 3
T4 6 6 0
Clinical N stage
N0 4 4 0
N1 9 8 1
N2 10 8 2
Clinical stage
IIA 3 2 1
IIB 3 3 0
IIIA 8 8 0
IIIB 9 7 2
Surgical treatment
Among the 20 patients who underwent surgery, 11 patients underwent lobectomy, 5 patients underwent sleeve resection/bronchoplasty, 2 patients received bilobectomy, and 2 patients underwent pneumonectomy. The results for surgical treatment, morbidity, and mortality are reported in the Table 3 shows. Surgical methods included Da Vinci’s/video-assisted thoracoscopic surgery (VATS) (n=14), conversion to thoracotomy (n=2), and thoracotomy (n=4). Complete resection (R0) was achieved in 95% of patients (19/20) who received surgery that in one case was considered as R1 resection due to the patient being lymph-node positive at the highest station. The median amount of blood lost was 212.5 mL (50–600 mL), and the mean operative time was 250 minutes (65–390 minutes).
Table 3 Surgical procedures
Characteristics Results
Extent of surgery
Lobectomy 11
Bilobectomy 2
Sleeve resection/bronchoplasty 5
Pneumonectomy 2
Surgical method
VATS/da Vinci 14
Conversion to thoracotomy 2
Thoracotomy 4
Operation time (min) 250 (65–390)
Bleeding (mL) 212.5 (50–600)
Hospital stay (days) 11.125 (6–22)
Chest tube duration (days) 4.18 (0–7)
Resection margins
R0 19
R1 1
R2 0
Safety
The post-operative complications were considered to be unrelated to neoadjuvant therapy and are summarized in the Table 4. There was no 30- or 90-day mortality, or any postoperative arrhythmia episode. The occurrence of AEs is shown in detail in the Table 5. The most common grade 1 or 2 neoadjuvant treatment-related AEs were fatigue (39.1%), alopecia (39.1%), vomiting (34.7%), leucopenia (30.4%), neutropenia (30.4%), and anorexia (30.4%). The treatment-related grade 3 AEs included anorexia, vomiting, fatigue, alopecia, arthralgia, bone pain, and hyperglycemia. Three patients experienced typical immune-related AEs including grade 1–2 hyperthyroidism, grade 3 hyperglycemia, and grade 1–2 rash.
Table 4 Postoperative complications
Characteristics N (%)
Intraoperative blood transfusion 2 (10%)
Death within 30 and 90 days 0
Heart failure 1 (5%)
Postoperative arrhythmia 0
Postoperative hoarseness 1 (5%)
Urinary tract infection or urinary retention 1 (5%)
Table 5 Adverse events
Characteristics Any grade Grade 1–2 Grade 3 Grade 4
Anemia 3 3
Leukopenia 7 7
Neutropenia 7 7
Anorexia 8 7 1
Vomiting 9 8 1
Diarrhea 2 2
Constipation 1 1
Fatigue 10 9 1
Alopecia 10 9 1
Hyperthyroidism 1 1
Lung abscess 1 1
Rash 1 1
Arthralgia and bone pain 2 1 1
Hyperglycemia 1 1
Antitumor activity
The activity of the neoadjuvant combination was evaluated according to the RECIST v.1.1 criteria after three/four treatment cycles. In particular, 17 out of the 23 showed a PR, while 6 further patients presented a SD (Figure 1A). The postoperative pathology results showed a MPR (50%) in 10 patients and a pCR (30%) in 6 patients (Figure 1A). A total of 15 patients (75%) resulted pathologically downstaged after surgery. On the overall, our analysis showed a median progression-free-survival (PFS) of 11.3 months (range, 3.1–18.7 months) (Figure 1B).
Figure 1 Waterfall plot. The horizontal dashed line represents partial response according to the RECIST v.1.1 criteria, and the different colors represent pathologic regression (A). Follow-up: duration of neoadjuvant therapy and PFS (B). pCR, pathological complete response; MPR, major pathological response; PFS, progression-free-survival.
Discussion
This is a clinical trial testing that a neoadjuvant PD-1 blockade and chemotherapy combination for potentially resectable (clinical stage IIA–IIIB) NSCLC patients. Our study yielded promising results resulting in a MPR and a pCR of 50% and 30%, respectively. This finding is of critical interest considering that previous studies in neoadjuvant setting, clearly show that both pCR and MPR are associated with survival benefits (8). For instance, Melek et al. examined a recorded a large database of 1,076 NSCLC patients who received surgery reporting a prolonged survival in those patients who achieved a pCR after neoadjuvant or induction therapy showing an outcome which was roughly the same as that recorded in patients diagnosed in a stage IB (1). These findings indicated a clinically significant association of pCR with 5-year OS (9). However, neither neoadjuvant chemotherapy, radiotherapy, nor TKI monotherapy has shown optimal pCR. The L’Intergroupe Francophone de Cancérologie Thoracique (IFCT) clinical trial reported that while only 41 (8.3%) of the 492 study patients achieved pCR, the 5-year OS of these patients reached 80.0%, compared to 55.8% for patients without pCR (10). These clinical results clearly suggest that the OS outcomes of neoadjuvant patients are independently associated with pCR.
With the growing expansion of PD-1 immune checkpoint inhibitors in clinical practice, the CheckMate159 trial was conducted to investigate the effects of neoadjuvant therapy with the PD-1 inhibitor, nivolumab yielding an MPR rate of 45% and a pCR rate of 15% (n=3) (7). This trial also reported that the rates of pCR and MPR in patients treated with neoadjuvant nivolumab were much higher than those recorded in patients who received traditional neoadjuvant regimens with chemotherapy, TKI- or chemoradiation (11-13). Notably, in study concerning locally resectable NSCLC patients treated with neoadjuvant atezolizumab and chemotherapy, 10 (33%) of 30 patients achieved a pCR which is in line with the results of our study (14).
Our data on AEs and complications indicate that the regimens used in this study were well tolerated, with no grade 4–5 AEs observed. AEs and complications occurred in this study at a similar frequency to those reported in the published data on neoadjuvant chemotherapy (15). In this study, we found that immune-related AEs could be well monitored and managed (16), which is similar to the observations made in the NADIM study (17). Only in 1 case did neoadjuvant therapy need to be halted after 1 cycle of treatment, with this patient’s complication being lung abscess caused by obstructive pneumonia, which was unrelated to PD-1 inhibitor treatment. After stopping the neoadjuvant treatment, the patient underwent surgery. Interestingly, he achieved MPR, despite only receiving 1 cycle of chemoimmunotherapy. Therefore, this study fully demonstrated that combination neoadjuvant chemoimmunotherapy has good safety and efficacy for the treatment of stage IIA–IIIB NSCLC.
In the present study, the rates of conversion to thoracotomy, completed thoracotomy, and completed pneumonectomy were 10%, 20%, and 10% respectively, which are similar to rates reported in a neoadjuvant chemotherapy study (conversion to thoracotomy, 26.5%; pneumonectomy, 17.6%) (18). This finding suggests that neoadjuvant chemoimmunotherapy does not increase the complexity of the surgical procedure compared with neoadjuvant chemotherapy.
There are several limitations to this research. First, this study mainly focused on the safety and efficacy of neoadjuvant therapy due to the small number of patients. In the future, we hope to observe the 5-year OS after neoadjuvant chemoimmunotherapy in a larger patient cohort. Secondly, PD-L1 was detected in some but not all of the patients, while the tumor mutational burden was not recorded for any patient in this study. Furthermore, we did not attempt to reach a conclusion on the relationship between potential biomarkers of PD-L1 and neoadjuvant therapy, and this will be explored in future study. Thirdly, 7 of the 23 patients included refused to continue the neoadjuvant treatment after 1–2 cycles, which might have caused bias regarding the safety and efficacy data. However, the safety and efficacy data of patients who accepted surgery treatment were analyzed according to the different centers, drug treatments, and cycles (Appendix 1). There was no statistical difference for pCR of patients according to the different drugs and cycles.
Conclusions
The existing data suggest that, in the neoadjuvant setting, PD-1 inhibitors combined with chemotherapy can significantly improve the rates of pCR and MPR among patients with resectable NSCLC. The safety profile and surgical complications of these combination regimens are the same as those previously observed among patients who have received chemotherapy alone as a neoadjuvant therapy.
Supplementary
The article’s supplementary files as
10.21037/tlcr-21-130 10.21037/tlcr-21-130 10.21037/tlcr-21-130 10.21037/tlcr-21-130
Acknowledgments
The authors appreciate the academic support from the AME Lung Cancer Collaborative Group.
Funding: This study was funded by the Tang Du Hospital Top-Level Talents Sponsorship Program, the Shaanxi Special Support Plan-Program for Leading Talents of Science and Technology Innovation, and the Tang Du Hospital’s Special Fund for Medical Technology.
Ethical Statement: The authors are 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tangdu Hospital of the Fourth Military Medical University (202012-12-KY-02-XW-01) and informed consent was taken from all individual participants.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/tlcr-21-130
Data Sharing Statement: Available at http://dx.doi.org/10.21037/tlcr-21-130
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-21-130). XY serves as an unpaid editorial board member of TLCR from Jun 2019 to Jun 2021. The other authors have no conflicts of interest to declare.
(English Language Editors: J. Grayand, J. Reynolds) | CARBOPLATIN, NIVOLUMAB, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33718040 | 19,803,636 | 2021-02 |
What was the dosage of drug 'CARBOPLATIN'? | Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable non-small cell lung cancer: an open-label, multicenter, single-arm study.
Neoadjuvant therapy has significantly improved the 5-year overall survival (OS) of patients with resectable non-small cell lung cancer (NSCLC). The CheckMate 159 trial showed that neoadjuvant therapy with a single-drug programmed cell death protein 1 (PD-1) inhibitor (nivolumab) achieved major pathological response (MPR) and pathological complete response (pCR) in 45% and 15%of participants, respectively. We conducted an open-label single-arm study to evaluate the safety and efficacy of neoadjuvant PD-1 inhibitors in combination with chemotherapy in the treatment of resectable NSCLC.
This study was conducted in a total of 2 hospitals in the Chinese cities of Xi'an and Chongqing, and included eligible patients over 18 years of age with clinically staged IIA-IIIB NSCLC. All patients were scheduled to receive surgery within 4-6 weeks after neoadjuvant treatment (3-4 cycles) consisting of PD-1 inhibitors combined with a conventional chemotherapy regimen on day 1 of each 21-day cycle.
Twenty-three patients, 22 males, and 1 female with just one of them with no smoking habits) were diagnosed with NSCL C in a stage IIA (3 cases), IIB (3 cases), IIIA (8 cases), and IIIB (9cases) and no druggable driver mutations/translocations were addressed to receive neoadjuvant treatment between June 2018 and June 2020. The treatment was well tolerated with just 3 typical immune-related adverse events (hyperthyroidism, hyperglycemia, and rash) recorded. There was a partial response (PR) and stable disease (SD) in 17 (73.9%) and 6 (26.1%) patients, with an overall response rate (ORR) of 73.9% according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). Six of these patients resulted in pCR (30%) while ten of them showed a MPR (50%). Twenty patients underwent surgical resection after treatment, while further 3 refused surgery. Surgical procedure included video-assisted thoracoscopic resection (10 cases), Vinci Robot surgery (4 cases), and thoracotomy in 4 cases while there were secondary compliance-related thoracotomy in two cases. The pathology analysis revealed a R0 in 19 cases (19/20, 95%).
Our results suggest that the neoadjuvant approach with chemotherapy and PD-1 blocking mAbs is safe and active in patients with resectable NSCLC where is associated with a promising high ORR, MPR and pCR.
pmcIntroduction
Neoadjuvant therapy is a promising treatment strategy for patients with resectable non-small cell lung cancer (NSCLC). This kind of treatment for many years has included chemotherapy, tyrosine kinase inhibitors (TKIs), radiotherapy, alone or in multiple combinations (1). A meta-analysis of data from NSCLC patients treated with neoadjuvant chemotherapy showed an absolute improvement in 5-year overall survival (OS) of 5% (40–45%) (2). The mortality risk was significantly reduced in patients who achieved a major pathological response (MPR) after neoadjuvant therapy. Similarly, the results of various clinical trials in patients with bladder, breast, and gastroesophageal cancer showed an improved OS in those who achieved a pathological complete response (pCR) after neoadjuvant therapies (3). In this context further exploration concerning innovative neoadjuvant strategies in resectable NSCLC patients is strongly required.
In more recent years, immunocheckpoint blockade with mAbs to PD-1/PD-L1 alone or in combination with platinum doublets has been shown to significant efficacy in lung cancer patients. The KEYNOTE189 trial in particular, reported the efficacy of an anti-PD-1 mA, pembrolizumab, in combination with chemotherapy in patients with advanced Lung adenocarcinoma. In particular, this trial showed a 12-month OS of 69.2% in the experimental group compared with a 49.4% reported in the group of patients who received the chemotherapy alone (4). Furthermore, in the KEYNOTE407 trial, the OS reached 15.9 months for patients with advanced squamous cell carcinoma in the chemo-immunotherapy arm, compared with 11.3 months recorded in the group addressed to chemotherapy alone (5). The above-mentioned trials have established the role of PD-1 blockade and chemotherapy in the treatment of NSCLC. In line with these results a recent meta-analysis showed that NSCLC patients over-expressing with the programmed death ligand 1 (PD-L1) (PD-L1 score >50%) receiving pembrolizumab-chemotherapy combination showed a much greater ORR, and progression-free survival (PFS) compared with the groups of patients receiving chemotherapy- or pembrolizumab-alone (6). Finally, the CheckMate159 trial reported an MPR rate of 45% in NSCLC patients receiving neoadjuvant therapy with nivolumab, which was much higher than that achieved by any previously tested chemotherapy regimens in neoadjuvant setting (7). The trial therefore suggested that PD-1 blockade is effective and may have definite advantages in patients with resectable NSCLC. Therefore, the present study was conducted to evaluate the anti-tumor activity and safety of neoadjuvant PD-1 blocking mAbs used in combination with standard chemotherapy for potentially resectable (clinical stage IIA–IIIB) NSCLC patients for only Asian performed setting in two different oncology centers in China (Xi’an and Chongqing). We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/tlcr-21-130).
Methods
This study is a multinstitutional single-arm observational study, including 23 patients who received the neoadjuvant treatment in two different Chinese center study. Clinical stages IIA–IIIB NSCLC patients over the age of 18 years with were eligible for inclusion. All of the enrolled patients were scheduled to receive surgery within 4–6 weeks after neoadjuvant therapy that consisted in 3–4 cycles of a conventional chemotherapy regimen with PD-1 inhibitors on day 1 of each cycle according to the international consensus. The specific chemoimmunotherapy regimens are detailed in the Table 1. Additional inclusion criteria included eligibility for surgery, as indicated by auxiliary examination including lung function and blood gas analysis; no distant metastasis; and no contraindications for PD-1 inhibitor therapy. The patients’ clinical staging was reviewed by 3 senior physicians and was confirmed if at least 2 of them agreed. Positron emission tomography/computed tomography (PET/CT) and immunohistochemicalPD-L1 detection were not necessary for inclusion. Patients with adenocarcinoma who had epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement were excluded. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tangdu Hospital of the Fourth Military Medical University (202012-12-KY-02-XW-01) and informed consent was taken from all individual participants.
Table 1 Specific chemoimmunotherapy regimens received by each patient
Patient no. Chemoimmunotherapy Cycles Pathological type Response as per RECIST v.1.1 pCR/MPR PD-L1 (TPS)
P1 Pemetrexed disodium (500 mg/m2, D1) + cisplatin (75 mg/m2, D1) + nivolumab (360 mg, D1) 3 Adenocarcinoma PR pCR N
P2 Nab-paclitaxel (260 mg/m2, D1) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P3 Gemcitabine (1000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma PR 70%
P4 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 3 Squamous carcinoma PR MPR N
P5 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 3 Squamous carcinoma PR MPR N
P6 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma SD <1%
P7 Gemcitabine (1,000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 1 Squamous carcinoma SD MPR N
P8 Gemcitabine (1,000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 2 Squamous carcinoma PR MPR N
P9 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 4 Squamous carcinoma PR pCR N
P10 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P11 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P12 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR pCR N
P13 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma PR 10%
P14 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Adenocarcinoma SD pCR 70%
P15 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 4 Squamous carcinoma PR 1%
P16 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma SD 15%
P17 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma SD <1%
P18 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 4 Adenocarcinoma PR pCR 15.4%
P19 Pemetrexed disodium (500 mg/m2, D1) + cisplatin (75 mg/m2, D1) + sintilimab (200 mg, D1) 3 Adenocarcinoma SD <1%
P20 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR pCR N
P21 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR N
P22 Paclitaxel (175 mg/m2, D1) + carboplatin (AUC=5, D1) + nivolumab (360 mg, D1) 2 Squamous carcinoma PR N
P23 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma PR N
pCR, pathological complete response; MPR, major pathological response; PR, partial response; SD, stable disease; N, none detected; AUC, area under the curve.
Study endpoints
The primary endpoints of the study were the safety and efficacy of neoadjuvant chemotherapy combined with PD-1 inhibitors. The safety-related endpoints included adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE, v.4.0). The efficacy-related endpoints included ORR according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1), and postoperative pathological down-staging according to the eighth edition of the National Comprehensive Cancer Network (NCCN) guidelines for tumor-node-metastasis (TNM) staging of NSCLC.
The secondary study endpoints were pCR, which was defined as the complete absence of tumor cells, and MPR, which was defined as <10% residual viable tumor (RVT).
Statistical analysis
Adverse events and feasibility were continuously monitored. Continuous variables are presented as means with standard deviation, while categorical variables are presented as frequencies.
Results
Patient characteristics
Twenty-three eligible candidates were recruited for this study. There were 22 men and one woman with just one of them with no smoking habits. A squamous histology and an adenocarcinoma were respectively, recorded in 19 and 4 of these patients with no driver mutations/translocation (EGFR or ALK etc.). Three cases were in IIA stage, 3 cases in IIB, 8 cases in IIIA, and 9 cases of IIIB stage (Table 2). Twenty patients underwent surgical resection Fourteen of them completed 3–4 cycles of chemo-immunotherapy as described elsewhere (method section) prior surgery; five further patients experienced grade 1 or 2 irAEs and where addressed to surgery after two treatment cycles while one last patient presented a lung abscess and underwent surgery after just one neo-adjuvant treatment cycle. All data on specific chemo-immunotherapy regimens are shown in Table 1. Three patients did not receive; in fact, two of them who completed the neoadjuvant program refused the risk of the surgery (Patients #21 and #23, Table 2) while another one (#22) refused to complete the neoadjuvant program after he developed a severe (grade 3) hyperglycemia during the second chemotherapy cycle.
Table 2 Baseline characteristics of the intention-to-treat population (N=23)
Characteristics Value Surgery Rejected surgery
Age, years
Median (range) 61.83
≥60 years 20 17 3
<60 years 3 3 0
Sex
Male 22 19 3
Female 1 1 0
BMI, kg/m2 (mean) 24.38
History of smoking
Current/ex-smoker 22 19 3
Never-smoker 1 1 0
KPS
90 21 19 2
100 2 1 1
Pathological type
Squamous carcinoma 19 16 3
Adenocarcinoma 4 4 0
Clinical T stage
T1 2 2 0
T2 4 4 0
T3 11 8 3
T4 6 6 0
Clinical N stage
N0 4 4 0
N1 9 8 1
N2 10 8 2
Clinical stage
IIA 3 2 1
IIB 3 3 0
IIIA 8 8 0
IIIB 9 7 2
Surgical treatment
Among the 20 patients who underwent surgery, 11 patients underwent lobectomy, 5 patients underwent sleeve resection/bronchoplasty, 2 patients received bilobectomy, and 2 patients underwent pneumonectomy. The results for surgical treatment, morbidity, and mortality are reported in the Table 3 shows. Surgical methods included Da Vinci’s/video-assisted thoracoscopic surgery (VATS) (n=14), conversion to thoracotomy (n=2), and thoracotomy (n=4). Complete resection (R0) was achieved in 95% of patients (19/20) who received surgery that in one case was considered as R1 resection due to the patient being lymph-node positive at the highest station. The median amount of blood lost was 212.5 mL (50–600 mL), and the mean operative time was 250 minutes (65–390 minutes).
Table 3 Surgical procedures
Characteristics Results
Extent of surgery
Lobectomy 11
Bilobectomy 2
Sleeve resection/bronchoplasty 5
Pneumonectomy 2
Surgical method
VATS/da Vinci 14
Conversion to thoracotomy 2
Thoracotomy 4
Operation time (min) 250 (65–390)
Bleeding (mL) 212.5 (50–600)
Hospital stay (days) 11.125 (6–22)
Chest tube duration (days) 4.18 (0–7)
Resection margins
R0 19
R1 1
R2 0
Safety
The post-operative complications were considered to be unrelated to neoadjuvant therapy and are summarized in the Table 4. There was no 30- or 90-day mortality, or any postoperative arrhythmia episode. The occurrence of AEs is shown in detail in the Table 5. The most common grade 1 or 2 neoadjuvant treatment-related AEs were fatigue (39.1%), alopecia (39.1%), vomiting (34.7%), leucopenia (30.4%), neutropenia (30.4%), and anorexia (30.4%). The treatment-related grade 3 AEs included anorexia, vomiting, fatigue, alopecia, arthralgia, bone pain, and hyperglycemia. Three patients experienced typical immune-related AEs including grade 1–2 hyperthyroidism, grade 3 hyperglycemia, and grade 1–2 rash.
Table 4 Postoperative complications
Characteristics N (%)
Intraoperative blood transfusion 2 (10%)
Death within 30 and 90 days 0
Heart failure 1 (5%)
Postoperative arrhythmia 0
Postoperative hoarseness 1 (5%)
Urinary tract infection or urinary retention 1 (5%)
Table 5 Adverse events
Characteristics Any grade Grade 1–2 Grade 3 Grade 4
Anemia 3 3
Leukopenia 7 7
Neutropenia 7 7
Anorexia 8 7 1
Vomiting 9 8 1
Diarrhea 2 2
Constipation 1 1
Fatigue 10 9 1
Alopecia 10 9 1
Hyperthyroidism 1 1
Lung abscess 1 1
Rash 1 1
Arthralgia and bone pain 2 1 1
Hyperglycemia 1 1
Antitumor activity
The activity of the neoadjuvant combination was evaluated according to the RECIST v.1.1 criteria after three/four treatment cycles. In particular, 17 out of the 23 showed a PR, while 6 further patients presented a SD (Figure 1A). The postoperative pathology results showed a MPR (50%) in 10 patients and a pCR (30%) in 6 patients (Figure 1A). A total of 15 patients (75%) resulted pathologically downstaged after surgery. On the overall, our analysis showed a median progression-free-survival (PFS) of 11.3 months (range, 3.1–18.7 months) (Figure 1B).
Figure 1 Waterfall plot. The horizontal dashed line represents partial response according to the RECIST v.1.1 criteria, and the different colors represent pathologic regression (A). Follow-up: duration of neoadjuvant therapy and PFS (B). pCR, pathological complete response; MPR, major pathological response; PFS, progression-free-survival.
Discussion
This is a clinical trial testing that a neoadjuvant PD-1 blockade and chemotherapy combination for potentially resectable (clinical stage IIA–IIIB) NSCLC patients. Our study yielded promising results resulting in a MPR and a pCR of 50% and 30%, respectively. This finding is of critical interest considering that previous studies in neoadjuvant setting, clearly show that both pCR and MPR are associated with survival benefits (8). For instance, Melek et al. examined a recorded a large database of 1,076 NSCLC patients who received surgery reporting a prolonged survival in those patients who achieved a pCR after neoadjuvant or induction therapy showing an outcome which was roughly the same as that recorded in patients diagnosed in a stage IB (1). These findings indicated a clinically significant association of pCR with 5-year OS (9). However, neither neoadjuvant chemotherapy, radiotherapy, nor TKI monotherapy has shown optimal pCR. The L’Intergroupe Francophone de Cancérologie Thoracique (IFCT) clinical trial reported that while only 41 (8.3%) of the 492 study patients achieved pCR, the 5-year OS of these patients reached 80.0%, compared to 55.8% for patients without pCR (10). These clinical results clearly suggest that the OS outcomes of neoadjuvant patients are independently associated with pCR.
With the growing expansion of PD-1 immune checkpoint inhibitors in clinical practice, the CheckMate159 trial was conducted to investigate the effects of neoadjuvant therapy with the PD-1 inhibitor, nivolumab yielding an MPR rate of 45% and a pCR rate of 15% (n=3) (7). This trial also reported that the rates of pCR and MPR in patients treated with neoadjuvant nivolumab were much higher than those recorded in patients who received traditional neoadjuvant regimens with chemotherapy, TKI- or chemoradiation (11-13). Notably, in study concerning locally resectable NSCLC patients treated with neoadjuvant atezolizumab and chemotherapy, 10 (33%) of 30 patients achieved a pCR which is in line with the results of our study (14).
Our data on AEs and complications indicate that the regimens used in this study were well tolerated, with no grade 4–5 AEs observed. AEs and complications occurred in this study at a similar frequency to those reported in the published data on neoadjuvant chemotherapy (15). In this study, we found that immune-related AEs could be well monitored and managed (16), which is similar to the observations made in the NADIM study (17). Only in 1 case did neoadjuvant therapy need to be halted after 1 cycle of treatment, with this patient’s complication being lung abscess caused by obstructive pneumonia, which was unrelated to PD-1 inhibitor treatment. After stopping the neoadjuvant treatment, the patient underwent surgery. Interestingly, he achieved MPR, despite only receiving 1 cycle of chemoimmunotherapy. Therefore, this study fully demonstrated that combination neoadjuvant chemoimmunotherapy has good safety and efficacy for the treatment of stage IIA–IIIB NSCLC.
In the present study, the rates of conversion to thoracotomy, completed thoracotomy, and completed pneumonectomy were 10%, 20%, and 10% respectively, which are similar to rates reported in a neoadjuvant chemotherapy study (conversion to thoracotomy, 26.5%; pneumonectomy, 17.6%) (18). This finding suggests that neoadjuvant chemoimmunotherapy does not increase the complexity of the surgical procedure compared with neoadjuvant chemotherapy.
There are several limitations to this research. First, this study mainly focused on the safety and efficacy of neoadjuvant therapy due to the small number of patients. In the future, we hope to observe the 5-year OS after neoadjuvant chemoimmunotherapy in a larger patient cohort. Secondly, PD-L1 was detected in some but not all of the patients, while the tumor mutational burden was not recorded for any patient in this study. Furthermore, we did not attempt to reach a conclusion on the relationship between potential biomarkers of PD-L1 and neoadjuvant therapy, and this will be explored in future study. Thirdly, 7 of the 23 patients included refused to continue the neoadjuvant treatment after 1–2 cycles, which might have caused bias regarding the safety and efficacy data. However, the safety and efficacy data of patients who accepted surgery treatment were analyzed according to the different centers, drug treatments, and cycles (Appendix 1). There was no statistical difference for pCR of patients according to the different drugs and cycles.
Conclusions
The existing data suggest that, in the neoadjuvant setting, PD-1 inhibitors combined with chemotherapy can significantly improve the rates of pCR and MPR among patients with resectable NSCLC. The safety profile and surgical complications of these combination regimens are the same as those previously observed among patients who have received chemotherapy alone as a neoadjuvant therapy.
Supplementary
The article’s supplementary files as
10.21037/tlcr-21-130 10.21037/tlcr-21-130 10.21037/tlcr-21-130 10.21037/tlcr-21-130
Acknowledgments
The authors appreciate the academic support from the AME Lung Cancer Collaborative Group.
Funding: This study was funded by the Tang Du Hospital Top-Level Talents Sponsorship Program, the Shaanxi Special Support Plan-Program for Leading Talents of Science and Technology Innovation, and the Tang Du Hospital’s Special Fund for Medical Technology.
Ethical Statement: The authors are 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tangdu Hospital of the Fourth Military Medical University (202012-12-KY-02-XW-01) and informed consent was taken from all individual participants.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/tlcr-21-130
Data Sharing Statement: Available at http://dx.doi.org/10.21037/tlcr-21-130
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-21-130). XY serves as an unpaid editorial board member of TLCR from Jun 2019 to Jun 2021. The other authors have no conflicts of interest to declare.
(English Language Editors: J. Grayand, J. Reynolds) | UNK, CYCLIC (AUC=5, D1) | DrugDosageText | CC BY-NC-ND | 33718040 | 19,803,636 | 2021-02 |
What was the dosage of drug 'NIVOLUMAB'? | Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable non-small cell lung cancer: an open-label, multicenter, single-arm study.
Neoadjuvant therapy has significantly improved the 5-year overall survival (OS) of patients with resectable non-small cell lung cancer (NSCLC). The CheckMate 159 trial showed that neoadjuvant therapy with a single-drug programmed cell death protein 1 (PD-1) inhibitor (nivolumab) achieved major pathological response (MPR) and pathological complete response (pCR) in 45% and 15%of participants, respectively. We conducted an open-label single-arm study to evaluate the safety and efficacy of neoadjuvant PD-1 inhibitors in combination with chemotherapy in the treatment of resectable NSCLC.
This study was conducted in a total of 2 hospitals in the Chinese cities of Xi'an and Chongqing, and included eligible patients over 18 years of age with clinically staged IIA-IIIB NSCLC. All patients were scheduled to receive surgery within 4-6 weeks after neoadjuvant treatment (3-4 cycles) consisting of PD-1 inhibitors combined with a conventional chemotherapy regimen on day 1 of each 21-day cycle.
Twenty-three patients, 22 males, and 1 female with just one of them with no smoking habits) were diagnosed with NSCL C in a stage IIA (3 cases), IIB (3 cases), IIIA (8 cases), and IIIB (9cases) and no druggable driver mutations/translocations were addressed to receive neoadjuvant treatment between June 2018 and June 2020. The treatment was well tolerated with just 3 typical immune-related adverse events (hyperthyroidism, hyperglycemia, and rash) recorded. There was a partial response (PR) and stable disease (SD) in 17 (73.9%) and 6 (26.1%) patients, with an overall response rate (ORR) of 73.9% according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). Six of these patients resulted in pCR (30%) while ten of them showed a MPR (50%). Twenty patients underwent surgical resection after treatment, while further 3 refused surgery. Surgical procedure included video-assisted thoracoscopic resection (10 cases), Vinci Robot surgery (4 cases), and thoracotomy in 4 cases while there were secondary compliance-related thoracotomy in two cases. The pathology analysis revealed a R0 in 19 cases (19/20, 95%).
Our results suggest that the neoadjuvant approach with chemotherapy and PD-1 blocking mAbs is safe and active in patients with resectable NSCLC where is associated with a promising high ORR, MPR and pCR.
pmcIntroduction
Neoadjuvant therapy is a promising treatment strategy for patients with resectable non-small cell lung cancer (NSCLC). This kind of treatment for many years has included chemotherapy, tyrosine kinase inhibitors (TKIs), radiotherapy, alone or in multiple combinations (1). A meta-analysis of data from NSCLC patients treated with neoadjuvant chemotherapy showed an absolute improvement in 5-year overall survival (OS) of 5% (40–45%) (2). The mortality risk was significantly reduced in patients who achieved a major pathological response (MPR) after neoadjuvant therapy. Similarly, the results of various clinical trials in patients with bladder, breast, and gastroesophageal cancer showed an improved OS in those who achieved a pathological complete response (pCR) after neoadjuvant therapies (3). In this context further exploration concerning innovative neoadjuvant strategies in resectable NSCLC patients is strongly required.
In more recent years, immunocheckpoint blockade with mAbs to PD-1/PD-L1 alone or in combination with platinum doublets has been shown to significant efficacy in lung cancer patients. The KEYNOTE189 trial in particular, reported the efficacy of an anti-PD-1 mA, pembrolizumab, in combination with chemotherapy in patients with advanced Lung adenocarcinoma. In particular, this trial showed a 12-month OS of 69.2% in the experimental group compared with a 49.4% reported in the group of patients who received the chemotherapy alone (4). Furthermore, in the KEYNOTE407 trial, the OS reached 15.9 months for patients with advanced squamous cell carcinoma in the chemo-immunotherapy arm, compared with 11.3 months recorded in the group addressed to chemotherapy alone (5). The above-mentioned trials have established the role of PD-1 blockade and chemotherapy in the treatment of NSCLC. In line with these results a recent meta-analysis showed that NSCLC patients over-expressing with the programmed death ligand 1 (PD-L1) (PD-L1 score >50%) receiving pembrolizumab-chemotherapy combination showed a much greater ORR, and progression-free survival (PFS) compared with the groups of patients receiving chemotherapy- or pembrolizumab-alone (6). Finally, the CheckMate159 trial reported an MPR rate of 45% in NSCLC patients receiving neoadjuvant therapy with nivolumab, which was much higher than that achieved by any previously tested chemotherapy regimens in neoadjuvant setting (7). The trial therefore suggested that PD-1 blockade is effective and may have definite advantages in patients with resectable NSCLC. Therefore, the present study was conducted to evaluate the anti-tumor activity and safety of neoadjuvant PD-1 blocking mAbs used in combination with standard chemotherapy for potentially resectable (clinical stage IIA–IIIB) NSCLC patients for only Asian performed setting in two different oncology centers in China (Xi’an and Chongqing). We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/tlcr-21-130).
Methods
This study is a multinstitutional single-arm observational study, including 23 patients who received the neoadjuvant treatment in two different Chinese center study. Clinical stages IIA–IIIB NSCLC patients over the age of 18 years with were eligible for inclusion. All of the enrolled patients were scheduled to receive surgery within 4–6 weeks after neoadjuvant therapy that consisted in 3–4 cycles of a conventional chemotherapy regimen with PD-1 inhibitors on day 1 of each cycle according to the international consensus. The specific chemoimmunotherapy regimens are detailed in the Table 1. Additional inclusion criteria included eligibility for surgery, as indicated by auxiliary examination including lung function and blood gas analysis; no distant metastasis; and no contraindications for PD-1 inhibitor therapy. The patients’ clinical staging was reviewed by 3 senior physicians and was confirmed if at least 2 of them agreed. Positron emission tomography/computed tomography (PET/CT) and immunohistochemicalPD-L1 detection were not necessary for inclusion. Patients with adenocarcinoma who had epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement were excluded. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tangdu Hospital of the Fourth Military Medical University (202012-12-KY-02-XW-01) and informed consent was taken from all individual participants.
Table 1 Specific chemoimmunotherapy regimens received by each patient
Patient no. Chemoimmunotherapy Cycles Pathological type Response as per RECIST v.1.1 pCR/MPR PD-L1 (TPS)
P1 Pemetrexed disodium (500 mg/m2, D1) + cisplatin (75 mg/m2, D1) + nivolumab (360 mg, D1) 3 Adenocarcinoma PR pCR N
P2 Nab-paclitaxel (260 mg/m2, D1) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P3 Gemcitabine (1000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma PR 70%
P4 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 3 Squamous carcinoma PR MPR N
P5 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 3 Squamous carcinoma PR MPR N
P6 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma SD <1%
P7 Gemcitabine (1,000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 1 Squamous carcinoma SD MPR N
P8 Gemcitabine (1,000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 2 Squamous carcinoma PR MPR N
P9 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 4 Squamous carcinoma PR pCR N
P10 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P11 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P12 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR pCR N
P13 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma PR 10%
P14 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Adenocarcinoma SD pCR 70%
P15 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 4 Squamous carcinoma PR 1%
P16 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma SD 15%
P17 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma SD <1%
P18 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 4 Adenocarcinoma PR pCR 15.4%
P19 Pemetrexed disodium (500 mg/m2, D1) + cisplatin (75 mg/m2, D1) + sintilimab (200 mg, D1) 3 Adenocarcinoma SD <1%
P20 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR pCR N
P21 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR N
P22 Paclitaxel (175 mg/m2, D1) + carboplatin (AUC=5, D1) + nivolumab (360 mg, D1) 2 Squamous carcinoma PR N
P23 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma PR N
pCR, pathological complete response; MPR, major pathological response; PR, partial response; SD, stable disease; N, none detected; AUC, area under the curve.
Study endpoints
The primary endpoints of the study were the safety and efficacy of neoadjuvant chemotherapy combined with PD-1 inhibitors. The safety-related endpoints included adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE, v.4.0). The efficacy-related endpoints included ORR according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1), and postoperative pathological down-staging according to the eighth edition of the National Comprehensive Cancer Network (NCCN) guidelines for tumor-node-metastasis (TNM) staging of NSCLC.
The secondary study endpoints were pCR, which was defined as the complete absence of tumor cells, and MPR, which was defined as <10% residual viable tumor (RVT).
Statistical analysis
Adverse events and feasibility were continuously monitored. Continuous variables are presented as means with standard deviation, while categorical variables are presented as frequencies.
Results
Patient characteristics
Twenty-three eligible candidates were recruited for this study. There were 22 men and one woman with just one of them with no smoking habits. A squamous histology and an adenocarcinoma were respectively, recorded in 19 and 4 of these patients with no driver mutations/translocation (EGFR or ALK etc.). Three cases were in IIA stage, 3 cases in IIB, 8 cases in IIIA, and 9 cases of IIIB stage (Table 2). Twenty patients underwent surgical resection Fourteen of them completed 3–4 cycles of chemo-immunotherapy as described elsewhere (method section) prior surgery; five further patients experienced grade 1 or 2 irAEs and where addressed to surgery after two treatment cycles while one last patient presented a lung abscess and underwent surgery after just one neo-adjuvant treatment cycle. All data on specific chemo-immunotherapy regimens are shown in Table 1. Three patients did not receive; in fact, two of them who completed the neoadjuvant program refused the risk of the surgery (Patients #21 and #23, Table 2) while another one (#22) refused to complete the neoadjuvant program after he developed a severe (grade 3) hyperglycemia during the second chemotherapy cycle.
Table 2 Baseline characteristics of the intention-to-treat population (N=23)
Characteristics Value Surgery Rejected surgery
Age, years
Median (range) 61.83
≥60 years 20 17 3
<60 years 3 3 0
Sex
Male 22 19 3
Female 1 1 0
BMI, kg/m2 (mean) 24.38
History of smoking
Current/ex-smoker 22 19 3
Never-smoker 1 1 0
KPS
90 21 19 2
100 2 1 1
Pathological type
Squamous carcinoma 19 16 3
Adenocarcinoma 4 4 0
Clinical T stage
T1 2 2 0
T2 4 4 0
T3 11 8 3
T4 6 6 0
Clinical N stage
N0 4 4 0
N1 9 8 1
N2 10 8 2
Clinical stage
IIA 3 2 1
IIB 3 3 0
IIIA 8 8 0
IIIB 9 7 2
Surgical treatment
Among the 20 patients who underwent surgery, 11 patients underwent lobectomy, 5 patients underwent sleeve resection/bronchoplasty, 2 patients received bilobectomy, and 2 patients underwent pneumonectomy. The results for surgical treatment, morbidity, and mortality are reported in the Table 3 shows. Surgical methods included Da Vinci’s/video-assisted thoracoscopic surgery (VATS) (n=14), conversion to thoracotomy (n=2), and thoracotomy (n=4). Complete resection (R0) was achieved in 95% of patients (19/20) who received surgery that in one case was considered as R1 resection due to the patient being lymph-node positive at the highest station. The median amount of blood lost was 212.5 mL (50–600 mL), and the mean operative time was 250 minutes (65–390 minutes).
Table 3 Surgical procedures
Characteristics Results
Extent of surgery
Lobectomy 11
Bilobectomy 2
Sleeve resection/bronchoplasty 5
Pneumonectomy 2
Surgical method
VATS/da Vinci 14
Conversion to thoracotomy 2
Thoracotomy 4
Operation time (min) 250 (65–390)
Bleeding (mL) 212.5 (50–600)
Hospital stay (days) 11.125 (6–22)
Chest tube duration (days) 4.18 (0–7)
Resection margins
R0 19
R1 1
R2 0
Safety
The post-operative complications were considered to be unrelated to neoadjuvant therapy and are summarized in the Table 4. There was no 30- or 90-day mortality, or any postoperative arrhythmia episode. The occurrence of AEs is shown in detail in the Table 5. The most common grade 1 or 2 neoadjuvant treatment-related AEs were fatigue (39.1%), alopecia (39.1%), vomiting (34.7%), leucopenia (30.4%), neutropenia (30.4%), and anorexia (30.4%). The treatment-related grade 3 AEs included anorexia, vomiting, fatigue, alopecia, arthralgia, bone pain, and hyperglycemia. Three patients experienced typical immune-related AEs including grade 1–2 hyperthyroidism, grade 3 hyperglycemia, and grade 1–2 rash.
Table 4 Postoperative complications
Characteristics N (%)
Intraoperative blood transfusion 2 (10%)
Death within 30 and 90 days 0
Heart failure 1 (5%)
Postoperative arrhythmia 0
Postoperative hoarseness 1 (5%)
Urinary tract infection or urinary retention 1 (5%)
Table 5 Adverse events
Characteristics Any grade Grade 1–2 Grade 3 Grade 4
Anemia 3 3
Leukopenia 7 7
Neutropenia 7 7
Anorexia 8 7 1
Vomiting 9 8 1
Diarrhea 2 2
Constipation 1 1
Fatigue 10 9 1
Alopecia 10 9 1
Hyperthyroidism 1 1
Lung abscess 1 1
Rash 1 1
Arthralgia and bone pain 2 1 1
Hyperglycemia 1 1
Antitumor activity
The activity of the neoadjuvant combination was evaluated according to the RECIST v.1.1 criteria after three/four treatment cycles. In particular, 17 out of the 23 showed a PR, while 6 further patients presented a SD (Figure 1A). The postoperative pathology results showed a MPR (50%) in 10 patients and a pCR (30%) in 6 patients (Figure 1A). A total of 15 patients (75%) resulted pathologically downstaged after surgery. On the overall, our analysis showed a median progression-free-survival (PFS) of 11.3 months (range, 3.1–18.7 months) (Figure 1B).
Figure 1 Waterfall plot. The horizontal dashed line represents partial response according to the RECIST v.1.1 criteria, and the different colors represent pathologic regression (A). Follow-up: duration of neoadjuvant therapy and PFS (B). pCR, pathological complete response; MPR, major pathological response; PFS, progression-free-survival.
Discussion
This is a clinical trial testing that a neoadjuvant PD-1 blockade and chemotherapy combination for potentially resectable (clinical stage IIA–IIIB) NSCLC patients. Our study yielded promising results resulting in a MPR and a pCR of 50% and 30%, respectively. This finding is of critical interest considering that previous studies in neoadjuvant setting, clearly show that both pCR and MPR are associated with survival benefits (8). For instance, Melek et al. examined a recorded a large database of 1,076 NSCLC patients who received surgery reporting a prolonged survival in those patients who achieved a pCR after neoadjuvant or induction therapy showing an outcome which was roughly the same as that recorded in patients diagnosed in a stage IB (1). These findings indicated a clinically significant association of pCR with 5-year OS (9). However, neither neoadjuvant chemotherapy, radiotherapy, nor TKI monotherapy has shown optimal pCR. The L’Intergroupe Francophone de Cancérologie Thoracique (IFCT) clinical trial reported that while only 41 (8.3%) of the 492 study patients achieved pCR, the 5-year OS of these patients reached 80.0%, compared to 55.8% for patients without pCR (10). These clinical results clearly suggest that the OS outcomes of neoadjuvant patients are independently associated with pCR.
With the growing expansion of PD-1 immune checkpoint inhibitors in clinical practice, the CheckMate159 trial was conducted to investigate the effects of neoadjuvant therapy with the PD-1 inhibitor, nivolumab yielding an MPR rate of 45% and a pCR rate of 15% (n=3) (7). This trial also reported that the rates of pCR and MPR in patients treated with neoadjuvant nivolumab were much higher than those recorded in patients who received traditional neoadjuvant regimens with chemotherapy, TKI- or chemoradiation (11-13). Notably, in study concerning locally resectable NSCLC patients treated with neoadjuvant atezolizumab and chemotherapy, 10 (33%) of 30 patients achieved a pCR which is in line with the results of our study (14).
Our data on AEs and complications indicate that the regimens used in this study were well tolerated, with no grade 4–5 AEs observed. AEs and complications occurred in this study at a similar frequency to those reported in the published data on neoadjuvant chemotherapy (15). In this study, we found that immune-related AEs could be well monitored and managed (16), which is similar to the observations made in the NADIM study (17). Only in 1 case did neoadjuvant therapy need to be halted after 1 cycle of treatment, with this patient’s complication being lung abscess caused by obstructive pneumonia, which was unrelated to PD-1 inhibitor treatment. After stopping the neoadjuvant treatment, the patient underwent surgery. Interestingly, he achieved MPR, despite only receiving 1 cycle of chemoimmunotherapy. Therefore, this study fully demonstrated that combination neoadjuvant chemoimmunotherapy has good safety and efficacy for the treatment of stage IIA–IIIB NSCLC.
In the present study, the rates of conversion to thoracotomy, completed thoracotomy, and completed pneumonectomy were 10%, 20%, and 10% respectively, which are similar to rates reported in a neoadjuvant chemotherapy study (conversion to thoracotomy, 26.5%; pneumonectomy, 17.6%) (18). This finding suggests that neoadjuvant chemoimmunotherapy does not increase the complexity of the surgical procedure compared with neoadjuvant chemotherapy.
There are several limitations to this research. First, this study mainly focused on the safety and efficacy of neoadjuvant therapy due to the small number of patients. In the future, we hope to observe the 5-year OS after neoadjuvant chemoimmunotherapy in a larger patient cohort. Secondly, PD-L1 was detected in some but not all of the patients, while the tumor mutational burden was not recorded for any patient in this study. Furthermore, we did not attempt to reach a conclusion on the relationship between potential biomarkers of PD-L1 and neoadjuvant therapy, and this will be explored in future study. Thirdly, 7 of the 23 patients included refused to continue the neoadjuvant treatment after 1–2 cycles, which might have caused bias regarding the safety and efficacy data. However, the safety and efficacy data of patients who accepted surgery treatment were analyzed according to the different centers, drug treatments, and cycles (Appendix 1). There was no statistical difference for pCR of patients according to the different drugs and cycles.
Conclusions
The existing data suggest that, in the neoadjuvant setting, PD-1 inhibitors combined with chemotherapy can significantly improve the rates of pCR and MPR among patients with resectable NSCLC. The safety profile and surgical complications of these combination regimens are the same as those previously observed among patients who have received chemotherapy alone as a neoadjuvant therapy.
Supplementary
The article’s supplementary files as
10.21037/tlcr-21-130 10.21037/tlcr-21-130 10.21037/tlcr-21-130 10.21037/tlcr-21-130
Acknowledgments
The authors appreciate the academic support from the AME Lung Cancer Collaborative Group.
Funding: This study was funded by the Tang Du Hospital Top-Level Talents Sponsorship Program, the Shaanxi Special Support Plan-Program for Leading Talents of Science and Technology Innovation, and the Tang Du Hospital’s Special Fund for Medical Technology.
Ethical Statement: The authors are 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tangdu Hospital of the Fourth Military Medical University (202012-12-KY-02-XW-01) and informed consent was taken from all individual participants.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/tlcr-21-130
Data Sharing Statement: Available at http://dx.doi.org/10.21037/tlcr-21-130
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-21-130). XY serves as an unpaid editorial board member of TLCR from Jun 2019 to Jun 2021. The other authors have no conflicts of interest to declare.
(English Language Editors: J. Grayand, J. Reynolds) | 360 MG, CYCLIC D1 | DrugDosageText | CC BY-NC-ND | 33718040 | 19,803,636 | 2021-02 |
What was the dosage of drug 'PACLITAXEL'? | Neoadjuvant programmed cell death protein 1 inhibitors combined with chemotherapy in resectable non-small cell lung cancer: an open-label, multicenter, single-arm study.
Neoadjuvant therapy has significantly improved the 5-year overall survival (OS) of patients with resectable non-small cell lung cancer (NSCLC). The CheckMate 159 trial showed that neoadjuvant therapy with a single-drug programmed cell death protein 1 (PD-1) inhibitor (nivolumab) achieved major pathological response (MPR) and pathological complete response (pCR) in 45% and 15%of participants, respectively. We conducted an open-label single-arm study to evaluate the safety and efficacy of neoadjuvant PD-1 inhibitors in combination with chemotherapy in the treatment of resectable NSCLC.
This study was conducted in a total of 2 hospitals in the Chinese cities of Xi'an and Chongqing, and included eligible patients over 18 years of age with clinically staged IIA-IIIB NSCLC. All patients were scheduled to receive surgery within 4-6 weeks after neoadjuvant treatment (3-4 cycles) consisting of PD-1 inhibitors combined with a conventional chemotherapy regimen on day 1 of each 21-day cycle.
Twenty-three patients, 22 males, and 1 female with just one of them with no smoking habits) were diagnosed with NSCL C in a stage IIA (3 cases), IIB (3 cases), IIIA (8 cases), and IIIB (9cases) and no druggable driver mutations/translocations were addressed to receive neoadjuvant treatment between June 2018 and June 2020. The treatment was well tolerated with just 3 typical immune-related adverse events (hyperthyroidism, hyperglycemia, and rash) recorded. There was a partial response (PR) and stable disease (SD) in 17 (73.9%) and 6 (26.1%) patients, with an overall response rate (ORR) of 73.9% according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). Six of these patients resulted in pCR (30%) while ten of them showed a MPR (50%). Twenty patients underwent surgical resection after treatment, while further 3 refused surgery. Surgical procedure included video-assisted thoracoscopic resection (10 cases), Vinci Robot surgery (4 cases), and thoracotomy in 4 cases while there were secondary compliance-related thoracotomy in two cases. The pathology analysis revealed a R0 in 19 cases (19/20, 95%).
Our results suggest that the neoadjuvant approach with chemotherapy and PD-1 blocking mAbs is safe and active in patients with resectable NSCLC where is associated with a promising high ORR, MPR and pCR.
pmcIntroduction
Neoadjuvant therapy is a promising treatment strategy for patients with resectable non-small cell lung cancer (NSCLC). This kind of treatment for many years has included chemotherapy, tyrosine kinase inhibitors (TKIs), radiotherapy, alone or in multiple combinations (1). A meta-analysis of data from NSCLC patients treated with neoadjuvant chemotherapy showed an absolute improvement in 5-year overall survival (OS) of 5% (40–45%) (2). The mortality risk was significantly reduced in patients who achieved a major pathological response (MPR) after neoadjuvant therapy. Similarly, the results of various clinical trials in patients with bladder, breast, and gastroesophageal cancer showed an improved OS in those who achieved a pathological complete response (pCR) after neoadjuvant therapies (3). In this context further exploration concerning innovative neoadjuvant strategies in resectable NSCLC patients is strongly required.
In more recent years, immunocheckpoint blockade with mAbs to PD-1/PD-L1 alone or in combination with platinum doublets has been shown to significant efficacy in lung cancer patients. The KEYNOTE189 trial in particular, reported the efficacy of an anti-PD-1 mA, pembrolizumab, in combination with chemotherapy in patients with advanced Lung adenocarcinoma. In particular, this trial showed a 12-month OS of 69.2% in the experimental group compared with a 49.4% reported in the group of patients who received the chemotherapy alone (4). Furthermore, in the KEYNOTE407 trial, the OS reached 15.9 months for patients with advanced squamous cell carcinoma in the chemo-immunotherapy arm, compared with 11.3 months recorded in the group addressed to chemotherapy alone (5). The above-mentioned trials have established the role of PD-1 blockade and chemotherapy in the treatment of NSCLC. In line with these results a recent meta-analysis showed that NSCLC patients over-expressing with the programmed death ligand 1 (PD-L1) (PD-L1 score >50%) receiving pembrolizumab-chemotherapy combination showed a much greater ORR, and progression-free survival (PFS) compared with the groups of patients receiving chemotherapy- or pembrolizumab-alone (6). Finally, the CheckMate159 trial reported an MPR rate of 45% in NSCLC patients receiving neoadjuvant therapy with nivolumab, which was much higher than that achieved by any previously tested chemotherapy regimens in neoadjuvant setting (7). The trial therefore suggested that PD-1 blockade is effective and may have definite advantages in patients with resectable NSCLC. Therefore, the present study was conducted to evaluate the anti-tumor activity and safety of neoadjuvant PD-1 blocking mAbs used in combination with standard chemotherapy for potentially resectable (clinical stage IIA–IIIB) NSCLC patients for only Asian performed setting in two different oncology centers in China (Xi’an and Chongqing). We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/tlcr-21-130).
Methods
This study is a multinstitutional single-arm observational study, including 23 patients who received the neoadjuvant treatment in two different Chinese center study. Clinical stages IIA–IIIB NSCLC patients over the age of 18 years with were eligible for inclusion. All of the enrolled patients were scheduled to receive surgery within 4–6 weeks after neoadjuvant therapy that consisted in 3–4 cycles of a conventional chemotherapy regimen with PD-1 inhibitors on day 1 of each cycle according to the international consensus. The specific chemoimmunotherapy regimens are detailed in the Table 1. Additional inclusion criteria included eligibility for surgery, as indicated by auxiliary examination including lung function and blood gas analysis; no distant metastasis; and no contraindications for PD-1 inhibitor therapy. The patients’ clinical staging was reviewed by 3 senior physicians and was confirmed if at least 2 of them agreed. Positron emission tomography/computed tomography (PET/CT) and immunohistochemicalPD-L1 detection were not necessary for inclusion. Patients with adenocarcinoma who had epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement were excluded. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tangdu Hospital of the Fourth Military Medical University (202012-12-KY-02-XW-01) and informed consent was taken from all individual participants.
Table 1 Specific chemoimmunotherapy regimens received by each patient
Patient no. Chemoimmunotherapy Cycles Pathological type Response as per RECIST v.1.1 pCR/MPR PD-L1 (TPS)
P1 Pemetrexed disodium (500 mg/m2, D1) + cisplatin (75 mg/m2, D1) + nivolumab (360 mg, D1) 3 Adenocarcinoma PR pCR N
P2 Nab-paclitaxel (260 mg/m2, D1) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P3 Gemcitabine (1000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma PR 70%
P4 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 3 Squamous carcinoma PR MPR N
P5 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 3 Squamous carcinoma PR MPR N
P6 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma SD <1%
P7 Gemcitabine (1,000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 1 Squamous carcinoma SD MPR N
P8 Gemcitabine (1,000 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 2 Squamous carcinoma PR MPR N
P9 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 4 Squamous carcinoma PR pCR N
P10 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P11 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR 5%
P12 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR pCR N
P13 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma PR 10%
P14 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Adenocarcinoma SD pCR 70%
P15 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 4 Squamous carcinoma PR 1%
P16 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma SD 15%
P17 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 2 Squamous carcinoma SD <1%
P18 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + nivolumab (200 mg, D1) 4 Adenocarcinoma PR pCR 15.4%
P19 Pemetrexed disodium (500 mg/m2, D1) + cisplatin (75 mg/m2, D1) + sintilimab (200 mg, D1) 3 Adenocarcinoma SD <1%
P20 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR pCR N
P21 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + pembrolizumab (200 mg, D1) 3 Squamous carcinoma PR N
P22 Paclitaxel (175 mg/m2, D1) + carboplatin (AUC=5, D1) + nivolumab (360 mg, D1) 2 Squamous carcinoma PR N
P23 Nab-paclitaxel (130 mg/m2, D1, 8) + nedaplatin (80 m/m2, D1) + sintilimab (200 mg, D1) 3 Squamous carcinoma PR N
pCR, pathological complete response; MPR, major pathological response; PR, partial response; SD, stable disease; N, none detected; AUC, area under the curve.
Study endpoints
The primary endpoints of the study were the safety and efficacy of neoadjuvant chemotherapy combined with PD-1 inhibitors. The safety-related endpoints included adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE, v.4.0). The efficacy-related endpoints included ORR according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1), and postoperative pathological down-staging according to the eighth edition of the National Comprehensive Cancer Network (NCCN) guidelines for tumor-node-metastasis (TNM) staging of NSCLC.
The secondary study endpoints were pCR, which was defined as the complete absence of tumor cells, and MPR, which was defined as <10% residual viable tumor (RVT).
Statistical analysis
Adverse events and feasibility were continuously monitored. Continuous variables are presented as means with standard deviation, while categorical variables are presented as frequencies.
Results
Patient characteristics
Twenty-three eligible candidates were recruited for this study. There were 22 men and one woman with just one of them with no smoking habits. A squamous histology and an adenocarcinoma were respectively, recorded in 19 and 4 of these patients with no driver mutations/translocation (EGFR or ALK etc.). Three cases were in IIA stage, 3 cases in IIB, 8 cases in IIIA, and 9 cases of IIIB stage (Table 2). Twenty patients underwent surgical resection Fourteen of them completed 3–4 cycles of chemo-immunotherapy as described elsewhere (method section) prior surgery; five further patients experienced grade 1 or 2 irAEs and where addressed to surgery after two treatment cycles while one last patient presented a lung abscess and underwent surgery after just one neo-adjuvant treatment cycle. All data on specific chemo-immunotherapy regimens are shown in Table 1. Three patients did not receive; in fact, two of them who completed the neoadjuvant program refused the risk of the surgery (Patients #21 and #23, Table 2) while another one (#22) refused to complete the neoadjuvant program after he developed a severe (grade 3) hyperglycemia during the second chemotherapy cycle.
Table 2 Baseline characteristics of the intention-to-treat population (N=23)
Characteristics Value Surgery Rejected surgery
Age, years
Median (range) 61.83
≥60 years 20 17 3
<60 years 3 3 0
Sex
Male 22 19 3
Female 1 1 0
BMI, kg/m2 (mean) 24.38
History of smoking
Current/ex-smoker 22 19 3
Never-smoker 1 1 0
KPS
90 21 19 2
100 2 1 1
Pathological type
Squamous carcinoma 19 16 3
Adenocarcinoma 4 4 0
Clinical T stage
T1 2 2 0
T2 4 4 0
T3 11 8 3
T4 6 6 0
Clinical N stage
N0 4 4 0
N1 9 8 1
N2 10 8 2
Clinical stage
IIA 3 2 1
IIB 3 3 0
IIIA 8 8 0
IIIB 9 7 2
Surgical treatment
Among the 20 patients who underwent surgery, 11 patients underwent lobectomy, 5 patients underwent sleeve resection/bronchoplasty, 2 patients received bilobectomy, and 2 patients underwent pneumonectomy. The results for surgical treatment, morbidity, and mortality are reported in the Table 3 shows. Surgical methods included Da Vinci’s/video-assisted thoracoscopic surgery (VATS) (n=14), conversion to thoracotomy (n=2), and thoracotomy (n=4). Complete resection (R0) was achieved in 95% of patients (19/20) who received surgery that in one case was considered as R1 resection due to the patient being lymph-node positive at the highest station. The median amount of blood lost was 212.5 mL (50–600 mL), and the mean operative time was 250 minutes (65–390 minutes).
Table 3 Surgical procedures
Characteristics Results
Extent of surgery
Lobectomy 11
Bilobectomy 2
Sleeve resection/bronchoplasty 5
Pneumonectomy 2
Surgical method
VATS/da Vinci 14
Conversion to thoracotomy 2
Thoracotomy 4
Operation time (min) 250 (65–390)
Bleeding (mL) 212.5 (50–600)
Hospital stay (days) 11.125 (6–22)
Chest tube duration (days) 4.18 (0–7)
Resection margins
R0 19
R1 1
R2 0
Safety
The post-operative complications were considered to be unrelated to neoadjuvant therapy and are summarized in the Table 4. There was no 30- or 90-day mortality, or any postoperative arrhythmia episode. The occurrence of AEs is shown in detail in the Table 5. The most common grade 1 or 2 neoadjuvant treatment-related AEs were fatigue (39.1%), alopecia (39.1%), vomiting (34.7%), leucopenia (30.4%), neutropenia (30.4%), and anorexia (30.4%). The treatment-related grade 3 AEs included anorexia, vomiting, fatigue, alopecia, arthralgia, bone pain, and hyperglycemia. Three patients experienced typical immune-related AEs including grade 1–2 hyperthyroidism, grade 3 hyperglycemia, and grade 1–2 rash.
Table 4 Postoperative complications
Characteristics N (%)
Intraoperative blood transfusion 2 (10%)
Death within 30 and 90 days 0
Heart failure 1 (5%)
Postoperative arrhythmia 0
Postoperative hoarseness 1 (5%)
Urinary tract infection or urinary retention 1 (5%)
Table 5 Adverse events
Characteristics Any grade Grade 1–2 Grade 3 Grade 4
Anemia 3 3
Leukopenia 7 7
Neutropenia 7 7
Anorexia 8 7 1
Vomiting 9 8 1
Diarrhea 2 2
Constipation 1 1
Fatigue 10 9 1
Alopecia 10 9 1
Hyperthyroidism 1 1
Lung abscess 1 1
Rash 1 1
Arthralgia and bone pain 2 1 1
Hyperglycemia 1 1
Antitumor activity
The activity of the neoadjuvant combination was evaluated according to the RECIST v.1.1 criteria after three/four treatment cycles. In particular, 17 out of the 23 showed a PR, while 6 further patients presented a SD (Figure 1A). The postoperative pathology results showed a MPR (50%) in 10 patients and a pCR (30%) in 6 patients (Figure 1A). A total of 15 patients (75%) resulted pathologically downstaged after surgery. On the overall, our analysis showed a median progression-free-survival (PFS) of 11.3 months (range, 3.1–18.7 months) (Figure 1B).
Figure 1 Waterfall plot. The horizontal dashed line represents partial response according to the RECIST v.1.1 criteria, and the different colors represent pathologic regression (A). Follow-up: duration of neoadjuvant therapy and PFS (B). pCR, pathological complete response; MPR, major pathological response; PFS, progression-free-survival.
Discussion
This is a clinical trial testing that a neoadjuvant PD-1 blockade and chemotherapy combination for potentially resectable (clinical stage IIA–IIIB) NSCLC patients. Our study yielded promising results resulting in a MPR and a pCR of 50% and 30%, respectively. This finding is of critical interest considering that previous studies in neoadjuvant setting, clearly show that both pCR and MPR are associated with survival benefits (8). For instance, Melek et al. examined a recorded a large database of 1,076 NSCLC patients who received surgery reporting a prolonged survival in those patients who achieved a pCR after neoadjuvant or induction therapy showing an outcome which was roughly the same as that recorded in patients diagnosed in a stage IB (1). These findings indicated a clinically significant association of pCR with 5-year OS (9). However, neither neoadjuvant chemotherapy, radiotherapy, nor TKI monotherapy has shown optimal pCR. The L’Intergroupe Francophone de Cancérologie Thoracique (IFCT) clinical trial reported that while only 41 (8.3%) of the 492 study patients achieved pCR, the 5-year OS of these patients reached 80.0%, compared to 55.8% for patients without pCR (10). These clinical results clearly suggest that the OS outcomes of neoadjuvant patients are independently associated with pCR.
With the growing expansion of PD-1 immune checkpoint inhibitors in clinical practice, the CheckMate159 trial was conducted to investigate the effects of neoadjuvant therapy with the PD-1 inhibitor, nivolumab yielding an MPR rate of 45% and a pCR rate of 15% (n=3) (7). This trial also reported that the rates of pCR and MPR in patients treated with neoadjuvant nivolumab were much higher than those recorded in patients who received traditional neoadjuvant regimens with chemotherapy, TKI- or chemoradiation (11-13). Notably, in study concerning locally resectable NSCLC patients treated with neoadjuvant atezolizumab and chemotherapy, 10 (33%) of 30 patients achieved a pCR which is in line with the results of our study (14).
Our data on AEs and complications indicate that the regimens used in this study were well tolerated, with no grade 4–5 AEs observed. AEs and complications occurred in this study at a similar frequency to those reported in the published data on neoadjuvant chemotherapy (15). In this study, we found that immune-related AEs could be well monitored and managed (16), which is similar to the observations made in the NADIM study (17). Only in 1 case did neoadjuvant therapy need to be halted after 1 cycle of treatment, with this patient’s complication being lung abscess caused by obstructive pneumonia, which was unrelated to PD-1 inhibitor treatment. After stopping the neoadjuvant treatment, the patient underwent surgery. Interestingly, he achieved MPR, despite only receiving 1 cycle of chemoimmunotherapy. Therefore, this study fully demonstrated that combination neoadjuvant chemoimmunotherapy has good safety and efficacy for the treatment of stage IIA–IIIB NSCLC.
In the present study, the rates of conversion to thoracotomy, completed thoracotomy, and completed pneumonectomy were 10%, 20%, and 10% respectively, which are similar to rates reported in a neoadjuvant chemotherapy study (conversion to thoracotomy, 26.5%; pneumonectomy, 17.6%) (18). This finding suggests that neoadjuvant chemoimmunotherapy does not increase the complexity of the surgical procedure compared with neoadjuvant chemotherapy.
There are several limitations to this research. First, this study mainly focused on the safety and efficacy of neoadjuvant therapy due to the small number of patients. In the future, we hope to observe the 5-year OS after neoadjuvant chemoimmunotherapy in a larger patient cohort. Secondly, PD-L1 was detected in some but not all of the patients, while the tumor mutational burden was not recorded for any patient in this study. Furthermore, we did not attempt to reach a conclusion on the relationship between potential biomarkers of PD-L1 and neoadjuvant therapy, and this will be explored in future study. Thirdly, 7 of the 23 patients included refused to continue the neoadjuvant treatment after 1–2 cycles, which might have caused bias regarding the safety and efficacy data. However, the safety and efficacy data of patients who accepted surgery treatment were analyzed according to the different centers, drug treatments, and cycles (Appendix 1). There was no statistical difference for pCR of patients according to the different drugs and cycles.
Conclusions
The existing data suggest that, in the neoadjuvant setting, PD-1 inhibitors combined with chemotherapy can significantly improve the rates of pCR and MPR among patients with resectable NSCLC. The safety profile and surgical complications of these combination regimens are the same as those previously observed among patients who have received chemotherapy alone as a neoadjuvant therapy.
Supplementary
The article’s supplementary files as
10.21037/tlcr-21-130 10.21037/tlcr-21-130 10.21037/tlcr-21-130 10.21037/tlcr-21-130
Acknowledgments
The authors appreciate the academic support from the AME Lung Cancer Collaborative Group.
Funding: This study was funded by the Tang Du Hospital Top-Level Talents Sponsorship Program, the Shaanxi Special Support Plan-Program for Leading Talents of Science and Technology Innovation, and the Tang Du Hospital’s Special Fund for Medical Technology.
Ethical Statement: The authors are 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tangdu Hospital of the Fourth Military Medical University (202012-12-KY-02-XW-01) and informed consent was taken from all individual participants.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/tlcr-21-130
Data Sharing Statement: Available at http://dx.doi.org/10.21037/tlcr-21-130
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-21-130). XY serves as an unpaid editorial board member of TLCR from Jun 2019 to Jun 2021. The other authors have no conflicts of interest to declare.
(English Language Editors: J. Grayand, J. Reynolds) | 175 MG/M2, CYCLIC (D1) | DrugDosageText | CC BY-NC-ND | 33718040 | 19,803,636 | 2021-02 |
What was the administration route of drug 'CISPLATIN'? | Case Report and Supporting Documentation: Acute Kidney Injury Manifested as Oliguria Is Reduced by Intravenous Magnesium Before Cisplatin.
After more than four decades of post-approval, cisplatin is still an important treatment for numerous cancers. However, acute kidney injury (AKI), defined as significant impairment of renal filtration as discussed below, is the major limiting side effect of cisplatin, occurring in approximately 30% of patients (25-33% after the first course). Cisplatin also damages the kidneys' ability to reabsorb magnesium in 40-100% of patients, with collateral health risks due to subsequent hypomagnesemia. Multiple methods and drugs have been proposed for preventing cisplatin-induced AKI, including saline infusion with or without mannitol, which has not always prevented AKI and has been found to activate a cellular stress response in renal tubular cells. While numerous reports and trials, as well as the National Comprehensive Cancer Network (NCCN), support premedication with magnesium and hydration, this practice has not been universally accepted. Many clinics administer intravenous magnesium (IV) only after identification of hypomagnesemia post-cisplatin treatment, thus placing patients at risk for AKI and chronic renal loss of magnesium. We present the following case report and additional supporting evidence identifying the immediate effect of IV magnesium prior to intraperitoneal cisplatin for cycle 4 because of documented hypomagnesemia resulting in normalization of oliguria, which had been experienced for the first three cycles. The patient subsequently requested and received IV magnesium before cisplatin for the next two cycles with continuation of normal urinary output. The effect of pretreatment with IV magnesium on urine output following cisplatin has not been previously reported and further supports pre-cisplatin administration. In addition, two recent meta-analyses of clinical trials and pre-clinical research are reviewed that demonstrate effectiveness of magnesium pretreatment to preventing AKI without reducing its chemotherapeutic efficacy. This case report with additional evidence supports the adoption of administration of 1-3 g IV magnesium before cisplatin as best practice to prevent cisplatin induced AKI and hypomagnesemia regardless of patient baseline serum magnesium levels.
Introduction
Oncologists now have numerous therapeutic agents for various cancers, but cisplatin, the first platinum compound the FDA approved in 1978, continues to be one of the most effective treatments against numerous cancers (1, 2). Cisplatin is highly effective in damaging cancer cell DNA, but its use is restrained by dose-limiting side effects, including AKI, considered to be the most serious toxicity, occurring in approximately one-third of patients (3). Even a single injection of cisplatin may result in a transient episode of AKI in 20–30% of patients (4, 5), which can be missed when measuring only the serum creatinine and blood urea nitrogen. Multiple reviews have discussed the molecular mechanism of AKI induced by cisplatin, which is beyond the scope of this case report (2, 6). Providers in outpatient clinics may not appreciate oliguria as a sign of AKI as manifested by the case report discussed below. Thus, identifying an agent that will prevent or ameliorate this irreversible side effect has been a priority.
The most recognized and followed recommendation to prevent AKI is fluid administration before and after cisplatin, typically with or without mannitol or furosemide (2, 7, 8). Magnesium administered concomitantly with cisplatin has been recommended by Vokes (9) since 1990 to prevent secondary hypomagnesemia due to distal tubular damage (10) and by multiple other clinicians to prevent AKI, (3, 11–16) but has not been established as a standard protocol and was not followed initially for this patient. This review will identify the benefits of this therapy for patients receiving cisplatin, regardless of serum magnesium levels, proposing the adoption of magnesium administration before cisplatin as best practice protocol.
Case Report
The patient is a 71-year-old board-certified internist who received intraperitoneal (IP) cisplatin and paclitaxel for recurrent ovarian cancer in December 2014.
Background: Stage 3C, poorly differentiated serous adenocarcinoma of the fallopian tube was diagnosed by exploratory surgery at Mercy Medical Center, Baltimore, MD by Dr. Neil Rosenshein in September 2012. Debulking was complete except for 1.5 cm tumor implant on the diaphragm. Chemotherapy with paclitaxel and carboplatin resulted in complete remission by 2013. Background medical history for patient includes: family history for breast cancer (mother and maternal grandmother); non-smoker, history of A–V dura fistula treated conservatively, primary hypothyroidism, allergic rhinitis; BP 112/78, pulse 72, BMI 20.9. Patient was entirely asymptomatic but CA 125 had increased from eight to 19 on 10/20/14 and a PET scan showed 1 cm implant on the right kidney on 10/31/14. Rather than accepting standard chemotherapy, the patient underwent exploratory laparotomy by Dr. Robert Edwards at Magee-Women’s hospital, UPMC, Pittsburgh, PA. No tumor implant was identified, but cell washings were atypical and an intraperitoneal port was placed for IP therapy.
Baseline serum lab included: blood urea nitrogen (BUN) 16, creatinine (Cr) 0.7, and magnesium 2.0 mg/dL (normal range: 1.7–2.2) on 12/26/14. Cisplatin and paclitaxel were administered via IP infusion every 21 days for six cycles beginning on 12/29/14 (day 1). Paclitaxel 135 mg/m2 in 500 ml of normal saline intravenous (IV) over 3 h was administered on day 1. After 1 L of normal saline IV, cisplatin at 75 mg/m2 was given in 1 L of normal saline IP followed by a second liter of normal saline IP, if tolerated. Another liter of normal saline IV was subsequently administered, too. Significant oliguria (concentrated, dark urine estimated at <30 cc h) was observed within 3 h after IP cisplatin. This oliguria and abdominal distention with pain continued for the next 36–48 h despite >2,000 cc oral intake of liquids and an additional liter of normal saline IV the following day.
Because the patient (an internist) recognized the disproportional oliguria, the on-call provider was consulted that evening within 6 h of cisplatin administration, but no action was recommended since the patient still had some urine output. AKI, which manifested as oliguria, was not recognized and stat renal function studies were not ordered. Diuresis had occurred by 1/3/15 when the following tests were obtained prior to having urgent surgery for a fractured wrist due to a fall on ice: BUN 20, Cr 0.74, and magnesium 1.3 mg/dL.
Oral magnesium oxide >500 mg was consumed daily. Intravenous magnesium was not administered unless serum magnesium dropped below 1.5 mg/dL, which was only checked immediately before each cycle of chemotherapy and not in between. On 2/9/15, prior to the next cycle, which had been delayed for 3 weeks due to a wrist fracture, BUN was 22, Cr 0.8, and magnesium 1.8.
The patient continued to experience severe oliguria immediately following cisplatin IP administration, lasting for approximately 48–72 h for the next two cycles, but on day 1 of cycle 4 on 3/25/15, 4 g (32.48 mEq) magnesium sulfate was administered IV prior to chemotherapy for a serum magnesium of 1.0 mg/dL. (Serum magnesium had been 1.6 on 3/2/15). The patient immediately observed normal urinary output on day 2 post-cisplatin and thereafter. In addition, abdomen distention and pain were significantly less than during the prior cycles.
Recognizing this response, the physician-patient completed a literature search regarding the effect of magnesium on cisplatin toxicity and consulted with a scientist who had recently published studies in rodents demonstrating the benefits of pretreating with magnesium to protect against cisplatin-induced AKI (17). Therefore, the patient subsequently requested and received 2 g of magnesium sulfate IV pre-cisplatin (on day 2) for cycles 5 and 6 even though serum magnesium was 1.7 mg/dL. To clearly demonstrate the effectiveness, she recorded the fluid intake and output for day 2, cycle 6: 4,800 cc combined IV, IP, and oral route, with a concomitant urine output of 4,950 cc in 24 h. The patient continued to demonstrate improved tolerance to the IP treatment with the administration of IV magnesium preceding cisplatin.
After completion of the six cycles, on 6/29/15, relevant values were: BUN 19, serum Cr 0.9, and magnesium 1.9. Patient at that time was receiving 1–2 g of IV magnesium weekly and has continued to suffer from persistent hypomagnesemia requiring 600 mg of oral magnesium threonate in divided doses daily to prevent tetany. These effects are presumed due to the irreversible AKI from cycles 1–3 prior to pretreatment with magnesium in subsequent cisplatin cycles. Glomerular filtration rate from 2015 until 2020 has been greater than 59 ml/min and current renal function on 8/27/20 was: BUN 23, Cr 1.04. As a physician, the patient strongly supports this case report to prevent AKI, hypermagnesemia, and the discomfort associated with intraperitoneal cisplatin that was diminished with magnesium preceding cisplatin.
Discussion
Overview of Acute Kidney Injury by Cisplatin
According to the Kidney Disease Improving Global Outcomes (KDIGO), AKI is defined as ≥0.3 mg/dL increase in serum creatinine or a 0.5 ml/kg/h decrease in urine output within 48 h; whereas Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAE v4.0) agrees on serum creatinine increase ≥0.3 mg/dL but with no time consideration (5).
Using CTCAE v4.0 criteria, 26.5% of patients experienced AKI after the first round of cisplatin-based chemotherapy in one retrospective study for urothelial cancer, resulting in >40% being unable to receive the planned second round, and 50% reduction in 3-year survival (5). Consequently, mortality is increased among patients with AKI, frequently due to inability to continue chemotherapy as scheduled (18, 19).
Risk factors for renal damage include people who are older, female, African American (20), smokers, have hypoalbuminemia, prior kidney damage, hypomagnesemia, dehydration, and/or have concomitant medical conditions such as diabetes, liver disease and use of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, diuretic therapy, and non-steroidal anti-inflammatory drugs (16–18).
Cisplatin is freely filtered at the glomeruli but is subsequently absorbed by the proximal tubule cell where it becomes a more potent toxin by multiple enzymatic pathways including gamma glutamyl transpeptidase (GGT), which has the highest activity in the kidneys (2, 6, 21).
However, a consistent amount of cisplatin is secreted from the blood into the urine through the cells of proximal tubules (22). Here, cisplatin uptake is accomplished by the human copper transport protein 1 (Ctr1) and the organic cation transporter 2 (OCT2) (23) located on the basolateral side of the proximal (24) and distal (25) renal tubules, as well as by passive diffusion (26). Concentration in the proximal tubule may be five times greater than the blood (27), with intrinsic damage of the proximal and distal tubules resulting in renal tubular cells death, affecting renal tubular blood flow, decreasing glomerular filtration rate, and preventing reabsorption of magnesium and other electrolytes (2). Excretion from the tubular cells is dependent on multidrug extrusion transporters (MATEs) (6, 28). Although renal tubular cells may recover, fibrotic scarring may occur resulting in chronic kidney disease (CKD) (29).
Bunel et al. (29) in a small human study, identified an increase in urinary biomarkers for acute renal damage within 3 h after cisplatin administration, but a diagnostic rise in plasma creatinine in each patient with AKI was delayed until 3–6 days post-administration, by which time urinary biomarkers had normalized.
Summary of Studies Demonstrating Effectiveness of Magnesium in Humans
In 2019, two systematic reviews and meta-analysis of therapies directed at prevention of cisplatin AKI were published, both suggesting a benefit with pre-administration of IV magnesium (30, 31) (Table 1). Casanova reviewed all placebo-controlled trials published up to 2017 (22 met their criteria), and concluded that 1 g (8 mEq) of IV magnesium before cisplatin reduced AKI (30).
Table 1 Published results on the association between cisplatin-induced AKI* and magnesium administration.
Study Intervention and outcome(s) Results P-value
Hamroun et al. (31)
Drugs Risk of cisplatin-induced AKI* Odds Ratio [95% Confidence Interval]
Magnesium dosage All dosages confounded 0.24 [0.19; 0.32] <0.001
8 mEq 0.23 [0.16; 0.34] <0.001
20 mEq 0.13 [0.06; 0.29] <0.001
25 mEq 0.28 [0.14; 0.54] <0.001
Casanova et al. (30)
Eur J Clin Pharmacol Risk of cisplatin-induced AKI* Odds Ratio [95% Confidence Interval]
Magnesium dosage All dosages confounded 0.22 [0.15; 0.33] <0.001
Modification in serum creatinine levels Mean difference of serum creatinine (mg/dL)
[95% Confidence Interval]
Magnesium dosage All dosages confounded −0.19 [−0.34; −0.05] < 0.001
*AKI, acute kidney injury defined by the 2012 KDIGO-AKI classification.
Hamroun et al. (31) searched Pubmed, Embase, and Web of Science from January 1, 1978, to June 1, 2018, assessing cisplatin AKI as defined by the 2012 AKI-KDIGO classification, which identified stage 1 as either serum creatinine 1.5–1.9 times OR ≥0.3 mg/dL (≥26.5 mmol/L) increase above baseline, or urine output decrease to 0.5 ml/kg/h for 6–12 h; stage 2: serum creatinine 2–2.9 × baseline, or decrease in urine output <0.5 ml/kg/h for × 12 h; stage 3: serum creatinine 3 × baseline or urine output <0.3 ml/kg/h (32). Of 4,520 eligible studies reviewed, 51 articles fulfilled the authors’ selection criteria, which included evaluating 21 different prevention methods. A meta-analysis was only performed on those studies that used magnesium at the same time as the first dose of cisplatin (15 observational involving 1,841 patients), and demonstrated a significant AKI protection for all grades of injury (31). Based upon analysis of the data regarding stage 1 AKI, “25 mEq of magnesium was associated with a significant nephron-protective effect (OR 0.20 [0.12–0.31], with a positive trend test (p = 0.002)” (31).
Magnesium Prevents Renal Toxicity in Animal Studies: Potential Mechanisms
Like humans, laboratory animals exhibit hypomagnesemia and AKI following serial cisplatin doses. Cisplatin specifically targets the proximal tubules, which comprise a significant portion of the kidneys. The proximal tubules contain a high density of epithelial cells with a large number of mitochondria necessary for providing the critical regulatory (pH balance, absorption, and secretion) and endocrine functions of the kidneys. In mice, organic cation transporters 1 and 2 (OCT 1 and OCT2) located on proximal tubule epithelial cells are considered to be the main transporters involved in cisplatin uptake by the renal proximal tubules (33, 34). Thus, this segment of the nephron is most susceptible to cisplatin-induced AKI (35, 36). Once taken up by the renal epithelial cell, cisplatin mediates its acute toxic effects by enhancing inflammation [via the Extracellular Signal Regulated Kinase (ERK) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling and subsequent cytokine production], increasing oxidative stress and by inducing cell death (apoptosis, necrosis, and autophagy).
Animal studies also demonstrate that cisplatin treatment lowers serum magnesium levels (37, 38) and that poor magnesium status enhances cisplatin-induced AKI (17, 37, 39, 40). Although the exact mechanism(s) involved are not completely understood, there is some evidence showing that magnesium absorption is impaired by cisplatin-mediated renal damage, suggesting that magnesium deficiency augments cisplatin uptake (probably via OCT2 and Ctr1) and reduces elimination (via MATE1) by kidney epithelial cells. Most importantly, the nephrotoxicity of cisplatin can be blocked by early and sustained magnesium supplementation in magnesium-deficient animals, preventing irreversible kidney injury (17, 39). Additional data support that the host’s magnesium status regulates multiple pathways associated with cisplatin-induced AKI, including oxidative stress, inflammation and apoptosis, and early magnesium supplementation protects against cisplatin-induced kidney damage through modulating these pathways (17, 40). Finally, while magnesium deficiency was associated with significantly larger tumors in mice and reduced cisplatin-mediated tumor killing in vivo, early magnesium supplementation was shown to protect the kidneys against cisplatin-mediated damage without compromising cisplatin anti-tumor efficacy while additionally potentiating the cytotoxic effect (39, 40). Together, these data strongly support that early magnesium supplementation exerts kidney-protective effects and may improve the anti-tumor efficacy of cisplatin.
Importance of Magnesium Homeostasis and Health Risks Associated with Hypomagnesemia
Over 300 biological enzymes are dependent on magnesium, the second most abundant intracellular cation, and fourth most abundant cation in the body (41). The normal body contains 22–26 g of magnesium; 52.9% in the bone, 27% in the muscle, 19.3 in soft tissue, 0.5% in red blood cells, and 0.3% in the serum (42).
Although magnesium deficiency is almost always asymptomatic (43), it may lead to long-term health problems including but not limited to: affecting cardiac electrical activity, including sudden death; association with insulin resistance, inhibiting acute phase of insulin release in hyperglycemia; contributing to progression of atherosclerosis by affecting lipid concentrations; hypertension; osteoporosis; increase frequency in renal calculi; reactive airway disease; muscle weakness; and multiple non-specific complaints including: fatigue, anorexia, fibromyalgia, tendonopathy, tetany, and mood alterations (41).
Measurement of the serum magnesium level is not an accurate reflection of total body stores. Renal excretion is predominantly responsible for maintaining serum balance with 70–80% of non-protein bound magnesium being filtered at the glomerulus, 95% of the magnesium in plasma is reabsorbed by the kidneys (60% at the ascending loop of Henle and 10% in the distal tubule, resulting in a loss of only 100 mg) (41, 42, 44).
Although not labeled AKI, the most common evidence of early renal damage is hypomagnesemia, first identified in 1979 (45). Hypomagnesemia may enhance the severity of nephrotoxicity (46). In addition, observational studies in humans, similar to those in animals, have demonstrated that premedication with magnesium prior to cisplatin may reduce the nephrotoxicity of magnesium loss. In 1990, Vokes (9) reported a randomized study of 23 patients treated with cisplatin for head and neck cancer using oral magnesium aspartate hydrochloride either by continuous oral magnesium, with dosage being increased or magnesium supplemented intravenously if unable to be tolerated versus intermittent administration only if the serum magnesium level dropped to ≤1.4 mg/dL. All patients receiving intermittent magnesium required magnesium at some point in the study, but 80% of patients receiving continuous magnesium never developed hypomagnesemia in a given cycle. Likewise, Martin et al. (47) demonstrated in 1992 that both intravenous (3 g before each cycle) and oral magnesium supplementation (2 g orally every 8 h, days 2–21 of each cycle) appeared effective in prevention of cisplatin-induced hypomagnesemia in the majority of patients with only mild gastrointestinal side effects observed with the oral group. Vokes concluded that “preventive administration of a magnesium supplement can ameliorate, if not completely eradicate, cisplatin-induced hypomagnesaemia.” (9) Hodgkinson, in 2006, also recommended routine supplementation of magnesium with each cycle of cisplatin to prevent cisplatin-induced hypomagnesemia (48). Most recently, a recent review by Duan supports magnesium administration to prevent AKI in elderly patients receiving cisplatin along with short hydration and amifostine (49).
Intravenous magnesium has been shown to be safe (50) and effective in multiple other medical conditions. It has been used to prevent AKI in contrast-induced nephropathy in primary percutaneous coronary intervention (51) and when administered intraoperatively with major laparoscopic abdominal surgery (52). Magnesium sulfate has been demonstrated to be more effective than anticonvulsants in acute eclampsia and reduces the risk of eclampsia by 50% in pre-eclampsia (41, 53). It has been used for status asthmaticus, torsades de pointes, and a higher concentration of magnesium has been correlated with better survival in chronic kidney disease (54). Lactate clearance has been shown to decrease in critically ill patients with severe sepsis with magnesium supplementation achieving a serum magnesium level near the upper limit of normal.
How exactly IV magnesium prevents AKI when given prior to cisplatin in humans is currently unknown and possibly involves numerous pathways as discussed previously. Although magnesium downregulated the OCT2 transporter and upregulated the MATE transporter, preventing AKI in rats, (55) this was not observed with acute exposure in recent experiments using cells expressing human OCT2 performed by Dr. Ciarimboli (see Figure 1 A–C). Therefore, further studies will be necessary to completely understand how magnesium prevents AKI in humans. Other drugs have demonstrated a downregulation of human OCT2 (hOCT2), protecting against AKI, such as carvedilol, (58) while metformin and cimetidine have been competitive substrates for hOCT2. Research has shown the renal protective effects of both of these agents from cisplatin toxicity (59, 60). However, two meta-analyses have both identified that IV magnesium prevents AKI from cisplatin and recommend it over all other agents at this time.
Figure 1 The effects of Mg2+ on hOCT2 function (A), on hOCT2-mediated Oxaliplatin toxicity (B), and on hMATE1 function (C). Function of the transporters was measured as uptake (hOCT2) or efflux (hMATE1) of the fluorescent organic cation 4-[4-(dimethylamino)styryl]-N-methylpyridinium (ASP+) as described in Wilde et al. (56) and Kantauskaite et al. (57) Panel (A) shows the changes of ASP+ uptake by hOCT2 stably expressed in Human Embryonic Kidney (HEK) cells in dependence from extracellular Mg2+ concentration compared to what was measured in Mg2+ absence (mean ± SEM). Only 1 mM Mg2+ significantly increased ASP+ uptake by hOCT2 (Kruskal–Wallis test with Dunn’s multiple comparison test). The presence of Mg2+ stimulates the activity of hOCT2, a transporter mediating nephrotoxicity of platinum derivatives, therefore regulation of hOCT2 by Mg2+ cannot explain Mg2+ protective effects against cisplatin nephrotoxicity. (B) shows the effects of Mg2+ supplementation (1 mM) on toxicity of 100 µM Oxaliplatin measured with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in hOCT2 overexpressing HEK cells (mean ± SEM). The presence of 1 mM Mg2+ does not protect the cells against hOCT2-mediated Oxaliplatin toxicity. Finally, (C) shows the changes of ASP+ efflux by hMATE1 stably expressed in HEK cells in dependence from extracellular Mg2+ concentration compared to what measured in Mg2+ absence (mean ± SEM). The extracellular presence of 1 mM Mg2+ slightly but significantly decreases the function of hMATE1 (Mann–Whitney-test), which is an efflux transporter for platinum derivatives. Therefore, also a regulation of hMATE1 by Mg2+ cannot explain Mg2+ protective effects against cisplatin nephrotoxicity. In (A, C) the numbers above the columns represent the number of replicates measured in at least three independent experiments. In (B) they represent the number of independent experiments.
Conclusion
Currently, there is no dispute regarding the renal toxicity associated with cisplatin. AKI, based on elevation of serum creatinine or decreased urine output, occurs in approximately one-third of all patients receiving cisplatin. Hypomagnesemia occurs in 40–100% of patients following cisplatin and may persist long after chemotherapy completion, reflecting irreversible cisplatin-mediated kidney damage. What has been controversial is the administration of IV magnesium prior to each dose of cisplatin, rather than after inevitable hypomagnesemia is subsequently identified. Compelling recent reviews of human trials and animal studies clearly support the pre-administration of IV magnesium for ameliorating both AKI and hypomagnesemia. Acute cisplatin-induced nephrotoxicity (including AKI and hypomagnesemia) may cause persistent and irreversible kidney impairment, resulting in further health complications.
Hesitancy regarding IV magnesium prior to cisplatin may have originated from the early termination of the Combined Oxaliplatin Neurotoxicity Prevention (CONcePT) in 2007, in which calcium/magnesium was infused before oxaliplatin chemotherapy for colon cancer to prevent neurotoxicity. Although initial data suggested a 52% reduction in oxaliplatin’s killing efficacy following calcium/magnesium administration, (61) this was subsequently reversed in 2008 and Wu, in 2012, published a systematic review concluding that IV calcium/magnesium does not impair oxaliplatin effectiveness (56). In addition, there has been no evidence in any of the trials analyzed that magnesium affected the chemotherapeutic effect of cisplatin, and a higher magnesium level actually potentiated cisplatin chemotherapeutic effect in mice (40). Finally, the OCT2 transporter that is involved in the cisplatin/oxaliplatin uptake and subsequent AKI has not been identified in tumors.
This case report along with supporting documentation provided by both clinical and pre-clinical studies clearly demonstrate the effectiveness of IV magnesium before cisplatin in preventing acute kidney injury manifested by oliguria. We recommend that at least 2 g of magnesium be administered prior to cisplatin since a recent study by Uhm found that 1 g still resulted in 33% of patients developing hypomagnesium (57), while a study by Hase supported the use of 20 mEq/L or approximately 2.5 g. (62)
Therefore, if we are to follow our oath to do no harm, it is imperative that IV magnesium administration with cisplatin become a “best practice” guideline at all oncology centers.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MM: concept for paper and case report. AH: review of human studies and comparison of recent meta-analyses, and development of table comparing these. CM: editing and review of paper. YS: review of renal receptors and effect of magnesium on them. CNM: summary of research in animals and editing of manuscript. SE: assistance in experiments using magnesium with human renal transporters GC: development and analysis of experiments using magnesium with human renal transporters. All authors contributed to the article and approved the submitted version.
Funding
Source for funding: Medical Research Fund Community Foundation of Washington County, Inc 37 S. Potomac Street Hagerstown, MD 21740.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Intraperitoneal | DrugAdministrationRoute | CC BY | 33718160 | 19,163,200 | 2021 |
What was the administration route of drug 'PACLITAXEL'? | Case Report and Supporting Documentation: Acute Kidney Injury Manifested as Oliguria Is Reduced by Intravenous Magnesium Before Cisplatin.
After more than four decades of post-approval, cisplatin is still an important treatment for numerous cancers. However, acute kidney injury (AKI), defined as significant impairment of renal filtration as discussed below, is the major limiting side effect of cisplatin, occurring in approximately 30% of patients (25-33% after the first course). Cisplatin also damages the kidneys' ability to reabsorb magnesium in 40-100% of patients, with collateral health risks due to subsequent hypomagnesemia. Multiple methods and drugs have been proposed for preventing cisplatin-induced AKI, including saline infusion with or without mannitol, which has not always prevented AKI and has been found to activate a cellular stress response in renal tubular cells. While numerous reports and trials, as well as the National Comprehensive Cancer Network (NCCN), support premedication with magnesium and hydration, this practice has not been universally accepted. Many clinics administer intravenous magnesium (IV) only after identification of hypomagnesemia post-cisplatin treatment, thus placing patients at risk for AKI and chronic renal loss of magnesium. We present the following case report and additional supporting evidence identifying the immediate effect of IV magnesium prior to intraperitoneal cisplatin for cycle 4 because of documented hypomagnesemia resulting in normalization of oliguria, which had been experienced for the first three cycles. The patient subsequently requested and received IV magnesium before cisplatin for the next two cycles with continuation of normal urinary output. The effect of pretreatment with IV magnesium on urine output following cisplatin has not been previously reported and further supports pre-cisplatin administration. In addition, two recent meta-analyses of clinical trials and pre-clinical research are reviewed that demonstrate effectiveness of magnesium pretreatment to preventing AKI without reducing its chemotherapeutic efficacy. This case report with additional evidence supports the adoption of administration of 1-3 g IV magnesium before cisplatin as best practice to prevent cisplatin induced AKI and hypomagnesemia regardless of patient baseline serum magnesium levels.
Introduction
Oncologists now have numerous therapeutic agents for various cancers, but cisplatin, the first platinum compound the FDA approved in 1978, continues to be one of the most effective treatments against numerous cancers (1, 2). Cisplatin is highly effective in damaging cancer cell DNA, but its use is restrained by dose-limiting side effects, including AKI, considered to be the most serious toxicity, occurring in approximately one-third of patients (3). Even a single injection of cisplatin may result in a transient episode of AKI in 20–30% of patients (4, 5), which can be missed when measuring only the serum creatinine and blood urea nitrogen. Multiple reviews have discussed the molecular mechanism of AKI induced by cisplatin, which is beyond the scope of this case report (2, 6). Providers in outpatient clinics may not appreciate oliguria as a sign of AKI as manifested by the case report discussed below. Thus, identifying an agent that will prevent or ameliorate this irreversible side effect has been a priority.
The most recognized and followed recommendation to prevent AKI is fluid administration before and after cisplatin, typically with or without mannitol or furosemide (2, 7, 8). Magnesium administered concomitantly with cisplatin has been recommended by Vokes (9) since 1990 to prevent secondary hypomagnesemia due to distal tubular damage (10) and by multiple other clinicians to prevent AKI, (3, 11–16) but has not been established as a standard protocol and was not followed initially for this patient. This review will identify the benefits of this therapy for patients receiving cisplatin, regardless of serum magnesium levels, proposing the adoption of magnesium administration before cisplatin as best practice protocol.
Case Report
The patient is a 71-year-old board-certified internist who received intraperitoneal (IP) cisplatin and paclitaxel for recurrent ovarian cancer in December 2014.
Background: Stage 3C, poorly differentiated serous adenocarcinoma of the fallopian tube was diagnosed by exploratory surgery at Mercy Medical Center, Baltimore, MD by Dr. Neil Rosenshein in September 2012. Debulking was complete except for 1.5 cm tumor implant on the diaphragm. Chemotherapy with paclitaxel and carboplatin resulted in complete remission by 2013. Background medical history for patient includes: family history for breast cancer (mother and maternal grandmother); non-smoker, history of A–V dura fistula treated conservatively, primary hypothyroidism, allergic rhinitis; BP 112/78, pulse 72, BMI 20.9. Patient was entirely asymptomatic but CA 125 had increased from eight to 19 on 10/20/14 and a PET scan showed 1 cm implant on the right kidney on 10/31/14. Rather than accepting standard chemotherapy, the patient underwent exploratory laparotomy by Dr. Robert Edwards at Magee-Women’s hospital, UPMC, Pittsburgh, PA. No tumor implant was identified, but cell washings were atypical and an intraperitoneal port was placed for IP therapy.
Baseline serum lab included: blood urea nitrogen (BUN) 16, creatinine (Cr) 0.7, and magnesium 2.0 mg/dL (normal range: 1.7–2.2) on 12/26/14. Cisplatin and paclitaxel were administered via IP infusion every 21 days for six cycles beginning on 12/29/14 (day 1). Paclitaxel 135 mg/m2 in 500 ml of normal saline intravenous (IV) over 3 h was administered on day 1. After 1 L of normal saline IV, cisplatin at 75 mg/m2 was given in 1 L of normal saline IP followed by a second liter of normal saline IP, if tolerated. Another liter of normal saline IV was subsequently administered, too. Significant oliguria (concentrated, dark urine estimated at <30 cc h) was observed within 3 h after IP cisplatin. This oliguria and abdominal distention with pain continued for the next 36–48 h despite >2,000 cc oral intake of liquids and an additional liter of normal saline IV the following day.
Because the patient (an internist) recognized the disproportional oliguria, the on-call provider was consulted that evening within 6 h of cisplatin administration, but no action was recommended since the patient still had some urine output. AKI, which manifested as oliguria, was not recognized and stat renal function studies were not ordered. Diuresis had occurred by 1/3/15 when the following tests were obtained prior to having urgent surgery for a fractured wrist due to a fall on ice: BUN 20, Cr 0.74, and magnesium 1.3 mg/dL.
Oral magnesium oxide >500 mg was consumed daily. Intravenous magnesium was not administered unless serum magnesium dropped below 1.5 mg/dL, which was only checked immediately before each cycle of chemotherapy and not in between. On 2/9/15, prior to the next cycle, which had been delayed for 3 weeks due to a wrist fracture, BUN was 22, Cr 0.8, and magnesium 1.8.
The patient continued to experience severe oliguria immediately following cisplatin IP administration, lasting for approximately 48–72 h for the next two cycles, but on day 1 of cycle 4 on 3/25/15, 4 g (32.48 mEq) magnesium sulfate was administered IV prior to chemotherapy for a serum magnesium of 1.0 mg/dL. (Serum magnesium had been 1.6 on 3/2/15). The patient immediately observed normal urinary output on day 2 post-cisplatin and thereafter. In addition, abdomen distention and pain were significantly less than during the prior cycles.
Recognizing this response, the physician-patient completed a literature search regarding the effect of magnesium on cisplatin toxicity and consulted with a scientist who had recently published studies in rodents demonstrating the benefits of pretreating with magnesium to protect against cisplatin-induced AKI (17). Therefore, the patient subsequently requested and received 2 g of magnesium sulfate IV pre-cisplatin (on day 2) for cycles 5 and 6 even though serum magnesium was 1.7 mg/dL. To clearly demonstrate the effectiveness, she recorded the fluid intake and output for day 2, cycle 6: 4,800 cc combined IV, IP, and oral route, with a concomitant urine output of 4,950 cc in 24 h. The patient continued to demonstrate improved tolerance to the IP treatment with the administration of IV magnesium preceding cisplatin.
After completion of the six cycles, on 6/29/15, relevant values were: BUN 19, serum Cr 0.9, and magnesium 1.9. Patient at that time was receiving 1–2 g of IV magnesium weekly and has continued to suffer from persistent hypomagnesemia requiring 600 mg of oral magnesium threonate in divided doses daily to prevent tetany. These effects are presumed due to the irreversible AKI from cycles 1–3 prior to pretreatment with magnesium in subsequent cisplatin cycles. Glomerular filtration rate from 2015 until 2020 has been greater than 59 ml/min and current renal function on 8/27/20 was: BUN 23, Cr 1.04. As a physician, the patient strongly supports this case report to prevent AKI, hypermagnesemia, and the discomfort associated with intraperitoneal cisplatin that was diminished with magnesium preceding cisplatin.
Discussion
Overview of Acute Kidney Injury by Cisplatin
According to the Kidney Disease Improving Global Outcomes (KDIGO), AKI is defined as ≥0.3 mg/dL increase in serum creatinine or a 0.5 ml/kg/h decrease in urine output within 48 h; whereas Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAE v4.0) agrees on serum creatinine increase ≥0.3 mg/dL but with no time consideration (5).
Using CTCAE v4.0 criteria, 26.5% of patients experienced AKI after the first round of cisplatin-based chemotherapy in one retrospective study for urothelial cancer, resulting in >40% being unable to receive the planned second round, and 50% reduction in 3-year survival (5). Consequently, mortality is increased among patients with AKI, frequently due to inability to continue chemotherapy as scheduled (18, 19).
Risk factors for renal damage include people who are older, female, African American (20), smokers, have hypoalbuminemia, prior kidney damage, hypomagnesemia, dehydration, and/or have concomitant medical conditions such as diabetes, liver disease and use of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, diuretic therapy, and non-steroidal anti-inflammatory drugs (16–18).
Cisplatin is freely filtered at the glomeruli but is subsequently absorbed by the proximal tubule cell where it becomes a more potent toxin by multiple enzymatic pathways including gamma glutamyl transpeptidase (GGT), which has the highest activity in the kidneys (2, 6, 21).
However, a consistent amount of cisplatin is secreted from the blood into the urine through the cells of proximal tubules (22). Here, cisplatin uptake is accomplished by the human copper transport protein 1 (Ctr1) and the organic cation transporter 2 (OCT2) (23) located on the basolateral side of the proximal (24) and distal (25) renal tubules, as well as by passive diffusion (26). Concentration in the proximal tubule may be five times greater than the blood (27), with intrinsic damage of the proximal and distal tubules resulting in renal tubular cells death, affecting renal tubular blood flow, decreasing glomerular filtration rate, and preventing reabsorption of magnesium and other electrolytes (2). Excretion from the tubular cells is dependent on multidrug extrusion transporters (MATEs) (6, 28). Although renal tubular cells may recover, fibrotic scarring may occur resulting in chronic kidney disease (CKD) (29).
Bunel et al. (29) in a small human study, identified an increase in urinary biomarkers for acute renal damage within 3 h after cisplatin administration, but a diagnostic rise in plasma creatinine in each patient with AKI was delayed until 3–6 days post-administration, by which time urinary biomarkers had normalized.
Summary of Studies Demonstrating Effectiveness of Magnesium in Humans
In 2019, two systematic reviews and meta-analysis of therapies directed at prevention of cisplatin AKI were published, both suggesting a benefit with pre-administration of IV magnesium (30, 31) (Table 1). Casanova reviewed all placebo-controlled trials published up to 2017 (22 met their criteria), and concluded that 1 g (8 mEq) of IV magnesium before cisplatin reduced AKI (30).
Table 1 Published results on the association between cisplatin-induced AKI* and magnesium administration.
Study Intervention and outcome(s) Results P-value
Hamroun et al. (31)
Drugs Risk of cisplatin-induced AKI* Odds Ratio [95% Confidence Interval]
Magnesium dosage All dosages confounded 0.24 [0.19; 0.32] <0.001
8 mEq 0.23 [0.16; 0.34] <0.001
20 mEq 0.13 [0.06; 0.29] <0.001
25 mEq 0.28 [0.14; 0.54] <0.001
Casanova et al. (30)
Eur J Clin Pharmacol Risk of cisplatin-induced AKI* Odds Ratio [95% Confidence Interval]
Magnesium dosage All dosages confounded 0.22 [0.15; 0.33] <0.001
Modification in serum creatinine levels Mean difference of serum creatinine (mg/dL)
[95% Confidence Interval]
Magnesium dosage All dosages confounded −0.19 [−0.34; −0.05] < 0.001
*AKI, acute kidney injury defined by the 2012 KDIGO-AKI classification.
Hamroun et al. (31) searched Pubmed, Embase, and Web of Science from January 1, 1978, to June 1, 2018, assessing cisplatin AKI as defined by the 2012 AKI-KDIGO classification, which identified stage 1 as either serum creatinine 1.5–1.9 times OR ≥0.3 mg/dL (≥26.5 mmol/L) increase above baseline, or urine output decrease to 0.5 ml/kg/h for 6–12 h; stage 2: serum creatinine 2–2.9 × baseline, or decrease in urine output <0.5 ml/kg/h for × 12 h; stage 3: serum creatinine 3 × baseline or urine output <0.3 ml/kg/h (32). Of 4,520 eligible studies reviewed, 51 articles fulfilled the authors’ selection criteria, which included evaluating 21 different prevention methods. A meta-analysis was only performed on those studies that used magnesium at the same time as the first dose of cisplatin (15 observational involving 1,841 patients), and demonstrated a significant AKI protection for all grades of injury (31). Based upon analysis of the data regarding stage 1 AKI, “25 mEq of magnesium was associated with a significant nephron-protective effect (OR 0.20 [0.12–0.31], with a positive trend test (p = 0.002)” (31).
Magnesium Prevents Renal Toxicity in Animal Studies: Potential Mechanisms
Like humans, laboratory animals exhibit hypomagnesemia and AKI following serial cisplatin doses. Cisplatin specifically targets the proximal tubules, which comprise a significant portion of the kidneys. The proximal tubules contain a high density of epithelial cells with a large number of mitochondria necessary for providing the critical regulatory (pH balance, absorption, and secretion) and endocrine functions of the kidneys. In mice, organic cation transporters 1 and 2 (OCT 1 and OCT2) located on proximal tubule epithelial cells are considered to be the main transporters involved in cisplatin uptake by the renal proximal tubules (33, 34). Thus, this segment of the nephron is most susceptible to cisplatin-induced AKI (35, 36). Once taken up by the renal epithelial cell, cisplatin mediates its acute toxic effects by enhancing inflammation [via the Extracellular Signal Regulated Kinase (ERK) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling and subsequent cytokine production], increasing oxidative stress and by inducing cell death (apoptosis, necrosis, and autophagy).
Animal studies also demonstrate that cisplatin treatment lowers serum magnesium levels (37, 38) and that poor magnesium status enhances cisplatin-induced AKI (17, 37, 39, 40). Although the exact mechanism(s) involved are not completely understood, there is some evidence showing that magnesium absorption is impaired by cisplatin-mediated renal damage, suggesting that magnesium deficiency augments cisplatin uptake (probably via OCT2 and Ctr1) and reduces elimination (via MATE1) by kidney epithelial cells. Most importantly, the nephrotoxicity of cisplatin can be blocked by early and sustained magnesium supplementation in magnesium-deficient animals, preventing irreversible kidney injury (17, 39). Additional data support that the host’s magnesium status regulates multiple pathways associated with cisplatin-induced AKI, including oxidative stress, inflammation and apoptosis, and early magnesium supplementation protects against cisplatin-induced kidney damage through modulating these pathways (17, 40). Finally, while magnesium deficiency was associated with significantly larger tumors in mice and reduced cisplatin-mediated tumor killing in vivo, early magnesium supplementation was shown to protect the kidneys against cisplatin-mediated damage without compromising cisplatin anti-tumor efficacy while additionally potentiating the cytotoxic effect (39, 40). Together, these data strongly support that early magnesium supplementation exerts kidney-protective effects and may improve the anti-tumor efficacy of cisplatin.
Importance of Magnesium Homeostasis and Health Risks Associated with Hypomagnesemia
Over 300 biological enzymes are dependent on magnesium, the second most abundant intracellular cation, and fourth most abundant cation in the body (41). The normal body contains 22–26 g of magnesium; 52.9% in the bone, 27% in the muscle, 19.3 in soft tissue, 0.5% in red blood cells, and 0.3% in the serum (42).
Although magnesium deficiency is almost always asymptomatic (43), it may lead to long-term health problems including but not limited to: affecting cardiac electrical activity, including sudden death; association with insulin resistance, inhibiting acute phase of insulin release in hyperglycemia; contributing to progression of atherosclerosis by affecting lipid concentrations; hypertension; osteoporosis; increase frequency in renal calculi; reactive airway disease; muscle weakness; and multiple non-specific complaints including: fatigue, anorexia, fibromyalgia, tendonopathy, tetany, and mood alterations (41).
Measurement of the serum magnesium level is not an accurate reflection of total body stores. Renal excretion is predominantly responsible for maintaining serum balance with 70–80% of non-protein bound magnesium being filtered at the glomerulus, 95% of the magnesium in plasma is reabsorbed by the kidneys (60% at the ascending loop of Henle and 10% in the distal tubule, resulting in a loss of only 100 mg) (41, 42, 44).
Although not labeled AKI, the most common evidence of early renal damage is hypomagnesemia, first identified in 1979 (45). Hypomagnesemia may enhance the severity of nephrotoxicity (46). In addition, observational studies in humans, similar to those in animals, have demonstrated that premedication with magnesium prior to cisplatin may reduce the nephrotoxicity of magnesium loss. In 1990, Vokes (9) reported a randomized study of 23 patients treated with cisplatin for head and neck cancer using oral magnesium aspartate hydrochloride either by continuous oral magnesium, with dosage being increased or magnesium supplemented intravenously if unable to be tolerated versus intermittent administration only if the serum magnesium level dropped to ≤1.4 mg/dL. All patients receiving intermittent magnesium required magnesium at some point in the study, but 80% of patients receiving continuous magnesium never developed hypomagnesemia in a given cycle. Likewise, Martin et al. (47) demonstrated in 1992 that both intravenous (3 g before each cycle) and oral magnesium supplementation (2 g orally every 8 h, days 2–21 of each cycle) appeared effective in prevention of cisplatin-induced hypomagnesemia in the majority of patients with only mild gastrointestinal side effects observed with the oral group. Vokes concluded that “preventive administration of a magnesium supplement can ameliorate, if not completely eradicate, cisplatin-induced hypomagnesaemia.” (9) Hodgkinson, in 2006, also recommended routine supplementation of magnesium with each cycle of cisplatin to prevent cisplatin-induced hypomagnesemia (48). Most recently, a recent review by Duan supports magnesium administration to prevent AKI in elderly patients receiving cisplatin along with short hydration and amifostine (49).
Intravenous magnesium has been shown to be safe (50) and effective in multiple other medical conditions. It has been used to prevent AKI in contrast-induced nephropathy in primary percutaneous coronary intervention (51) and when administered intraoperatively with major laparoscopic abdominal surgery (52). Magnesium sulfate has been demonstrated to be more effective than anticonvulsants in acute eclampsia and reduces the risk of eclampsia by 50% in pre-eclampsia (41, 53). It has been used for status asthmaticus, torsades de pointes, and a higher concentration of magnesium has been correlated with better survival in chronic kidney disease (54). Lactate clearance has been shown to decrease in critically ill patients with severe sepsis with magnesium supplementation achieving a serum magnesium level near the upper limit of normal.
How exactly IV magnesium prevents AKI when given prior to cisplatin in humans is currently unknown and possibly involves numerous pathways as discussed previously. Although magnesium downregulated the OCT2 transporter and upregulated the MATE transporter, preventing AKI in rats, (55) this was not observed with acute exposure in recent experiments using cells expressing human OCT2 performed by Dr. Ciarimboli (see Figure 1 A–C). Therefore, further studies will be necessary to completely understand how magnesium prevents AKI in humans. Other drugs have demonstrated a downregulation of human OCT2 (hOCT2), protecting against AKI, such as carvedilol, (58) while metformin and cimetidine have been competitive substrates for hOCT2. Research has shown the renal protective effects of both of these agents from cisplatin toxicity (59, 60). However, two meta-analyses have both identified that IV magnesium prevents AKI from cisplatin and recommend it over all other agents at this time.
Figure 1 The effects of Mg2+ on hOCT2 function (A), on hOCT2-mediated Oxaliplatin toxicity (B), and on hMATE1 function (C). Function of the transporters was measured as uptake (hOCT2) or efflux (hMATE1) of the fluorescent organic cation 4-[4-(dimethylamino)styryl]-N-methylpyridinium (ASP+) as described in Wilde et al. (56) and Kantauskaite et al. (57) Panel (A) shows the changes of ASP+ uptake by hOCT2 stably expressed in Human Embryonic Kidney (HEK) cells in dependence from extracellular Mg2+ concentration compared to what was measured in Mg2+ absence (mean ± SEM). Only 1 mM Mg2+ significantly increased ASP+ uptake by hOCT2 (Kruskal–Wallis test with Dunn’s multiple comparison test). The presence of Mg2+ stimulates the activity of hOCT2, a transporter mediating nephrotoxicity of platinum derivatives, therefore regulation of hOCT2 by Mg2+ cannot explain Mg2+ protective effects against cisplatin nephrotoxicity. (B) shows the effects of Mg2+ supplementation (1 mM) on toxicity of 100 µM Oxaliplatin measured with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in hOCT2 overexpressing HEK cells (mean ± SEM). The presence of 1 mM Mg2+ does not protect the cells against hOCT2-mediated Oxaliplatin toxicity. Finally, (C) shows the changes of ASP+ efflux by hMATE1 stably expressed in HEK cells in dependence from extracellular Mg2+ concentration compared to what measured in Mg2+ absence (mean ± SEM). The extracellular presence of 1 mM Mg2+ slightly but significantly decreases the function of hMATE1 (Mann–Whitney-test), which is an efflux transporter for platinum derivatives. Therefore, also a regulation of hMATE1 by Mg2+ cannot explain Mg2+ protective effects against cisplatin nephrotoxicity. In (A, C) the numbers above the columns represent the number of replicates measured in at least three independent experiments. In (B) they represent the number of independent experiments.
Conclusion
Currently, there is no dispute regarding the renal toxicity associated with cisplatin. AKI, based on elevation of serum creatinine or decreased urine output, occurs in approximately one-third of all patients receiving cisplatin. Hypomagnesemia occurs in 40–100% of patients following cisplatin and may persist long after chemotherapy completion, reflecting irreversible cisplatin-mediated kidney damage. What has been controversial is the administration of IV magnesium prior to each dose of cisplatin, rather than after inevitable hypomagnesemia is subsequently identified. Compelling recent reviews of human trials and animal studies clearly support the pre-administration of IV magnesium for ameliorating both AKI and hypomagnesemia. Acute cisplatin-induced nephrotoxicity (including AKI and hypomagnesemia) may cause persistent and irreversible kidney impairment, resulting in further health complications.
Hesitancy regarding IV magnesium prior to cisplatin may have originated from the early termination of the Combined Oxaliplatin Neurotoxicity Prevention (CONcePT) in 2007, in which calcium/magnesium was infused before oxaliplatin chemotherapy for colon cancer to prevent neurotoxicity. Although initial data suggested a 52% reduction in oxaliplatin’s killing efficacy following calcium/magnesium administration, (61) this was subsequently reversed in 2008 and Wu, in 2012, published a systematic review concluding that IV calcium/magnesium does not impair oxaliplatin effectiveness (56). In addition, there has been no evidence in any of the trials analyzed that magnesium affected the chemotherapeutic effect of cisplatin, and a higher magnesium level actually potentiated cisplatin chemotherapeutic effect in mice (40). Finally, the OCT2 transporter that is involved in the cisplatin/oxaliplatin uptake and subsequent AKI has not been identified in tumors.
This case report along with supporting documentation provided by both clinical and pre-clinical studies clearly demonstrate the effectiveness of IV magnesium before cisplatin in preventing acute kidney injury manifested by oliguria. We recommend that at least 2 g of magnesium be administered prior to cisplatin since a recent study by Uhm found that 1 g still resulted in 33% of patients developing hypomagnesium (57), while a study by Hase supported the use of 20 mEq/L or approximately 2.5 g. (62)
Therefore, if we are to follow our oath to do no harm, it is imperative that IV magnesium administration with cisplatin become a “best practice” guideline at all oncology centers.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MM: concept for paper and case report. AH: review of human studies and comparison of recent meta-analyses, and development of table comparing these. CM: editing and review of paper. YS: review of renal receptors and effect of magnesium on them. CNM: summary of research in animals and editing of manuscript. SE: assistance in experiments using magnesium with human renal transporters GC: development and analysis of experiments using magnesium with human renal transporters. All authors contributed to the article and approved the submitted version.
Funding
Source for funding: Medical Research Fund Community Foundation of Washington County, Inc 37 S. Potomac Street Hagerstown, MD 21740.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33718160 | 19,163,200 | 2021 |
What was the administration route of drug 'SODIUM CHLORIDE'? | Case Report and Supporting Documentation: Acute Kidney Injury Manifested as Oliguria Is Reduced by Intravenous Magnesium Before Cisplatin.
After more than four decades of post-approval, cisplatin is still an important treatment for numerous cancers. However, acute kidney injury (AKI), defined as significant impairment of renal filtration as discussed below, is the major limiting side effect of cisplatin, occurring in approximately 30% of patients (25-33% after the first course). Cisplatin also damages the kidneys' ability to reabsorb magnesium in 40-100% of patients, with collateral health risks due to subsequent hypomagnesemia. Multiple methods and drugs have been proposed for preventing cisplatin-induced AKI, including saline infusion with or without mannitol, which has not always prevented AKI and has been found to activate a cellular stress response in renal tubular cells. While numerous reports and trials, as well as the National Comprehensive Cancer Network (NCCN), support premedication with magnesium and hydration, this practice has not been universally accepted. Many clinics administer intravenous magnesium (IV) only after identification of hypomagnesemia post-cisplatin treatment, thus placing patients at risk for AKI and chronic renal loss of magnesium. We present the following case report and additional supporting evidence identifying the immediate effect of IV magnesium prior to intraperitoneal cisplatin for cycle 4 because of documented hypomagnesemia resulting in normalization of oliguria, which had been experienced for the first three cycles. The patient subsequently requested and received IV magnesium before cisplatin for the next two cycles with continuation of normal urinary output. The effect of pretreatment with IV magnesium on urine output following cisplatin has not been previously reported and further supports pre-cisplatin administration. In addition, two recent meta-analyses of clinical trials and pre-clinical research are reviewed that demonstrate effectiveness of magnesium pretreatment to preventing AKI without reducing its chemotherapeutic efficacy. This case report with additional evidence supports the adoption of administration of 1-3 g IV magnesium before cisplatin as best practice to prevent cisplatin induced AKI and hypomagnesemia regardless of patient baseline serum magnesium levels.
Introduction
Oncologists now have numerous therapeutic agents for various cancers, but cisplatin, the first platinum compound the FDA approved in 1978, continues to be one of the most effective treatments against numerous cancers (1, 2). Cisplatin is highly effective in damaging cancer cell DNA, but its use is restrained by dose-limiting side effects, including AKI, considered to be the most serious toxicity, occurring in approximately one-third of patients (3). Even a single injection of cisplatin may result in a transient episode of AKI in 20–30% of patients (4, 5), which can be missed when measuring only the serum creatinine and blood urea nitrogen. Multiple reviews have discussed the molecular mechanism of AKI induced by cisplatin, which is beyond the scope of this case report (2, 6). Providers in outpatient clinics may not appreciate oliguria as a sign of AKI as manifested by the case report discussed below. Thus, identifying an agent that will prevent or ameliorate this irreversible side effect has been a priority.
The most recognized and followed recommendation to prevent AKI is fluid administration before and after cisplatin, typically with or without mannitol or furosemide (2, 7, 8). Magnesium administered concomitantly with cisplatin has been recommended by Vokes (9) since 1990 to prevent secondary hypomagnesemia due to distal tubular damage (10) and by multiple other clinicians to prevent AKI, (3, 11–16) but has not been established as a standard protocol and was not followed initially for this patient. This review will identify the benefits of this therapy for patients receiving cisplatin, regardless of serum magnesium levels, proposing the adoption of magnesium administration before cisplatin as best practice protocol.
Case Report
The patient is a 71-year-old board-certified internist who received intraperitoneal (IP) cisplatin and paclitaxel for recurrent ovarian cancer in December 2014.
Background: Stage 3C, poorly differentiated serous adenocarcinoma of the fallopian tube was diagnosed by exploratory surgery at Mercy Medical Center, Baltimore, MD by Dr. Neil Rosenshein in September 2012. Debulking was complete except for 1.5 cm tumor implant on the diaphragm. Chemotherapy with paclitaxel and carboplatin resulted in complete remission by 2013. Background medical history for patient includes: family history for breast cancer (mother and maternal grandmother); non-smoker, history of A–V dura fistula treated conservatively, primary hypothyroidism, allergic rhinitis; BP 112/78, pulse 72, BMI 20.9. Patient was entirely asymptomatic but CA 125 had increased from eight to 19 on 10/20/14 and a PET scan showed 1 cm implant on the right kidney on 10/31/14. Rather than accepting standard chemotherapy, the patient underwent exploratory laparotomy by Dr. Robert Edwards at Magee-Women’s hospital, UPMC, Pittsburgh, PA. No tumor implant was identified, but cell washings were atypical and an intraperitoneal port was placed for IP therapy.
Baseline serum lab included: blood urea nitrogen (BUN) 16, creatinine (Cr) 0.7, and magnesium 2.0 mg/dL (normal range: 1.7–2.2) on 12/26/14. Cisplatin and paclitaxel were administered via IP infusion every 21 days for six cycles beginning on 12/29/14 (day 1). Paclitaxel 135 mg/m2 in 500 ml of normal saline intravenous (IV) over 3 h was administered on day 1. After 1 L of normal saline IV, cisplatin at 75 mg/m2 was given in 1 L of normal saline IP followed by a second liter of normal saline IP, if tolerated. Another liter of normal saline IV was subsequently administered, too. Significant oliguria (concentrated, dark urine estimated at <30 cc h) was observed within 3 h after IP cisplatin. This oliguria and abdominal distention with pain continued for the next 36–48 h despite >2,000 cc oral intake of liquids and an additional liter of normal saline IV the following day.
Because the patient (an internist) recognized the disproportional oliguria, the on-call provider was consulted that evening within 6 h of cisplatin administration, but no action was recommended since the patient still had some urine output. AKI, which manifested as oliguria, was not recognized and stat renal function studies were not ordered. Diuresis had occurred by 1/3/15 when the following tests were obtained prior to having urgent surgery for a fractured wrist due to a fall on ice: BUN 20, Cr 0.74, and magnesium 1.3 mg/dL.
Oral magnesium oxide >500 mg was consumed daily. Intravenous magnesium was not administered unless serum magnesium dropped below 1.5 mg/dL, which was only checked immediately before each cycle of chemotherapy and not in between. On 2/9/15, prior to the next cycle, which had been delayed for 3 weeks due to a wrist fracture, BUN was 22, Cr 0.8, and magnesium 1.8.
The patient continued to experience severe oliguria immediately following cisplatin IP administration, lasting for approximately 48–72 h for the next two cycles, but on day 1 of cycle 4 on 3/25/15, 4 g (32.48 mEq) magnesium sulfate was administered IV prior to chemotherapy for a serum magnesium of 1.0 mg/dL. (Serum magnesium had been 1.6 on 3/2/15). The patient immediately observed normal urinary output on day 2 post-cisplatin and thereafter. In addition, abdomen distention and pain were significantly less than during the prior cycles.
Recognizing this response, the physician-patient completed a literature search regarding the effect of magnesium on cisplatin toxicity and consulted with a scientist who had recently published studies in rodents demonstrating the benefits of pretreating with magnesium to protect against cisplatin-induced AKI (17). Therefore, the patient subsequently requested and received 2 g of magnesium sulfate IV pre-cisplatin (on day 2) for cycles 5 and 6 even though serum magnesium was 1.7 mg/dL. To clearly demonstrate the effectiveness, she recorded the fluid intake and output for day 2, cycle 6: 4,800 cc combined IV, IP, and oral route, with a concomitant urine output of 4,950 cc in 24 h. The patient continued to demonstrate improved tolerance to the IP treatment with the administration of IV magnesium preceding cisplatin.
After completion of the six cycles, on 6/29/15, relevant values were: BUN 19, serum Cr 0.9, and magnesium 1.9. Patient at that time was receiving 1–2 g of IV magnesium weekly and has continued to suffer from persistent hypomagnesemia requiring 600 mg of oral magnesium threonate in divided doses daily to prevent tetany. These effects are presumed due to the irreversible AKI from cycles 1–3 prior to pretreatment with magnesium in subsequent cisplatin cycles. Glomerular filtration rate from 2015 until 2020 has been greater than 59 ml/min and current renal function on 8/27/20 was: BUN 23, Cr 1.04. As a physician, the patient strongly supports this case report to prevent AKI, hypermagnesemia, and the discomfort associated with intraperitoneal cisplatin that was diminished with magnesium preceding cisplatin.
Discussion
Overview of Acute Kidney Injury by Cisplatin
According to the Kidney Disease Improving Global Outcomes (KDIGO), AKI is defined as ≥0.3 mg/dL increase in serum creatinine or a 0.5 ml/kg/h decrease in urine output within 48 h; whereas Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAE v4.0) agrees on serum creatinine increase ≥0.3 mg/dL but with no time consideration (5).
Using CTCAE v4.0 criteria, 26.5% of patients experienced AKI after the first round of cisplatin-based chemotherapy in one retrospective study for urothelial cancer, resulting in >40% being unable to receive the planned second round, and 50% reduction in 3-year survival (5). Consequently, mortality is increased among patients with AKI, frequently due to inability to continue chemotherapy as scheduled (18, 19).
Risk factors for renal damage include people who are older, female, African American (20), smokers, have hypoalbuminemia, prior kidney damage, hypomagnesemia, dehydration, and/or have concomitant medical conditions such as diabetes, liver disease and use of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, diuretic therapy, and non-steroidal anti-inflammatory drugs (16–18).
Cisplatin is freely filtered at the glomeruli but is subsequently absorbed by the proximal tubule cell where it becomes a more potent toxin by multiple enzymatic pathways including gamma glutamyl transpeptidase (GGT), which has the highest activity in the kidneys (2, 6, 21).
However, a consistent amount of cisplatin is secreted from the blood into the urine through the cells of proximal tubules (22). Here, cisplatin uptake is accomplished by the human copper transport protein 1 (Ctr1) and the organic cation transporter 2 (OCT2) (23) located on the basolateral side of the proximal (24) and distal (25) renal tubules, as well as by passive diffusion (26). Concentration in the proximal tubule may be five times greater than the blood (27), with intrinsic damage of the proximal and distal tubules resulting in renal tubular cells death, affecting renal tubular blood flow, decreasing glomerular filtration rate, and preventing reabsorption of magnesium and other electrolytes (2). Excretion from the tubular cells is dependent on multidrug extrusion transporters (MATEs) (6, 28). Although renal tubular cells may recover, fibrotic scarring may occur resulting in chronic kidney disease (CKD) (29).
Bunel et al. (29) in a small human study, identified an increase in urinary biomarkers for acute renal damage within 3 h after cisplatin administration, but a diagnostic rise in plasma creatinine in each patient with AKI was delayed until 3–6 days post-administration, by which time urinary biomarkers had normalized.
Summary of Studies Demonstrating Effectiveness of Magnesium in Humans
In 2019, two systematic reviews and meta-analysis of therapies directed at prevention of cisplatin AKI were published, both suggesting a benefit with pre-administration of IV magnesium (30, 31) (Table 1). Casanova reviewed all placebo-controlled trials published up to 2017 (22 met their criteria), and concluded that 1 g (8 mEq) of IV magnesium before cisplatin reduced AKI (30).
Table 1 Published results on the association between cisplatin-induced AKI* and magnesium administration.
Study Intervention and outcome(s) Results P-value
Hamroun et al. (31)
Drugs Risk of cisplatin-induced AKI* Odds Ratio [95% Confidence Interval]
Magnesium dosage All dosages confounded 0.24 [0.19; 0.32] <0.001
8 mEq 0.23 [0.16; 0.34] <0.001
20 mEq 0.13 [0.06; 0.29] <0.001
25 mEq 0.28 [0.14; 0.54] <0.001
Casanova et al. (30)
Eur J Clin Pharmacol Risk of cisplatin-induced AKI* Odds Ratio [95% Confidence Interval]
Magnesium dosage All dosages confounded 0.22 [0.15; 0.33] <0.001
Modification in serum creatinine levels Mean difference of serum creatinine (mg/dL)
[95% Confidence Interval]
Magnesium dosage All dosages confounded −0.19 [−0.34; −0.05] < 0.001
*AKI, acute kidney injury defined by the 2012 KDIGO-AKI classification.
Hamroun et al. (31) searched Pubmed, Embase, and Web of Science from January 1, 1978, to June 1, 2018, assessing cisplatin AKI as defined by the 2012 AKI-KDIGO classification, which identified stage 1 as either serum creatinine 1.5–1.9 times OR ≥0.3 mg/dL (≥26.5 mmol/L) increase above baseline, or urine output decrease to 0.5 ml/kg/h for 6–12 h; stage 2: serum creatinine 2–2.9 × baseline, or decrease in urine output <0.5 ml/kg/h for × 12 h; stage 3: serum creatinine 3 × baseline or urine output <0.3 ml/kg/h (32). Of 4,520 eligible studies reviewed, 51 articles fulfilled the authors’ selection criteria, which included evaluating 21 different prevention methods. A meta-analysis was only performed on those studies that used magnesium at the same time as the first dose of cisplatin (15 observational involving 1,841 patients), and demonstrated a significant AKI protection for all grades of injury (31). Based upon analysis of the data regarding stage 1 AKI, “25 mEq of magnesium was associated with a significant nephron-protective effect (OR 0.20 [0.12–0.31], with a positive trend test (p = 0.002)” (31).
Magnesium Prevents Renal Toxicity in Animal Studies: Potential Mechanisms
Like humans, laboratory animals exhibit hypomagnesemia and AKI following serial cisplatin doses. Cisplatin specifically targets the proximal tubules, which comprise a significant portion of the kidneys. The proximal tubules contain a high density of epithelial cells with a large number of mitochondria necessary for providing the critical regulatory (pH balance, absorption, and secretion) and endocrine functions of the kidneys. In mice, organic cation transporters 1 and 2 (OCT 1 and OCT2) located on proximal tubule epithelial cells are considered to be the main transporters involved in cisplatin uptake by the renal proximal tubules (33, 34). Thus, this segment of the nephron is most susceptible to cisplatin-induced AKI (35, 36). Once taken up by the renal epithelial cell, cisplatin mediates its acute toxic effects by enhancing inflammation [via the Extracellular Signal Regulated Kinase (ERK) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling and subsequent cytokine production], increasing oxidative stress and by inducing cell death (apoptosis, necrosis, and autophagy).
Animal studies also demonstrate that cisplatin treatment lowers serum magnesium levels (37, 38) and that poor magnesium status enhances cisplatin-induced AKI (17, 37, 39, 40). Although the exact mechanism(s) involved are not completely understood, there is some evidence showing that magnesium absorption is impaired by cisplatin-mediated renal damage, suggesting that magnesium deficiency augments cisplatin uptake (probably via OCT2 and Ctr1) and reduces elimination (via MATE1) by kidney epithelial cells. Most importantly, the nephrotoxicity of cisplatin can be blocked by early and sustained magnesium supplementation in magnesium-deficient animals, preventing irreversible kidney injury (17, 39). Additional data support that the host’s magnesium status regulates multiple pathways associated with cisplatin-induced AKI, including oxidative stress, inflammation and apoptosis, and early magnesium supplementation protects against cisplatin-induced kidney damage through modulating these pathways (17, 40). Finally, while magnesium deficiency was associated with significantly larger tumors in mice and reduced cisplatin-mediated tumor killing in vivo, early magnesium supplementation was shown to protect the kidneys against cisplatin-mediated damage without compromising cisplatin anti-tumor efficacy while additionally potentiating the cytotoxic effect (39, 40). Together, these data strongly support that early magnesium supplementation exerts kidney-protective effects and may improve the anti-tumor efficacy of cisplatin.
Importance of Magnesium Homeostasis and Health Risks Associated with Hypomagnesemia
Over 300 biological enzymes are dependent on magnesium, the second most abundant intracellular cation, and fourth most abundant cation in the body (41). The normal body contains 22–26 g of magnesium; 52.9% in the bone, 27% in the muscle, 19.3 in soft tissue, 0.5% in red blood cells, and 0.3% in the serum (42).
Although magnesium deficiency is almost always asymptomatic (43), it may lead to long-term health problems including but not limited to: affecting cardiac electrical activity, including sudden death; association with insulin resistance, inhibiting acute phase of insulin release in hyperglycemia; contributing to progression of atherosclerosis by affecting lipid concentrations; hypertension; osteoporosis; increase frequency in renal calculi; reactive airway disease; muscle weakness; and multiple non-specific complaints including: fatigue, anorexia, fibromyalgia, tendonopathy, tetany, and mood alterations (41).
Measurement of the serum magnesium level is not an accurate reflection of total body stores. Renal excretion is predominantly responsible for maintaining serum balance with 70–80% of non-protein bound magnesium being filtered at the glomerulus, 95% of the magnesium in plasma is reabsorbed by the kidneys (60% at the ascending loop of Henle and 10% in the distal tubule, resulting in a loss of only 100 mg) (41, 42, 44).
Although not labeled AKI, the most common evidence of early renal damage is hypomagnesemia, first identified in 1979 (45). Hypomagnesemia may enhance the severity of nephrotoxicity (46). In addition, observational studies in humans, similar to those in animals, have demonstrated that premedication with magnesium prior to cisplatin may reduce the nephrotoxicity of magnesium loss. In 1990, Vokes (9) reported a randomized study of 23 patients treated with cisplatin for head and neck cancer using oral magnesium aspartate hydrochloride either by continuous oral magnesium, with dosage being increased or magnesium supplemented intravenously if unable to be tolerated versus intermittent administration only if the serum magnesium level dropped to ≤1.4 mg/dL. All patients receiving intermittent magnesium required magnesium at some point in the study, but 80% of patients receiving continuous magnesium never developed hypomagnesemia in a given cycle. Likewise, Martin et al. (47) demonstrated in 1992 that both intravenous (3 g before each cycle) and oral magnesium supplementation (2 g orally every 8 h, days 2–21 of each cycle) appeared effective in prevention of cisplatin-induced hypomagnesemia in the majority of patients with only mild gastrointestinal side effects observed with the oral group. Vokes concluded that “preventive administration of a magnesium supplement can ameliorate, if not completely eradicate, cisplatin-induced hypomagnesaemia.” (9) Hodgkinson, in 2006, also recommended routine supplementation of magnesium with each cycle of cisplatin to prevent cisplatin-induced hypomagnesemia (48). Most recently, a recent review by Duan supports magnesium administration to prevent AKI in elderly patients receiving cisplatin along with short hydration and amifostine (49).
Intravenous magnesium has been shown to be safe (50) and effective in multiple other medical conditions. It has been used to prevent AKI in contrast-induced nephropathy in primary percutaneous coronary intervention (51) and when administered intraoperatively with major laparoscopic abdominal surgery (52). Magnesium sulfate has been demonstrated to be more effective than anticonvulsants in acute eclampsia and reduces the risk of eclampsia by 50% in pre-eclampsia (41, 53). It has been used for status asthmaticus, torsades de pointes, and a higher concentration of magnesium has been correlated with better survival in chronic kidney disease (54). Lactate clearance has been shown to decrease in critically ill patients with severe sepsis with magnesium supplementation achieving a serum magnesium level near the upper limit of normal.
How exactly IV magnesium prevents AKI when given prior to cisplatin in humans is currently unknown and possibly involves numerous pathways as discussed previously. Although magnesium downregulated the OCT2 transporter and upregulated the MATE transporter, preventing AKI in rats, (55) this was not observed with acute exposure in recent experiments using cells expressing human OCT2 performed by Dr. Ciarimboli (see Figure 1 A–C). Therefore, further studies will be necessary to completely understand how magnesium prevents AKI in humans. Other drugs have demonstrated a downregulation of human OCT2 (hOCT2), protecting against AKI, such as carvedilol, (58) while metformin and cimetidine have been competitive substrates for hOCT2. Research has shown the renal protective effects of both of these agents from cisplatin toxicity (59, 60). However, two meta-analyses have both identified that IV magnesium prevents AKI from cisplatin and recommend it over all other agents at this time.
Figure 1 The effects of Mg2+ on hOCT2 function (A), on hOCT2-mediated Oxaliplatin toxicity (B), and on hMATE1 function (C). Function of the transporters was measured as uptake (hOCT2) or efflux (hMATE1) of the fluorescent organic cation 4-[4-(dimethylamino)styryl]-N-methylpyridinium (ASP+) as described in Wilde et al. (56) and Kantauskaite et al. (57) Panel (A) shows the changes of ASP+ uptake by hOCT2 stably expressed in Human Embryonic Kidney (HEK) cells in dependence from extracellular Mg2+ concentration compared to what was measured in Mg2+ absence (mean ± SEM). Only 1 mM Mg2+ significantly increased ASP+ uptake by hOCT2 (Kruskal–Wallis test with Dunn’s multiple comparison test). The presence of Mg2+ stimulates the activity of hOCT2, a transporter mediating nephrotoxicity of platinum derivatives, therefore regulation of hOCT2 by Mg2+ cannot explain Mg2+ protective effects against cisplatin nephrotoxicity. (B) shows the effects of Mg2+ supplementation (1 mM) on toxicity of 100 µM Oxaliplatin measured with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in hOCT2 overexpressing HEK cells (mean ± SEM). The presence of 1 mM Mg2+ does not protect the cells against hOCT2-mediated Oxaliplatin toxicity. Finally, (C) shows the changes of ASP+ efflux by hMATE1 stably expressed in HEK cells in dependence from extracellular Mg2+ concentration compared to what measured in Mg2+ absence (mean ± SEM). The extracellular presence of 1 mM Mg2+ slightly but significantly decreases the function of hMATE1 (Mann–Whitney-test), which is an efflux transporter for platinum derivatives. Therefore, also a regulation of hMATE1 by Mg2+ cannot explain Mg2+ protective effects against cisplatin nephrotoxicity. In (A, C) the numbers above the columns represent the number of replicates measured in at least three independent experiments. In (B) they represent the number of independent experiments.
Conclusion
Currently, there is no dispute regarding the renal toxicity associated with cisplatin. AKI, based on elevation of serum creatinine or decreased urine output, occurs in approximately one-third of all patients receiving cisplatin. Hypomagnesemia occurs in 40–100% of patients following cisplatin and may persist long after chemotherapy completion, reflecting irreversible cisplatin-mediated kidney damage. What has been controversial is the administration of IV magnesium prior to each dose of cisplatin, rather than after inevitable hypomagnesemia is subsequently identified. Compelling recent reviews of human trials and animal studies clearly support the pre-administration of IV magnesium for ameliorating both AKI and hypomagnesemia. Acute cisplatin-induced nephrotoxicity (including AKI and hypomagnesemia) may cause persistent and irreversible kidney impairment, resulting in further health complications.
Hesitancy regarding IV magnesium prior to cisplatin may have originated from the early termination of the Combined Oxaliplatin Neurotoxicity Prevention (CONcePT) in 2007, in which calcium/magnesium was infused before oxaliplatin chemotherapy for colon cancer to prevent neurotoxicity. Although initial data suggested a 52% reduction in oxaliplatin’s killing efficacy following calcium/magnesium administration, (61) this was subsequently reversed in 2008 and Wu, in 2012, published a systematic review concluding that IV calcium/magnesium does not impair oxaliplatin effectiveness (56). In addition, there has been no evidence in any of the trials analyzed that magnesium affected the chemotherapeutic effect of cisplatin, and a higher magnesium level actually potentiated cisplatin chemotherapeutic effect in mice (40). Finally, the OCT2 transporter that is involved in the cisplatin/oxaliplatin uptake and subsequent AKI has not been identified in tumors.
This case report along with supporting documentation provided by both clinical and pre-clinical studies clearly demonstrate the effectiveness of IV magnesium before cisplatin in preventing acute kidney injury manifested by oliguria. We recommend that at least 2 g of magnesium be administered prior to cisplatin since a recent study by Uhm found that 1 g still resulted in 33% of patients developing hypomagnesium (57), while a study by Hase supported the use of 20 mEq/L or approximately 2.5 g. (62)
Therefore, if we are to follow our oath to do no harm, it is imperative that IV magnesium administration with cisplatin become a “best practice” guideline at all oncology centers.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MM: concept for paper and case report. AH: review of human studies and comparison of recent meta-analyses, and development of table comparing these. CM: editing and review of paper. YS: review of renal receptors and effect of magnesium on them. CNM: summary of research in animals and editing of manuscript. SE: assistance in experiments using magnesium with human renal transporters GC: development and analysis of experiments using magnesium with human renal transporters. All authors contributed to the article and approved the submitted version.
Funding
Source for funding: Medical Research Fund Community Foundation of Washington County, Inc 37 S. Potomac Street Hagerstown, MD 21740.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33718160 | 19,163,200 | 2021 |
What was the outcome of reaction 'Hypomagnesaemia'? | Case Report and Supporting Documentation: Acute Kidney Injury Manifested as Oliguria Is Reduced by Intravenous Magnesium Before Cisplatin.
After more than four decades of post-approval, cisplatin is still an important treatment for numerous cancers. However, acute kidney injury (AKI), defined as significant impairment of renal filtration as discussed below, is the major limiting side effect of cisplatin, occurring in approximately 30% of patients (25-33% after the first course). Cisplatin also damages the kidneys' ability to reabsorb magnesium in 40-100% of patients, with collateral health risks due to subsequent hypomagnesemia. Multiple methods and drugs have been proposed for preventing cisplatin-induced AKI, including saline infusion with or without mannitol, which has not always prevented AKI and has been found to activate a cellular stress response in renal tubular cells. While numerous reports and trials, as well as the National Comprehensive Cancer Network (NCCN), support premedication with magnesium and hydration, this practice has not been universally accepted. Many clinics administer intravenous magnesium (IV) only after identification of hypomagnesemia post-cisplatin treatment, thus placing patients at risk for AKI and chronic renal loss of magnesium. We present the following case report and additional supporting evidence identifying the immediate effect of IV magnesium prior to intraperitoneal cisplatin for cycle 4 because of documented hypomagnesemia resulting in normalization of oliguria, which had been experienced for the first three cycles. The patient subsequently requested and received IV magnesium before cisplatin for the next two cycles with continuation of normal urinary output. The effect of pretreatment with IV magnesium on urine output following cisplatin has not been previously reported and further supports pre-cisplatin administration. In addition, two recent meta-analyses of clinical trials and pre-clinical research are reviewed that demonstrate effectiveness of magnesium pretreatment to preventing AKI without reducing its chemotherapeutic efficacy. This case report with additional evidence supports the adoption of administration of 1-3 g IV magnesium before cisplatin as best practice to prevent cisplatin induced AKI and hypomagnesemia regardless of patient baseline serum magnesium levels.
Introduction
Oncologists now have numerous therapeutic agents for various cancers, but cisplatin, the first platinum compound the FDA approved in 1978, continues to be one of the most effective treatments against numerous cancers (1, 2). Cisplatin is highly effective in damaging cancer cell DNA, but its use is restrained by dose-limiting side effects, including AKI, considered to be the most serious toxicity, occurring in approximately one-third of patients (3). Even a single injection of cisplatin may result in a transient episode of AKI in 20–30% of patients (4, 5), which can be missed when measuring only the serum creatinine and blood urea nitrogen. Multiple reviews have discussed the molecular mechanism of AKI induced by cisplatin, which is beyond the scope of this case report (2, 6). Providers in outpatient clinics may not appreciate oliguria as a sign of AKI as manifested by the case report discussed below. Thus, identifying an agent that will prevent or ameliorate this irreversible side effect has been a priority.
The most recognized and followed recommendation to prevent AKI is fluid administration before and after cisplatin, typically with or without mannitol or furosemide (2, 7, 8). Magnesium administered concomitantly with cisplatin has been recommended by Vokes (9) since 1990 to prevent secondary hypomagnesemia due to distal tubular damage (10) and by multiple other clinicians to prevent AKI, (3, 11–16) but has not been established as a standard protocol and was not followed initially for this patient. This review will identify the benefits of this therapy for patients receiving cisplatin, regardless of serum magnesium levels, proposing the adoption of magnesium administration before cisplatin as best practice protocol.
Case Report
The patient is a 71-year-old board-certified internist who received intraperitoneal (IP) cisplatin and paclitaxel for recurrent ovarian cancer in December 2014.
Background: Stage 3C, poorly differentiated serous adenocarcinoma of the fallopian tube was diagnosed by exploratory surgery at Mercy Medical Center, Baltimore, MD by Dr. Neil Rosenshein in September 2012. Debulking was complete except for 1.5 cm tumor implant on the diaphragm. Chemotherapy with paclitaxel and carboplatin resulted in complete remission by 2013. Background medical history for patient includes: family history for breast cancer (mother and maternal grandmother); non-smoker, history of A–V dura fistula treated conservatively, primary hypothyroidism, allergic rhinitis; BP 112/78, pulse 72, BMI 20.9. Patient was entirely asymptomatic but CA 125 had increased from eight to 19 on 10/20/14 and a PET scan showed 1 cm implant on the right kidney on 10/31/14. Rather than accepting standard chemotherapy, the patient underwent exploratory laparotomy by Dr. Robert Edwards at Magee-Women’s hospital, UPMC, Pittsburgh, PA. No tumor implant was identified, but cell washings were atypical and an intraperitoneal port was placed for IP therapy.
Baseline serum lab included: blood urea nitrogen (BUN) 16, creatinine (Cr) 0.7, and magnesium 2.0 mg/dL (normal range: 1.7–2.2) on 12/26/14. Cisplatin and paclitaxel were administered via IP infusion every 21 days for six cycles beginning on 12/29/14 (day 1). Paclitaxel 135 mg/m2 in 500 ml of normal saline intravenous (IV) over 3 h was administered on day 1. After 1 L of normal saline IV, cisplatin at 75 mg/m2 was given in 1 L of normal saline IP followed by a second liter of normal saline IP, if tolerated. Another liter of normal saline IV was subsequently administered, too. Significant oliguria (concentrated, dark urine estimated at <30 cc h) was observed within 3 h after IP cisplatin. This oliguria and abdominal distention with pain continued for the next 36–48 h despite >2,000 cc oral intake of liquids and an additional liter of normal saline IV the following day.
Because the patient (an internist) recognized the disproportional oliguria, the on-call provider was consulted that evening within 6 h of cisplatin administration, but no action was recommended since the patient still had some urine output. AKI, which manifested as oliguria, was not recognized and stat renal function studies were not ordered. Diuresis had occurred by 1/3/15 when the following tests were obtained prior to having urgent surgery for a fractured wrist due to a fall on ice: BUN 20, Cr 0.74, and magnesium 1.3 mg/dL.
Oral magnesium oxide >500 mg was consumed daily. Intravenous magnesium was not administered unless serum magnesium dropped below 1.5 mg/dL, which was only checked immediately before each cycle of chemotherapy and not in between. On 2/9/15, prior to the next cycle, which had been delayed for 3 weeks due to a wrist fracture, BUN was 22, Cr 0.8, and magnesium 1.8.
The patient continued to experience severe oliguria immediately following cisplatin IP administration, lasting for approximately 48–72 h for the next two cycles, but on day 1 of cycle 4 on 3/25/15, 4 g (32.48 mEq) magnesium sulfate was administered IV prior to chemotherapy for a serum magnesium of 1.0 mg/dL. (Serum magnesium had been 1.6 on 3/2/15). The patient immediately observed normal urinary output on day 2 post-cisplatin and thereafter. In addition, abdomen distention and pain were significantly less than during the prior cycles.
Recognizing this response, the physician-patient completed a literature search regarding the effect of magnesium on cisplatin toxicity and consulted with a scientist who had recently published studies in rodents demonstrating the benefits of pretreating with magnesium to protect against cisplatin-induced AKI (17). Therefore, the patient subsequently requested and received 2 g of magnesium sulfate IV pre-cisplatin (on day 2) for cycles 5 and 6 even though serum magnesium was 1.7 mg/dL. To clearly demonstrate the effectiveness, she recorded the fluid intake and output for day 2, cycle 6: 4,800 cc combined IV, IP, and oral route, with a concomitant urine output of 4,950 cc in 24 h. The patient continued to demonstrate improved tolerance to the IP treatment with the administration of IV magnesium preceding cisplatin.
After completion of the six cycles, on 6/29/15, relevant values were: BUN 19, serum Cr 0.9, and magnesium 1.9. Patient at that time was receiving 1–2 g of IV magnesium weekly and has continued to suffer from persistent hypomagnesemia requiring 600 mg of oral magnesium threonate in divided doses daily to prevent tetany. These effects are presumed due to the irreversible AKI from cycles 1–3 prior to pretreatment with magnesium in subsequent cisplatin cycles. Glomerular filtration rate from 2015 until 2020 has been greater than 59 ml/min and current renal function on 8/27/20 was: BUN 23, Cr 1.04. As a physician, the patient strongly supports this case report to prevent AKI, hypermagnesemia, and the discomfort associated with intraperitoneal cisplatin that was diminished with magnesium preceding cisplatin.
Discussion
Overview of Acute Kidney Injury by Cisplatin
According to the Kidney Disease Improving Global Outcomes (KDIGO), AKI is defined as ≥0.3 mg/dL increase in serum creatinine or a 0.5 ml/kg/h decrease in urine output within 48 h; whereas Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAE v4.0) agrees on serum creatinine increase ≥0.3 mg/dL but with no time consideration (5).
Using CTCAE v4.0 criteria, 26.5% of patients experienced AKI after the first round of cisplatin-based chemotherapy in one retrospective study for urothelial cancer, resulting in >40% being unable to receive the planned second round, and 50% reduction in 3-year survival (5). Consequently, mortality is increased among patients with AKI, frequently due to inability to continue chemotherapy as scheduled (18, 19).
Risk factors for renal damage include people who are older, female, African American (20), smokers, have hypoalbuminemia, prior kidney damage, hypomagnesemia, dehydration, and/or have concomitant medical conditions such as diabetes, liver disease and use of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, diuretic therapy, and non-steroidal anti-inflammatory drugs (16–18).
Cisplatin is freely filtered at the glomeruli but is subsequently absorbed by the proximal tubule cell where it becomes a more potent toxin by multiple enzymatic pathways including gamma glutamyl transpeptidase (GGT), which has the highest activity in the kidneys (2, 6, 21).
However, a consistent amount of cisplatin is secreted from the blood into the urine through the cells of proximal tubules (22). Here, cisplatin uptake is accomplished by the human copper transport protein 1 (Ctr1) and the organic cation transporter 2 (OCT2) (23) located on the basolateral side of the proximal (24) and distal (25) renal tubules, as well as by passive diffusion (26). Concentration in the proximal tubule may be five times greater than the blood (27), with intrinsic damage of the proximal and distal tubules resulting in renal tubular cells death, affecting renal tubular blood flow, decreasing glomerular filtration rate, and preventing reabsorption of magnesium and other electrolytes (2). Excretion from the tubular cells is dependent on multidrug extrusion transporters (MATEs) (6, 28). Although renal tubular cells may recover, fibrotic scarring may occur resulting in chronic kidney disease (CKD) (29).
Bunel et al. (29) in a small human study, identified an increase in urinary biomarkers for acute renal damage within 3 h after cisplatin administration, but a diagnostic rise in plasma creatinine in each patient with AKI was delayed until 3–6 days post-administration, by which time urinary biomarkers had normalized.
Summary of Studies Demonstrating Effectiveness of Magnesium in Humans
In 2019, two systematic reviews and meta-analysis of therapies directed at prevention of cisplatin AKI were published, both suggesting a benefit with pre-administration of IV magnesium (30, 31) (Table 1). Casanova reviewed all placebo-controlled trials published up to 2017 (22 met their criteria), and concluded that 1 g (8 mEq) of IV magnesium before cisplatin reduced AKI (30).
Table 1 Published results on the association between cisplatin-induced AKI* and magnesium administration.
Study Intervention and outcome(s) Results P-value
Hamroun et al. (31)
Drugs Risk of cisplatin-induced AKI* Odds Ratio [95% Confidence Interval]
Magnesium dosage All dosages confounded 0.24 [0.19; 0.32] <0.001
8 mEq 0.23 [0.16; 0.34] <0.001
20 mEq 0.13 [0.06; 0.29] <0.001
25 mEq 0.28 [0.14; 0.54] <0.001
Casanova et al. (30)
Eur J Clin Pharmacol Risk of cisplatin-induced AKI* Odds Ratio [95% Confidence Interval]
Magnesium dosage All dosages confounded 0.22 [0.15; 0.33] <0.001
Modification in serum creatinine levels Mean difference of serum creatinine (mg/dL)
[95% Confidence Interval]
Magnesium dosage All dosages confounded −0.19 [−0.34; −0.05] < 0.001
*AKI, acute kidney injury defined by the 2012 KDIGO-AKI classification.
Hamroun et al. (31) searched Pubmed, Embase, and Web of Science from January 1, 1978, to June 1, 2018, assessing cisplatin AKI as defined by the 2012 AKI-KDIGO classification, which identified stage 1 as either serum creatinine 1.5–1.9 times OR ≥0.3 mg/dL (≥26.5 mmol/L) increase above baseline, or urine output decrease to 0.5 ml/kg/h for 6–12 h; stage 2: serum creatinine 2–2.9 × baseline, or decrease in urine output <0.5 ml/kg/h for × 12 h; stage 3: serum creatinine 3 × baseline or urine output <0.3 ml/kg/h (32). Of 4,520 eligible studies reviewed, 51 articles fulfilled the authors’ selection criteria, which included evaluating 21 different prevention methods. A meta-analysis was only performed on those studies that used magnesium at the same time as the first dose of cisplatin (15 observational involving 1,841 patients), and demonstrated a significant AKI protection for all grades of injury (31). Based upon analysis of the data regarding stage 1 AKI, “25 mEq of magnesium was associated with a significant nephron-protective effect (OR 0.20 [0.12–0.31], with a positive trend test (p = 0.002)” (31).
Magnesium Prevents Renal Toxicity in Animal Studies: Potential Mechanisms
Like humans, laboratory animals exhibit hypomagnesemia and AKI following serial cisplatin doses. Cisplatin specifically targets the proximal tubules, which comprise a significant portion of the kidneys. The proximal tubules contain a high density of epithelial cells with a large number of mitochondria necessary for providing the critical regulatory (pH balance, absorption, and secretion) and endocrine functions of the kidneys. In mice, organic cation transporters 1 and 2 (OCT 1 and OCT2) located on proximal tubule epithelial cells are considered to be the main transporters involved in cisplatin uptake by the renal proximal tubules (33, 34). Thus, this segment of the nephron is most susceptible to cisplatin-induced AKI (35, 36). Once taken up by the renal epithelial cell, cisplatin mediates its acute toxic effects by enhancing inflammation [via the Extracellular Signal Regulated Kinase (ERK) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling and subsequent cytokine production], increasing oxidative stress and by inducing cell death (apoptosis, necrosis, and autophagy).
Animal studies also demonstrate that cisplatin treatment lowers serum magnesium levels (37, 38) and that poor magnesium status enhances cisplatin-induced AKI (17, 37, 39, 40). Although the exact mechanism(s) involved are not completely understood, there is some evidence showing that magnesium absorption is impaired by cisplatin-mediated renal damage, suggesting that magnesium deficiency augments cisplatin uptake (probably via OCT2 and Ctr1) and reduces elimination (via MATE1) by kidney epithelial cells. Most importantly, the nephrotoxicity of cisplatin can be blocked by early and sustained magnesium supplementation in magnesium-deficient animals, preventing irreversible kidney injury (17, 39). Additional data support that the host’s magnesium status regulates multiple pathways associated with cisplatin-induced AKI, including oxidative stress, inflammation and apoptosis, and early magnesium supplementation protects against cisplatin-induced kidney damage through modulating these pathways (17, 40). Finally, while magnesium deficiency was associated with significantly larger tumors in mice and reduced cisplatin-mediated tumor killing in vivo, early magnesium supplementation was shown to protect the kidneys against cisplatin-mediated damage without compromising cisplatin anti-tumor efficacy while additionally potentiating the cytotoxic effect (39, 40). Together, these data strongly support that early magnesium supplementation exerts kidney-protective effects and may improve the anti-tumor efficacy of cisplatin.
Importance of Magnesium Homeostasis and Health Risks Associated with Hypomagnesemia
Over 300 biological enzymes are dependent on magnesium, the second most abundant intracellular cation, and fourth most abundant cation in the body (41). The normal body contains 22–26 g of magnesium; 52.9% in the bone, 27% in the muscle, 19.3 in soft tissue, 0.5% in red blood cells, and 0.3% in the serum (42).
Although magnesium deficiency is almost always asymptomatic (43), it may lead to long-term health problems including but not limited to: affecting cardiac electrical activity, including sudden death; association with insulin resistance, inhibiting acute phase of insulin release in hyperglycemia; contributing to progression of atherosclerosis by affecting lipid concentrations; hypertension; osteoporosis; increase frequency in renal calculi; reactive airway disease; muscle weakness; and multiple non-specific complaints including: fatigue, anorexia, fibromyalgia, tendonopathy, tetany, and mood alterations (41).
Measurement of the serum magnesium level is not an accurate reflection of total body stores. Renal excretion is predominantly responsible for maintaining serum balance with 70–80% of non-protein bound magnesium being filtered at the glomerulus, 95% of the magnesium in plasma is reabsorbed by the kidneys (60% at the ascending loop of Henle and 10% in the distal tubule, resulting in a loss of only 100 mg) (41, 42, 44).
Although not labeled AKI, the most common evidence of early renal damage is hypomagnesemia, first identified in 1979 (45). Hypomagnesemia may enhance the severity of nephrotoxicity (46). In addition, observational studies in humans, similar to those in animals, have demonstrated that premedication with magnesium prior to cisplatin may reduce the nephrotoxicity of magnesium loss. In 1990, Vokes (9) reported a randomized study of 23 patients treated with cisplatin for head and neck cancer using oral magnesium aspartate hydrochloride either by continuous oral magnesium, with dosage being increased or magnesium supplemented intravenously if unable to be tolerated versus intermittent administration only if the serum magnesium level dropped to ≤1.4 mg/dL. All patients receiving intermittent magnesium required magnesium at some point in the study, but 80% of patients receiving continuous magnesium never developed hypomagnesemia in a given cycle. Likewise, Martin et al. (47) demonstrated in 1992 that both intravenous (3 g before each cycle) and oral magnesium supplementation (2 g orally every 8 h, days 2–21 of each cycle) appeared effective in prevention of cisplatin-induced hypomagnesemia in the majority of patients with only mild gastrointestinal side effects observed with the oral group. Vokes concluded that “preventive administration of a magnesium supplement can ameliorate, if not completely eradicate, cisplatin-induced hypomagnesaemia.” (9) Hodgkinson, in 2006, also recommended routine supplementation of magnesium with each cycle of cisplatin to prevent cisplatin-induced hypomagnesemia (48). Most recently, a recent review by Duan supports magnesium administration to prevent AKI in elderly patients receiving cisplatin along with short hydration and amifostine (49).
Intravenous magnesium has been shown to be safe (50) and effective in multiple other medical conditions. It has been used to prevent AKI in contrast-induced nephropathy in primary percutaneous coronary intervention (51) and when administered intraoperatively with major laparoscopic abdominal surgery (52). Magnesium sulfate has been demonstrated to be more effective than anticonvulsants in acute eclampsia and reduces the risk of eclampsia by 50% in pre-eclampsia (41, 53). It has been used for status asthmaticus, torsades de pointes, and a higher concentration of magnesium has been correlated with better survival in chronic kidney disease (54). Lactate clearance has been shown to decrease in critically ill patients with severe sepsis with magnesium supplementation achieving a serum magnesium level near the upper limit of normal.
How exactly IV magnesium prevents AKI when given prior to cisplatin in humans is currently unknown and possibly involves numerous pathways as discussed previously. Although magnesium downregulated the OCT2 transporter and upregulated the MATE transporter, preventing AKI in rats, (55) this was not observed with acute exposure in recent experiments using cells expressing human OCT2 performed by Dr. Ciarimboli (see Figure 1 A–C). Therefore, further studies will be necessary to completely understand how magnesium prevents AKI in humans. Other drugs have demonstrated a downregulation of human OCT2 (hOCT2), protecting against AKI, such as carvedilol, (58) while metformin and cimetidine have been competitive substrates for hOCT2. Research has shown the renal protective effects of both of these agents from cisplatin toxicity (59, 60). However, two meta-analyses have both identified that IV magnesium prevents AKI from cisplatin and recommend it over all other agents at this time.
Figure 1 The effects of Mg2+ on hOCT2 function (A), on hOCT2-mediated Oxaliplatin toxicity (B), and on hMATE1 function (C). Function of the transporters was measured as uptake (hOCT2) or efflux (hMATE1) of the fluorescent organic cation 4-[4-(dimethylamino)styryl]-N-methylpyridinium (ASP+) as described in Wilde et al. (56) and Kantauskaite et al. (57) Panel (A) shows the changes of ASP+ uptake by hOCT2 stably expressed in Human Embryonic Kidney (HEK) cells in dependence from extracellular Mg2+ concentration compared to what was measured in Mg2+ absence (mean ± SEM). Only 1 mM Mg2+ significantly increased ASP+ uptake by hOCT2 (Kruskal–Wallis test with Dunn’s multiple comparison test). The presence of Mg2+ stimulates the activity of hOCT2, a transporter mediating nephrotoxicity of platinum derivatives, therefore regulation of hOCT2 by Mg2+ cannot explain Mg2+ protective effects against cisplatin nephrotoxicity. (B) shows the effects of Mg2+ supplementation (1 mM) on toxicity of 100 µM Oxaliplatin measured with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in hOCT2 overexpressing HEK cells (mean ± SEM). The presence of 1 mM Mg2+ does not protect the cells against hOCT2-mediated Oxaliplatin toxicity. Finally, (C) shows the changes of ASP+ efflux by hMATE1 stably expressed in HEK cells in dependence from extracellular Mg2+ concentration compared to what measured in Mg2+ absence (mean ± SEM). The extracellular presence of 1 mM Mg2+ slightly but significantly decreases the function of hMATE1 (Mann–Whitney-test), which is an efflux transporter for platinum derivatives. Therefore, also a regulation of hMATE1 by Mg2+ cannot explain Mg2+ protective effects against cisplatin nephrotoxicity. In (A, C) the numbers above the columns represent the number of replicates measured in at least three independent experiments. In (B) they represent the number of independent experiments.
Conclusion
Currently, there is no dispute regarding the renal toxicity associated with cisplatin. AKI, based on elevation of serum creatinine or decreased urine output, occurs in approximately one-third of all patients receiving cisplatin. Hypomagnesemia occurs in 40–100% of patients following cisplatin and may persist long after chemotherapy completion, reflecting irreversible cisplatin-mediated kidney damage. What has been controversial is the administration of IV magnesium prior to each dose of cisplatin, rather than after inevitable hypomagnesemia is subsequently identified. Compelling recent reviews of human trials and animal studies clearly support the pre-administration of IV magnesium for ameliorating both AKI and hypomagnesemia. Acute cisplatin-induced nephrotoxicity (including AKI and hypomagnesemia) may cause persistent and irreversible kidney impairment, resulting in further health complications.
Hesitancy regarding IV magnesium prior to cisplatin may have originated from the early termination of the Combined Oxaliplatin Neurotoxicity Prevention (CONcePT) in 2007, in which calcium/magnesium was infused before oxaliplatin chemotherapy for colon cancer to prevent neurotoxicity. Although initial data suggested a 52% reduction in oxaliplatin’s killing efficacy following calcium/magnesium administration, (61) this was subsequently reversed in 2008 and Wu, in 2012, published a systematic review concluding that IV calcium/magnesium does not impair oxaliplatin effectiveness (56). In addition, there has been no evidence in any of the trials analyzed that magnesium affected the chemotherapeutic effect of cisplatin, and a higher magnesium level actually potentiated cisplatin chemotherapeutic effect in mice (40). Finally, the OCT2 transporter that is involved in the cisplatin/oxaliplatin uptake and subsequent AKI has not been identified in tumors.
This case report along with supporting documentation provided by both clinical and pre-clinical studies clearly demonstrate the effectiveness of IV magnesium before cisplatin in preventing acute kidney injury manifested by oliguria. We recommend that at least 2 g of magnesium be administered prior to cisplatin since a recent study by Uhm found that 1 g still resulted in 33% of patients developing hypomagnesium (57), while a study by Hase supported the use of 20 mEq/L or approximately 2.5 g. (62)
Therefore, if we are to follow our oath to do no harm, it is imperative that IV magnesium administration with cisplatin become a “best practice” guideline at all oncology centers.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MM: concept for paper and case report. AH: review of human studies and comparison of recent meta-analyses, and development of table comparing these. CM: editing and review of paper. YS: review of renal receptors and effect of magnesium on them. CNM: summary of research in animals and editing of manuscript. SE: assistance in experiments using magnesium with human renal transporters GC: development and analysis of experiments using magnesium with human renal transporters. All authors contributed to the article and approved the submitted version.
Funding
Source for funding: Medical Research Fund Community Foundation of Washington County, Inc 37 S. Potomac Street Hagerstown, MD 21740.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Not recovered | ReactionOutcome | CC BY | 33718160 | 19,163,200 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Liver injury'. | Case Report: Complete Response of Recurrent and Metastatic Cystadenocarcinoma of the Parotid Gland With a Single Course of Combined Nivolumab and Ipilimumab Therapy.
Although cystadenocarcinoma is classified as a low-grade histological subtype of salivary gland carcinoma (SGC), recurrence and metastases sometimes develop. However, standard treatments for advanced cases have not yet been established. Here, we present a case of unresectable local recurrence and cervical lymph node metastases of cystadenocarcinoma of the parotid gland with multiple lung nodules, all of which showed complete response with only a single course of combined nivolumab and ipilimumab therapy. The patient's medical history of metastatic melanoma roused our suspicions that the multiple lung nodules were cystadenocarcinoma metastases or malignant melanoma. Combination therapy was used based on our suspected diagnosis of lung metastases of melanoma although histological examination of the lung nodules could not be performed. While various chemotherapies are used for advanced SGCs including cystadenocarcinoma, overall, the results are unsatisfactory. In contrast, there have not yet been any reports of advanced cystadenocarcinoma of the salivary gland treated with immune checkpoint inhibitors (ICIs). Given that, in our case, a single course of combined ICI therapy induced a complete response in the unresectable and lymph node metastases from the cystadenocarcinoma and the multiple lung nodules, ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Introduction
Salivary gland carcinomas (SGCs) are relatively rare, and the most common histopathological SGC types are mucoepidermoid carcinoma and adenoid cystic carcinoma (1). In contrast, cystadenocarcinoma is extremely rare, with the estimated incidence being only 2% of all SGCs (2). Although cystadenocarcinoma is classified as a low-grade histological subtype of SGC, recurrence and metastases sometimes develop (2, 3). However, standard treatments for advanced cases have not been established (3). Here, we present a case of unresectable, metastatic cystadenocarcinoma of the parotid gland with multiple lung nodules suspected to be metastatic lesions of cystadenocarcinoma or malignant melanoma, all of which showed complete response (CR) with a single course of combined nivolumab and ipilimumab therapy.
Case Description
A 65-year old man noticed a cutaneous nodule on his left forearm, which had gradually grown. He had a medical history of diabetes mellitus and hypertension. The cutaneous nodule was resected, and was diagnosed to be malignant melanoma. He was referred to our hospital, and underwent wide resection with left axillar lymph node (LN) dissection. The surgical margin of the primary tumor was negative, and one out of the 11 dissected LNs showed metastases. 1 year after the surgery, computed tomography (CT) revealed a nodule in the right parotid gland. The nodule was resected, and histological analyses revealed multiple cysts of various sizes lined by cuboidal, eosinophilic cells with mild to moderate atypia (Figures 1A–C). The cyst lumen contained eosinophilic materials, and some of the cuboidal cells showed decapitation secretion (Figures 1A–C). There were no myoepithelial cells around the luminal cells. In some parts, the tumor cells showed microinvasion. From these findings, a diagnosis of cystadenocarcinoma was made. 4 months after the resection, a nodule with cystadenocarcinoma recurred in the right parotid gland, and right superficial parotidectomy was performed. The surgical margin was negative, and the patient received postoperative irradiation with 60Gy. At 4 and 6 years after the parotidectomy, resection was performed on two cutaneous nodules with metastatic melanoma that appeared on the left forearm (Figure 1D). PD-L1 expression level was <1%, and BRAF mutations were not detected. 9 years after the parotidectomy, positron emission tomography (PET)-CT revealed a 40 × 40 mm mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose (FDG) accumulation (Figure 1E). In addition, multiple small nodules appeared in the lung. The mass in the parotid gland was resected, and histological analyses revealed multiple cysts with frequent papillary projection consisting of a proliferation of cuboidal cells with pleomorphism, indicating recurrent cystadenocarcinoma (Figure 1F). Tumor nests had invaded into the fibrotic stroma and multiple perineural invasions were also observed (Figures 1G,H). Because the mass had extended widely, it could not be completely excised and large parts of the surgical margin remained positive. 8 months after the last surgery, PET-CT revealed an irregularly shaped mass with high FDG accumulation below the surgical wound of the parotid gland (Figure 2A). In addition, right upper deep cervical LNs also showed high FDG accumulation (Figure 2B), indicating local recurrence and cervical LN metastases of cystadenocarcinoma. The size and number of lung nodules had also increased (Figures 2C,D). Because the lung nodules and the mass of recurrent cystadenocarcinoma appeared simultaneously, the nodules may be lung metastases of the cystadenocarcinoma. However, the lung nodules were also suspected to be metastatic melanoma because of the patient's medical history of lymph node and multiple skin metastases of melanoma. The patient would not agree to proposed partial lung resection for histological examination of the nodules. Therefore, based on our suspected diagnosis of lung metastases of melanoma, we proposed treatment with either anti-PD-1 antibody monotherapy or nivolumab and ipilimumab combination therapy. He selected the combination therapy, and was treated with combined nivolumab (80 mg/body) and ipilimumab (3 mg/kg) therapy. 2 weeks after the first administration of these antibodies, he developed Grade 4 liver injury, which required cessation of the treatment and a high-dose oral steroid with mycophenolate mofetil followed by steroid pulse therapy for improvement of the liver injury. However, PET-CT 4 months after the single course of the combination therapy showed that the FDG accumulation of both the mass below the surgical wound of the parotid gland and the cervical LNs had disappeared (Figures 2A,B). In addition, all of the lung nodules had disappeared (Figures 2C,D), suggesting that the combination therapy induced CR. At 10 months' follow-up after the immune checkpoint inhibitor (ICI) treatment, there was no recurrence.
Figure 1 (A) Multiple cysts of various size lined by cuboidal, eosinophilic cells, which contained eosinophilic materials (Hematoxylin and eosin [HE], ×40). (B) The tumor cells showed mild to moderate atypia (HE, ×400). (C) Some of the tumor cells showed decapitation secretion (HE, ×400). (D) The cutaneous nodules revealed proliferation of large atypical epithelioid cell with melanin pigmentation, suggesting metastatic melanoma (HE, ×400). (E) Positron emission tomography-computed tomography revealed a mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose accumulation. (F) Multiple cysts with frequent papillary projection consisting of the proliferation of cuboidal cells with pleomorphism (HE, ×200). (G,H). Tumor nests invaded into the fibrotic stroma, and multiple perineural invasions were also observed (HE, ×200).
Figure 2 (A–D) Fluorodeoxyglucose (FDG) accumulation of the mass below the surgical wound of the parotid gland (A) and right upper deep cervical lymph nodes (LNs) (B), and multiple lung nodules (C,D) disappeared after a single course of combined nivolumab and ipilimumab therapy. Left and right panels indicate positron emission tomography-computed tomography (PET-CT) (A,B) or CT (C,D) before and 4 months after a single course of combined therapy, respectively. Arrow heads indicate the mass below the surgical wound of the parotid gland (A) and the cervical LNs (B) with high FDG accumulation, respectively. (E) Some of the tumor cells of the recurrent cystadenocarcinoma were positive for PD-L1 (clone: sp142, ×200).
Discussion
In our case, the mass below the surgical wound and the cervical LNs with high FDG accumulation were regarded as local recurrence and metastases of the cystadenocarcinoma, respectively. However, it was unclear whether the multiple lung nodules were metastases of cystadenocarcinoma or melanoma. Management of advanced melanoma is rapidly evolving, and recent clinical trials revealed that ICIs, such as anti-PD-1 antibody (nivolumab, pembrolizumab) and anti-CTLA-4 antibody (ipilimumab), significantly prolonged the survival of melanoma patients (4–6). Despite having higher rates of adverse events (AEs), nivolumab and ipilimumab combination therapy is known to show higher efficacy compared with either agent alone (7). Based on the suspected diagnosis of metastatic melanoma of the lung and according to the patient's intent, we treated the lesions with this combination therapy. As a result, despite the occurrence of severe liver AE, only a single course of the therapy induced CR.
Cystadenocarcinoma is characterized by prominent cystic structures lined with cuboidal, columnar or mucus-secreting cells, but lacking features of other specific SGC types (8). Although most cases of cystadenocarcinoma show an indolent behavior, recurrence and LN metastases may also develop (9, 10). In addition, cases showing distant metastases such as lung and bone metastases have been reported (3). While various chemotherapies are used for advanced SGCs and their efficacy may be dependent on histological type, overall, the results are unsatisfactory and there have been no reports of significant tumor responses to systemic chemotherapies in advanced cystadenocarcinoma (1, 11–13).
Programmed death ligand 1 (PD-L1) expression in SGC tumor cells is frequently observed, indicating that it may play an important role in the immune tolerance and progression of SGC (14). On examining PD-L1 expression, it was detected in more than 5% of the tumor cells of the recurrent cystadenocarcinoma although not in the metastatic melanoma (Figure 2E). In contrast, Ross et al. analyzed tumor mutation burden (TMB), which is known to be associated with favorable tumor response to ICIs, in 623 cases of SGC, and reported that the TMB of SGC was significantly lower than that of other tumor types for which ICIs were approved such as melanoma and breast cancer, although cases of cystadenocarcinoma were not included in this study (15). Consistently, recent studies demonstrated limited efficacy of anti-PD-1 monotherapy for advanced SGCs (16–18). However, there were no cases of cystadenocarcinoma within these studies, and there have been no reports of advanced cystadenocarcinoma of the salivary gland treated with ICIs. In our patient, the recurrent tumor of the parotid gland and cervical LN metastases of cystadenocarcinoma as well as the multiple lung nodules achieved CR with only a single course of combined nivolumab and ipilimumab therapy. Thus, our case suggests that ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
This patient has provided written, informed consent for publication. A copy of the signed consent form is available on request.
Author Contributions
YN, MN, and BN designed the study. NO, RT, YI, SM, and YF interpreted the results. YN and MN wrote the manuscript. All authors reviewed the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Dr. Thomas D. Mayers of the University of Tsukuba Medical English Communication Center for English editing of this manuscript. We also thank Yuriko Hirota (Department of Dermatology, Faculty of Medicine, University of Tsukuba) for the technical support. | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY | 33718174 | 19,095,795 | 2021 |
What was the administration route of drug 'IPILIMUMAB'? | Case Report: Complete Response of Recurrent and Metastatic Cystadenocarcinoma of the Parotid Gland With a Single Course of Combined Nivolumab and Ipilimumab Therapy.
Although cystadenocarcinoma is classified as a low-grade histological subtype of salivary gland carcinoma (SGC), recurrence and metastases sometimes develop. However, standard treatments for advanced cases have not yet been established. Here, we present a case of unresectable local recurrence and cervical lymph node metastases of cystadenocarcinoma of the parotid gland with multiple lung nodules, all of which showed complete response with only a single course of combined nivolumab and ipilimumab therapy. The patient's medical history of metastatic melanoma roused our suspicions that the multiple lung nodules were cystadenocarcinoma metastases or malignant melanoma. Combination therapy was used based on our suspected diagnosis of lung metastases of melanoma although histological examination of the lung nodules could not be performed. While various chemotherapies are used for advanced SGCs including cystadenocarcinoma, overall, the results are unsatisfactory. In contrast, there have not yet been any reports of advanced cystadenocarcinoma of the salivary gland treated with immune checkpoint inhibitors (ICIs). Given that, in our case, a single course of combined ICI therapy induced a complete response in the unresectable and lymph node metastases from the cystadenocarcinoma and the multiple lung nodules, ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Introduction
Salivary gland carcinomas (SGCs) are relatively rare, and the most common histopathological SGC types are mucoepidermoid carcinoma and adenoid cystic carcinoma (1). In contrast, cystadenocarcinoma is extremely rare, with the estimated incidence being only 2% of all SGCs (2). Although cystadenocarcinoma is classified as a low-grade histological subtype of SGC, recurrence and metastases sometimes develop (2, 3). However, standard treatments for advanced cases have not been established (3). Here, we present a case of unresectable, metastatic cystadenocarcinoma of the parotid gland with multiple lung nodules suspected to be metastatic lesions of cystadenocarcinoma or malignant melanoma, all of which showed complete response (CR) with a single course of combined nivolumab and ipilimumab therapy.
Case Description
A 65-year old man noticed a cutaneous nodule on his left forearm, which had gradually grown. He had a medical history of diabetes mellitus and hypertension. The cutaneous nodule was resected, and was diagnosed to be malignant melanoma. He was referred to our hospital, and underwent wide resection with left axillar lymph node (LN) dissection. The surgical margin of the primary tumor was negative, and one out of the 11 dissected LNs showed metastases. 1 year after the surgery, computed tomography (CT) revealed a nodule in the right parotid gland. The nodule was resected, and histological analyses revealed multiple cysts of various sizes lined by cuboidal, eosinophilic cells with mild to moderate atypia (Figures 1A–C). The cyst lumen contained eosinophilic materials, and some of the cuboidal cells showed decapitation secretion (Figures 1A–C). There were no myoepithelial cells around the luminal cells. In some parts, the tumor cells showed microinvasion. From these findings, a diagnosis of cystadenocarcinoma was made. 4 months after the resection, a nodule with cystadenocarcinoma recurred in the right parotid gland, and right superficial parotidectomy was performed. The surgical margin was negative, and the patient received postoperative irradiation with 60Gy. At 4 and 6 years after the parotidectomy, resection was performed on two cutaneous nodules with metastatic melanoma that appeared on the left forearm (Figure 1D). PD-L1 expression level was <1%, and BRAF mutations were not detected. 9 years after the parotidectomy, positron emission tomography (PET)-CT revealed a 40 × 40 mm mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose (FDG) accumulation (Figure 1E). In addition, multiple small nodules appeared in the lung. The mass in the parotid gland was resected, and histological analyses revealed multiple cysts with frequent papillary projection consisting of a proliferation of cuboidal cells with pleomorphism, indicating recurrent cystadenocarcinoma (Figure 1F). Tumor nests had invaded into the fibrotic stroma and multiple perineural invasions were also observed (Figures 1G,H). Because the mass had extended widely, it could not be completely excised and large parts of the surgical margin remained positive. 8 months after the last surgery, PET-CT revealed an irregularly shaped mass with high FDG accumulation below the surgical wound of the parotid gland (Figure 2A). In addition, right upper deep cervical LNs also showed high FDG accumulation (Figure 2B), indicating local recurrence and cervical LN metastases of cystadenocarcinoma. The size and number of lung nodules had also increased (Figures 2C,D). Because the lung nodules and the mass of recurrent cystadenocarcinoma appeared simultaneously, the nodules may be lung metastases of the cystadenocarcinoma. However, the lung nodules were also suspected to be metastatic melanoma because of the patient's medical history of lymph node and multiple skin metastases of melanoma. The patient would not agree to proposed partial lung resection for histological examination of the nodules. Therefore, based on our suspected diagnosis of lung metastases of melanoma, we proposed treatment with either anti-PD-1 antibody monotherapy or nivolumab and ipilimumab combination therapy. He selected the combination therapy, and was treated with combined nivolumab (80 mg/body) and ipilimumab (3 mg/kg) therapy. 2 weeks after the first administration of these antibodies, he developed Grade 4 liver injury, which required cessation of the treatment and a high-dose oral steroid with mycophenolate mofetil followed by steroid pulse therapy for improvement of the liver injury. However, PET-CT 4 months after the single course of the combination therapy showed that the FDG accumulation of both the mass below the surgical wound of the parotid gland and the cervical LNs had disappeared (Figures 2A,B). In addition, all of the lung nodules had disappeared (Figures 2C,D), suggesting that the combination therapy induced CR. At 10 months' follow-up after the immune checkpoint inhibitor (ICI) treatment, there was no recurrence.
Figure 1 (A) Multiple cysts of various size lined by cuboidal, eosinophilic cells, which contained eosinophilic materials (Hematoxylin and eosin [HE], ×40). (B) The tumor cells showed mild to moderate atypia (HE, ×400). (C) Some of the tumor cells showed decapitation secretion (HE, ×400). (D) The cutaneous nodules revealed proliferation of large atypical epithelioid cell with melanin pigmentation, suggesting metastatic melanoma (HE, ×400). (E) Positron emission tomography-computed tomography revealed a mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose accumulation. (F) Multiple cysts with frequent papillary projection consisting of the proliferation of cuboidal cells with pleomorphism (HE, ×200). (G,H). Tumor nests invaded into the fibrotic stroma, and multiple perineural invasions were also observed (HE, ×200).
Figure 2 (A–D) Fluorodeoxyglucose (FDG) accumulation of the mass below the surgical wound of the parotid gland (A) and right upper deep cervical lymph nodes (LNs) (B), and multiple lung nodules (C,D) disappeared after a single course of combined nivolumab and ipilimumab therapy. Left and right panels indicate positron emission tomography-computed tomography (PET-CT) (A,B) or CT (C,D) before and 4 months after a single course of combined therapy, respectively. Arrow heads indicate the mass below the surgical wound of the parotid gland (A) and the cervical LNs (B) with high FDG accumulation, respectively. (E) Some of the tumor cells of the recurrent cystadenocarcinoma were positive for PD-L1 (clone: sp142, ×200).
Discussion
In our case, the mass below the surgical wound and the cervical LNs with high FDG accumulation were regarded as local recurrence and metastases of the cystadenocarcinoma, respectively. However, it was unclear whether the multiple lung nodules were metastases of cystadenocarcinoma or melanoma. Management of advanced melanoma is rapidly evolving, and recent clinical trials revealed that ICIs, such as anti-PD-1 antibody (nivolumab, pembrolizumab) and anti-CTLA-4 antibody (ipilimumab), significantly prolonged the survival of melanoma patients (4–6). Despite having higher rates of adverse events (AEs), nivolumab and ipilimumab combination therapy is known to show higher efficacy compared with either agent alone (7). Based on the suspected diagnosis of metastatic melanoma of the lung and according to the patient's intent, we treated the lesions with this combination therapy. As a result, despite the occurrence of severe liver AE, only a single course of the therapy induced CR.
Cystadenocarcinoma is characterized by prominent cystic structures lined with cuboidal, columnar or mucus-secreting cells, but lacking features of other specific SGC types (8). Although most cases of cystadenocarcinoma show an indolent behavior, recurrence and LN metastases may also develop (9, 10). In addition, cases showing distant metastases such as lung and bone metastases have been reported (3). While various chemotherapies are used for advanced SGCs and their efficacy may be dependent on histological type, overall, the results are unsatisfactory and there have been no reports of significant tumor responses to systemic chemotherapies in advanced cystadenocarcinoma (1, 11–13).
Programmed death ligand 1 (PD-L1) expression in SGC tumor cells is frequently observed, indicating that it may play an important role in the immune tolerance and progression of SGC (14). On examining PD-L1 expression, it was detected in more than 5% of the tumor cells of the recurrent cystadenocarcinoma although not in the metastatic melanoma (Figure 2E). In contrast, Ross et al. analyzed tumor mutation burden (TMB), which is known to be associated with favorable tumor response to ICIs, in 623 cases of SGC, and reported that the TMB of SGC was significantly lower than that of other tumor types for which ICIs were approved such as melanoma and breast cancer, although cases of cystadenocarcinoma were not included in this study (15). Consistently, recent studies demonstrated limited efficacy of anti-PD-1 monotherapy for advanced SGCs (16–18). However, there were no cases of cystadenocarcinoma within these studies, and there have been no reports of advanced cystadenocarcinoma of the salivary gland treated with ICIs. In our patient, the recurrent tumor of the parotid gland and cervical LN metastases of cystadenocarcinoma as well as the multiple lung nodules achieved CR with only a single course of combined nivolumab and ipilimumab therapy. Thus, our case suggests that ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
This patient has provided written, informed consent for publication. A copy of the signed consent form is available on request.
Author Contributions
YN, MN, and BN designed the study. NO, RT, YI, SM, and YF interpreted the results. YN and MN wrote the manuscript. All authors reviewed the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Dr. Thomas D. Mayers of the University of Tsukuba Medical English Communication Center for English editing of this manuscript. We also thank Yuriko Hirota (Department of Dermatology, Faculty of Medicine, University of Tsukuba) for the technical support. | Intravenous drip | DrugAdministrationRoute | CC BY | 33718174 | 19,095,795 | 2021 |
What was the administration route of drug 'NIVOLUMAB'? | Case Report: Complete Response of Recurrent and Metastatic Cystadenocarcinoma of the Parotid Gland With a Single Course of Combined Nivolumab and Ipilimumab Therapy.
Although cystadenocarcinoma is classified as a low-grade histological subtype of salivary gland carcinoma (SGC), recurrence and metastases sometimes develop. However, standard treatments for advanced cases have not yet been established. Here, we present a case of unresectable local recurrence and cervical lymph node metastases of cystadenocarcinoma of the parotid gland with multiple lung nodules, all of which showed complete response with only a single course of combined nivolumab and ipilimumab therapy. The patient's medical history of metastatic melanoma roused our suspicions that the multiple lung nodules were cystadenocarcinoma metastases or malignant melanoma. Combination therapy was used based on our suspected diagnosis of lung metastases of melanoma although histological examination of the lung nodules could not be performed. While various chemotherapies are used for advanced SGCs including cystadenocarcinoma, overall, the results are unsatisfactory. In contrast, there have not yet been any reports of advanced cystadenocarcinoma of the salivary gland treated with immune checkpoint inhibitors (ICIs). Given that, in our case, a single course of combined ICI therapy induced a complete response in the unresectable and lymph node metastases from the cystadenocarcinoma and the multiple lung nodules, ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Introduction
Salivary gland carcinomas (SGCs) are relatively rare, and the most common histopathological SGC types are mucoepidermoid carcinoma and adenoid cystic carcinoma (1). In contrast, cystadenocarcinoma is extremely rare, with the estimated incidence being only 2% of all SGCs (2). Although cystadenocarcinoma is classified as a low-grade histological subtype of SGC, recurrence and metastases sometimes develop (2, 3). However, standard treatments for advanced cases have not been established (3). Here, we present a case of unresectable, metastatic cystadenocarcinoma of the parotid gland with multiple lung nodules suspected to be metastatic lesions of cystadenocarcinoma or malignant melanoma, all of which showed complete response (CR) with a single course of combined nivolumab and ipilimumab therapy.
Case Description
A 65-year old man noticed a cutaneous nodule on his left forearm, which had gradually grown. He had a medical history of diabetes mellitus and hypertension. The cutaneous nodule was resected, and was diagnosed to be malignant melanoma. He was referred to our hospital, and underwent wide resection with left axillar lymph node (LN) dissection. The surgical margin of the primary tumor was negative, and one out of the 11 dissected LNs showed metastases. 1 year after the surgery, computed tomography (CT) revealed a nodule in the right parotid gland. The nodule was resected, and histological analyses revealed multiple cysts of various sizes lined by cuboidal, eosinophilic cells with mild to moderate atypia (Figures 1A–C). The cyst lumen contained eosinophilic materials, and some of the cuboidal cells showed decapitation secretion (Figures 1A–C). There were no myoepithelial cells around the luminal cells. In some parts, the tumor cells showed microinvasion. From these findings, a diagnosis of cystadenocarcinoma was made. 4 months after the resection, a nodule with cystadenocarcinoma recurred in the right parotid gland, and right superficial parotidectomy was performed. The surgical margin was negative, and the patient received postoperative irradiation with 60Gy. At 4 and 6 years after the parotidectomy, resection was performed on two cutaneous nodules with metastatic melanoma that appeared on the left forearm (Figure 1D). PD-L1 expression level was <1%, and BRAF mutations were not detected. 9 years after the parotidectomy, positron emission tomography (PET)-CT revealed a 40 × 40 mm mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose (FDG) accumulation (Figure 1E). In addition, multiple small nodules appeared in the lung. The mass in the parotid gland was resected, and histological analyses revealed multiple cysts with frequent papillary projection consisting of a proliferation of cuboidal cells with pleomorphism, indicating recurrent cystadenocarcinoma (Figure 1F). Tumor nests had invaded into the fibrotic stroma and multiple perineural invasions were also observed (Figures 1G,H). Because the mass had extended widely, it could not be completely excised and large parts of the surgical margin remained positive. 8 months after the last surgery, PET-CT revealed an irregularly shaped mass with high FDG accumulation below the surgical wound of the parotid gland (Figure 2A). In addition, right upper deep cervical LNs also showed high FDG accumulation (Figure 2B), indicating local recurrence and cervical LN metastases of cystadenocarcinoma. The size and number of lung nodules had also increased (Figures 2C,D). Because the lung nodules and the mass of recurrent cystadenocarcinoma appeared simultaneously, the nodules may be lung metastases of the cystadenocarcinoma. However, the lung nodules were also suspected to be metastatic melanoma because of the patient's medical history of lymph node and multiple skin metastases of melanoma. The patient would not agree to proposed partial lung resection for histological examination of the nodules. Therefore, based on our suspected diagnosis of lung metastases of melanoma, we proposed treatment with either anti-PD-1 antibody monotherapy or nivolumab and ipilimumab combination therapy. He selected the combination therapy, and was treated with combined nivolumab (80 mg/body) and ipilimumab (3 mg/kg) therapy. 2 weeks after the first administration of these antibodies, he developed Grade 4 liver injury, which required cessation of the treatment and a high-dose oral steroid with mycophenolate mofetil followed by steroid pulse therapy for improvement of the liver injury. However, PET-CT 4 months after the single course of the combination therapy showed that the FDG accumulation of both the mass below the surgical wound of the parotid gland and the cervical LNs had disappeared (Figures 2A,B). In addition, all of the lung nodules had disappeared (Figures 2C,D), suggesting that the combination therapy induced CR. At 10 months' follow-up after the immune checkpoint inhibitor (ICI) treatment, there was no recurrence.
Figure 1 (A) Multiple cysts of various size lined by cuboidal, eosinophilic cells, which contained eosinophilic materials (Hematoxylin and eosin [HE], ×40). (B) The tumor cells showed mild to moderate atypia (HE, ×400). (C) Some of the tumor cells showed decapitation secretion (HE, ×400). (D) The cutaneous nodules revealed proliferation of large atypical epithelioid cell with melanin pigmentation, suggesting metastatic melanoma (HE, ×400). (E) Positron emission tomography-computed tomography revealed a mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose accumulation. (F) Multiple cysts with frequent papillary projection consisting of the proliferation of cuboidal cells with pleomorphism (HE, ×200). (G,H). Tumor nests invaded into the fibrotic stroma, and multiple perineural invasions were also observed (HE, ×200).
Figure 2 (A–D) Fluorodeoxyglucose (FDG) accumulation of the mass below the surgical wound of the parotid gland (A) and right upper deep cervical lymph nodes (LNs) (B), and multiple lung nodules (C,D) disappeared after a single course of combined nivolumab and ipilimumab therapy. Left and right panels indicate positron emission tomography-computed tomography (PET-CT) (A,B) or CT (C,D) before and 4 months after a single course of combined therapy, respectively. Arrow heads indicate the mass below the surgical wound of the parotid gland (A) and the cervical LNs (B) with high FDG accumulation, respectively. (E) Some of the tumor cells of the recurrent cystadenocarcinoma were positive for PD-L1 (clone: sp142, ×200).
Discussion
In our case, the mass below the surgical wound and the cervical LNs with high FDG accumulation were regarded as local recurrence and metastases of the cystadenocarcinoma, respectively. However, it was unclear whether the multiple lung nodules were metastases of cystadenocarcinoma or melanoma. Management of advanced melanoma is rapidly evolving, and recent clinical trials revealed that ICIs, such as anti-PD-1 antibody (nivolumab, pembrolizumab) and anti-CTLA-4 antibody (ipilimumab), significantly prolonged the survival of melanoma patients (4–6). Despite having higher rates of adverse events (AEs), nivolumab and ipilimumab combination therapy is known to show higher efficacy compared with either agent alone (7). Based on the suspected diagnosis of metastatic melanoma of the lung and according to the patient's intent, we treated the lesions with this combination therapy. As a result, despite the occurrence of severe liver AE, only a single course of the therapy induced CR.
Cystadenocarcinoma is characterized by prominent cystic structures lined with cuboidal, columnar or mucus-secreting cells, but lacking features of other specific SGC types (8). Although most cases of cystadenocarcinoma show an indolent behavior, recurrence and LN metastases may also develop (9, 10). In addition, cases showing distant metastases such as lung and bone metastases have been reported (3). While various chemotherapies are used for advanced SGCs and their efficacy may be dependent on histological type, overall, the results are unsatisfactory and there have been no reports of significant tumor responses to systemic chemotherapies in advanced cystadenocarcinoma (1, 11–13).
Programmed death ligand 1 (PD-L1) expression in SGC tumor cells is frequently observed, indicating that it may play an important role in the immune tolerance and progression of SGC (14). On examining PD-L1 expression, it was detected in more than 5% of the tumor cells of the recurrent cystadenocarcinoma although not in the metastatic melanoma (Figure 2E). In contrast, Ross et al. analyzed tumor mutation burden (TMB), which is known to be associated with favorable tumor response to ICIs, in 623 cases of SGC, and reported that the TMB of SGC was significantly lower than that of other tumor types for which ICIs were approved such as melanoma and breast cancer, although cases of cystadenocarcinoma were not included in this study (15). Consistently, recent studies demonstrated limited efficacy of anti-PD-1 monotherapy for advanced SGCs (16–18). However, there were no cases of cystadenocarcinoma within these studies, and there have been no reports of advanced cystadenocarcinoma of the salivary gland treated with ICIs. In our patient, the recurrent tumor of the parotid gland and cervical LN metastases of cystadenocarcinoma as well as the multiple lung nodules achieved CR with only a single course of combined nivolumab and ipilimumab therapy. Thus, our case suggests that ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
This patient has provided written, informed consent for publication. A copy of the signed consent form is available on request.
Author Contributions
YN, MN, and BN designed the study. NO, RT, YI, SM, and YF interpreted the results. YN and MN wrote the manuscript. All authors reviewed the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Dr. Thomas D. Mayers of the University of Tsukuba Medical English Communication Center for English editing of this manuscript. We also thank Yuriko Hirota (Department of Dermatology, Faculty of Medicine, University of Tsukuba) for the technical support. | Intravenous drip | DrugAdministrationRoute | CC BY | 33718174 | 19,095,795 | 2021 |
What was the dosage of drug 'IPILIMUMAB'? | Case Report: Complete Response of Recurrent and Metastatic Cystadenocarcinoma of the Parotid Gland With a Single Course of Combined Nivolumab and Ipilimumab Therapy.
Although cystadenocarcinoma is classified as a low-grade histological subtype of salivary gland carcinoma (SGC), recurrence and metastases sometimes develop. However, standard treatments for advanced cases have not yet been established. Here, we present a case of unresectable local recurrence and cervical lymph node metastases of cystadenocarcinoma of the parotid gland with multiple lung nodules, all of which showed complete response with only a single course of combined nivolumab and ipilimumab therapy. The patient's medical history of metastatic melanoma roused our suspicions that the multiple lung nodules were cystadenocarcinoma metastases or malignant melanoma. Combination therapy was used based on our suspected diagnosis of lung metastases of melanoma although histological examination of the lung nodules could not be performed. While various chemotherapies are used for advanced SGCs including cystadenocarcinoma, overall, the results are unsatisfactory. In contrast, there have not yet been any reports of advanced cystadenocarcinoma of the salivary gland treated with immune checkpoint inhibitors (ICIs). Given that, in our case, a single course of combined ICI therapy induced a complete response in the unresectable and lymph node metastases from the cystadenocarcinoma and the multiple lung nodules, ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Introduction
Salivary gland carcinomas (SGCs) are relatively rare, and the most common histopathological SGC types are mucoepidermoid carcinoma and adenoid cystic carcinoma (1). In contrast, cystadenocarcinoma is extremely rare, with the estimated incidence being only 2% of all SGCs (2). Although cystadenocarcinoma is classified as a low-grade histological subtype of SGC, recurrence and metastases sometimes develop (2, 3). However, standard treatments for advanced cases have not been established (3). Here, we present a case of unresectable, metastatic cystadenocarcinoma of the parotid gland with multiple lung nodules suspected to be metastatic lesions of cystadenocarcinoma or malignant melanoma, all of which showed complete response (CR) with a single course of combined nivolumab and ipilimumab therapy.
Case Description
A 65-year old man noticed a cutaneous nodule on his left forearm, which had gradually grown. He had a medical history of diabetes mellitus and hypertension. The cutaneous nodule was resected, and was diagnosed to be malignant melanoma. He was referred to our hospital, and underwent wide resection with left axillar lymph node (LN) dissection. The surgical margin of the primary tumor was negative, and one out of the 11 dissected LNs showed metastases. 1 year after the surgery, computed tomography (CT) revealed a nodule in the right parotid gland. The nodule was resected, and histological analyses revealed multiple cysts of various sizes lined by cuboidal, eosinophilic cells with mild to moderate atypia (Figures 1A–C). The cyst lumen contained eosinophilic materials, and some of the cuboidal cells showed decapitation secretion (Figures 1A–C). There were no myoepithelial cells around the luminal cells. In some parts, the tumor cells showed microinvasion. From these findings, a diagnosis of cystadenocarcinoma was made. 4 months after the resection, a nodule with cystadenocarcinoma recurred in the right parotid gland, and right superficial parotidectomy was performed. The surgical margin was negative, and the patient received postoperative irradiation with 60Gy. At 4 and 6 years after the parotidectomy, resection was performed on two cutaneous nodules with metastatic melanoma that appeared on the left forearm (Figure 1D). PD-L1 expression level was <1%, and BRAF mutations were not detected. 9 years after the parotidectomy, positron emission tomography (PET)-CT revealed a 40 × 40 mm mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose (FDG) accumulation (Figure 1E). In addition, multiple small nodules appeared in the lung. The mass in the parotid gland was resected, and histological analyses revealed multiple cysts with frequent papillary projection consisting of a proliferation of cuboidal cells with pleomorphism, indicating recurrent cystadenocarcinoma (Figure 1F). Tumor nests had invaded into the fibrotic stroma and multiple perineural invasions were also observed (Figures 1G,H). Because the mass had extended widely, it could not be completely excised and large parts of the surgical margin remained positive. 8 months after the last surgery, PET-CT revealed an irregularly shaped mass with high FDG accumulation below the surgical wound of the parotid gland (Figure 2A). In addition, right upper deep cervical LNs also showed high FDG accumulation (Figure 2B), indicating local recurrence and cervical LN metastases of cystadenocarcinoma. The size and number of lung nodules had also increased (Figures 2C,D). Because the lung nodules and the mass of recurrent cystadenocarcinoma appeared simultaneously, the nodules may be lung metastases of the cystadenocarcinoma. However, the lung nodules were also suspected to be metastatic melanoma because of the patient's medical history of lymph node and multiple skin metastases of melanoma. The patient would not agree to proposed partial lung resection for histological examination of the nodules. Therefore, based on our suspected diagnosis of lung metastases of melanoma, we proposed treatment with either anti-PD-1 antibody monotherapy or nivolumab and ipilimumab combination therapy. He selected the combination therapy, and was treated with combined nivolumab (80 mg/body) and ipilimumab (3 mg/kg) therapy. 2 weeks after the first administration of these antibodies, he developed Grade 4 liver injury, which required cessation of the treatment and a high-dose oral steroid with mycophenolate mofetil followed by steroid pulse therapy for improvement of the liver injury. However, PET-CT 4 months after the single course of the combination therapy showed that the FDG accumulation of both the mass below the surgical wound of the parotid gland and the cervical LNs had disappeared (Figures 2A,B). In addition, all of the lung nodules had disappeared (Figures 2C,D), suggesting that the combination therapy induced CR. At 10 months' follow-up after the immune checkpoint inhibitor (ICI) treatment, there was no recurrence.
Figure 1 (A) Multiple cysts of various size lined by cuboidal, eosinophilic cells, which contained eosinophilic materials (Hematoxylin and eosin [HE], ×40). (B) The tumor cells showed mild to moderate atypia (HE, ×400). (C) Some of the tumor cells showed decapitation secretion (HE, ×400). (D) The cutaneous nodules revealed proliferation of large atypical epithelioid cell with melanin pigmentation, suggesting metastatic melanoma (HE, ×400). (E) Positron emission tomography-computed tomography revealed a mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose accumulation. (F) Multiple cysts with frequent papillary projection consisting of the proliferation of cuboidal cells with pleomorphism (HE, ×200). (G,H). Tumor nests invaded into the fibrotic stroma, and multiple perineural invasions were also observed (HE, ×200).
Figure 2 (A–D) Fluorodeoxyglucose (FDG) accumulation of the mass below the surgical wound of the parotid gland (A) and right upper deep cervical lymph nodes (LNs) (B), and multiple lung nodules (C,D) disappeared after a single course of combined nivolumab and ipilimumab therapy. Left and right panels indicate positron emission tomography-computed tomography (PET-CT) (A,B) or CT (C,D) before and 4 months after a single course of combined therapy, respectively. Arrow heads indicate the mass below the surgical wound of the parotid gland (A) and the cervical LNs (B) with high FDG accumulation, respectively. (E) Some of the tumor cells of the recurrent cystadenocarcinoma were positive for PD-L1 (clone: sp142, ×200).
Discussion
In our case, the mass below the surgical wound and the cervical LNs with high FDG accumulation were regarded as local recurrence and metastases of the cystadenocarcinoma, respectively. However, it was unclear whether the multiple lung nodules were metastases of cystadenocarcinoma or melanoma. Management of advanced melanoma is rapidly evolving, and recent clinical trials revealed that ICIs, such as anti-PD-1 antibody (nivolumab, pembrolizumab) and anti-CTLA-4 antibody (ipilimumab), significantly prolonged the survival of melanoma patients (4–6). Despite having higher rates of adverse events (AEs), nivolumab and ipilimumab combination therapy is known to show higher efficacy compared with either agent alone (7). Based on the suspected diagnosis of metastatic melanoma of the lung and according to the patient's intent, we treated the lesions with this combination therapy. As a result, despite the occurrence of severe liver AE, only a single course of the therapy induced CR.
Cystadenocarcinoma is characterized by prominent cystic structures lined with cuboidal, columnar or mucus-secreting cells, but lacking features of other specific SGC types (8). Although most cases of cystadenocarcinoma show an indolent behavior, recurrence and LN metastases may also develop (9, 10). In addition, cases showing distant metastases such as lung and bone metastases have been reported (3). While various chemotherapies are used for advanced SGCs and their efficacy may be dependent on histological type, overall, the results are unsatisfactory and there have been no reports of significant tumor responses to systemic chemotherapies in advanced cystadenocarcinoma (1, 11–13).
Programmed death ligand 1 (PD-L1) expression in SGC tumor cells is frequently observed, indicating that it may play an important role in the immune tolerance and progression of SGC (14). On examining PD-L1 expression, it was detected in more than 5% of the tumor cells of the recurrent cystadenocarcinoma although not in the metastatic melanoma (Figure 2E). In contrast, Ross et al. analyzed tumor mutation burden (TMB), which is known to be associated with favorable tumor response to ICIs, in 623 cases of SGC, and reported that the TMB of SGC was significantly lower than that of other tumor types for which ICIs were approved such as melanoma and breast cancer, although cases of cystadenocarcinoma were not included in this study (15). Consistently, recent studies demonstrated limited efficacy of anti-PD-1 monotherapy for advanced SGCs (16–18). However, there were no cases of cystadenocarcinoma within these studies, and there have been no reports of advanced cystadenocarcinoma of the salivary gland treated with ICIs. In our patient, the recurrent tumor of the parotid gland and cervical LN metastases of cystadenocarcinoma as well as the multiple lung nodules achieved CR with only a single course of combined nivolumab and ipilimumab therapy. Thus, our case suggests that ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
This patient has provided written, informed consent for publication. A copy of the signed consent form is available on request.
Author Contributions
YN, MN, and BN designed the study. NO, RT, YI, SM, and YF interpreted the results. YN and MN wrote the manuscript. All authors reviewed the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Dr. Thomas D. Mayers of the University of Tsukuba Medical English Communication Center for English editing of this manuscript. We also thank Yuriko Hirota (Department of Dermatology, Faculty of Medicine, University of Tsukuba) for the technical support. | 3 MILLIGRAM/KILOGRAM. SINGLE | DrugDosageText | CC BY | 33718174 | 19,095,795 | 2021 |
What was the dosage of drug 'NIVOLUMAB'? | Case Report: Complete Response of Recurrent and Metastatic Cystadenocarcinoma of the Parotid Gland With a Single Course of Combined Nivolumab and Ipilimumab Therapy.
Although cystadenocarcinoma is classified as a low-grade histological subtype of salivary gland carcinoma (SGC), recurrence and metastases sometimes develop. However, standard treatments for advanced cases have not yet been established. Here, we present a case of unresectable local recurrence and cervical lymph node metastases of cystadenocarcinoma of the parotid gland with multiple lung nodules, all of which showed complete response with only a single course of combined nivolumab and ipilimumab therapy. The patient's medical history of metastatic melanoma roused our suspicions that the multiple lung nodules were cystadenocarcinoma metastases or malignant melanoma. Combination therapy was used based on our suspected diagnosis of lung metastases of melanoma although histological examination of the lung nodules could not be performed. While various chemotherapies are used for advanced SGCs including cystadenocarcinoma, overall, the results are unsatisfactory. In contrast, there have not yet been any reports of advanced cystadenocarcinoma of the salivary gland treated with immune checkpoint inhibitors (ICIs). Given that, in our case, a single course of combined ICI therapy induced a complete response in the unresectable and lymph node metastases from the cystadenocarcinoma and the multiple lung nodules, ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Introduction
Salivary gland carcinomas (SGCs) are relatively rare, and the most common histopathological SGC types are mucoepidermoid carcinoma and adenoid cystic carcinoma (1). In contrast, cystadenocarcinoma is extremely rare, with the estimated incidence being only 2% of all SGCs (2). Although cystadenocarcinoma is classified as a low-grade histological subtype of SGC, recurrence and metastases sometimes develop (2, 3). However, standard treatments for advanced cases have not been established (3). Here, we present a case of unresectable, metastatic cystadenocarcinoma of the parotid gland with multiple lung nodules suspected to be metastatic lesions of cystadenocarcinoma or malignant melanoma, all of which showed complete response (CR) with a single course of combined nivolumab and ipilimumab therapy.
Case Description
A 65-year old man noticed a cutaneous nodule on his left forearm, which had gradually grown. He had a medical history of diabetes mellitus and hypertension. The cutaneous nodule was resected, and was diagnosed to be malignant melanoma. He was referred to our hospital, and underwent wide resection with left axillar lymph node (LN) dissection. The surgical margin of the primary tumor was negative, and one out of the 11 dissected LNs showed metastases. 1 year after the surgery, computed tomography (CT) revealed a nodule in the right parotid gland. The nodule was resected, and histological analyses revealed multiple cysts of various sizes lined by cuboidal, eosinophilic cells with mild to moderate atypia (Figures 1A–C). The cyst lumen contained eosinophilic materials, and some of the cuboidal cells showed decapitation secretion (Figures 1A–C). There were no myoepithelial cells around the luminal cells. In some parts, the tumor cells showed microinvasion. From these findings, a diagnosis of cystadenocarcinoma was made. 4 months after the resection, a nodule with cystadenocarcinoma recurred in the right parotid gland, and right superficial parotidectomy was performed. The surgical margin was negative, and the patient received postoperative irradiation with 60Gy. At 4 and 6 years after the parotidectomy, resection was performed on two cutaneous nodules with metastatic melanoma that appeared on the left forearm (Figure 1D). PD-L1 expression level was <1%, and BRAF mutations were not detected. 9 years after the parotidectomy, positron emission tomography (PET)-CT revealed a 40 × 40 mm mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose (FDG) accumulation (Figure 1E). In addition, multiple small nodules appeared in the lung. The mass in the parotid gland was resected, and histological analyses revealed multiple cysts with frequent papillary projection consisting of a proliferation of cuboidal cells with pleomorphism, indicating recurrent cystadenocarcinoma (Figure 1F). Tumor nests had invaded into the fibrotic stroma and multiple perineural invasions were also observed (Figures 1G,H). Because the mass had extended widely, it could not be completely excised and large parts of the surgical margin remained positive. 8 months after the last surgery, PET-CT revealed an irregularly shaped mass with high FDG accumulation below the surgical wound of the parotid gland (Figure 2A). In addition, right upper deep cervical LNs also showed high FDG accumulation (Figure 2B), indicating local recurrence and cervical LN metastases of cystadenocarcinoma. The size and number of lung nodules had also increased (Figures 2C,D). Because the lung nodules and the mass of recurrent cystadenocarcinoma appeared simultaneously, the nodules may be lung metastases of the cystadenocarcinoma. However, the lung nodules were also suspected to be metastatic melanoma because of the patient's medical history of lymph node and multiple skin metastases of melanoma. The patient would not agree to proposed partial lung resection for histological examination of the nodules. Therefore, based on our suspected diagnosis of lung metastases of melanoma, we proposed treatment with either anti-PD-1 antibody monotherapy or nivolumab and ipilimumab combination therapy. He selected the combination therapy, and was treated with combined nivolumab (80 mg/body) and ipilimumab (3 mg/kg) therapy. 2 weeks after the first administration of these antibodies, he developed Grade 4 liver injury, which required cessation of the treatment and a high-dose oral steroid with mycophenolate mofetil followed by steroid pulse therapy for improvement of the liver injury. However, PET-CT 4 months after the single course of the combination therapy showed that the FDG accumulation of both the mass below the surgical wound of the parotid gland and the cervical LNs had disappeared (Figures 2A,B). In addition, all of the lung nodules had disappeared (Figures 2C,D), suggesting that the combination therapy induced CR. At 10 months' follow-up after the immune checkpoint inhibitor (ICI) treatment, there was no recurrence.
Figure 1 (A) Multiple cysts of various size lined by cuboidal, eosinophilic cells, which contained eosinophilic materials (Hematoxylin and eosin [HE], ×40). (B) The tumor cells showed mild to moderate atypia (HE, ×400). (C) Some of the tumor cells showed decapitation secretion (HE, ×400). (D) The cutaneous nodules revealed proliferation of large atypical epithelioid cell with melanin pigmentation, suggesting metastatic melanoma (HE, ×400). (E) Positron emission tomography-computed tomography revealed a mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose accumulation. (F) Multiple cysts with frequent papillary projection consisting of the proliferation of cuboidal cells with pleomorphism (HE, ×200). (G,H). Tumor nests invaded into the fibrotic stroma, and multiple perineural invasions were also observed (HE, ×200).
Figure 2 (A–D) Fluorodeoxyglucose (FDG) accumulation of the mass below the surgical wound of the parotid gland (A) and right upper deep cervical lymph nodes (LNs) (B), and multiple lung nodules (C,D) disappeared after a single course of combined nivolumab and ipilimumab therapy. Left and right panels indicate positron emission tomography-computed tomography (PET-CT) (A,B) or CT (C,D) before and 4 months after a single course of combined therapy, respectively. Arrow heads indicate the mass below the surgical wound of the parotid gland (A) and the cervical LNs (B) with high FDG accumulation, respectively. (E) Some of the tumor cells of the recurrent cystadenocarcinoma were positive for PD-L1 (clone: sp142, ×200).
Discussion
In our case, the mass below the surgical wound and the cervical LNs with high FDG accumulation were regarded as local recurrence and metastases of the cystadenocarcinoma, respectively. However, it was unclear whether the multiple lung nodules were metastases of cystadenocarcinoma or melanoma. Management of advanced melanoma is rapidly evolving, and recent clinical trials revealed that ICIs, such as anti-PD-1 antibody (nivolumab, pembrolizumab) and anti-CTLA-4 antibody (ipilimumab), significantly prolonged the survival of melanoma patients (4–6). Despite having higher rates of adverse events (AEs), nivolumab and ipilimumab combination therapy is known to show higher efficacy compared with either agent alone (7). Based on the suspected diagnosis of metastatic melanoma of the lung and according to the patient's intent, we treated the lesions with this combination therapy. As a result, despite the occurrence of severe liver AE, only a single course of the therapy induced CR.
Cystadenocarcinoma is characterized by prominent cystic structures lined with cuboidal, columnar or mucus-secreting cells, but lacking features of other specific SGC types (8). Although most cases of cystadenocarcinoma show an indolent behavior, recurrence and LN metastases may also develop (9, 10). In addition, cases showing distant metastases such as lung and bone metastases have been reported (3). While various chemotherapies are used for advanced SGCs and their efficacy may be dependent on histological type, overall, the results are unsatisfactory and there have been no reports of significant tumor responses to systemic chemotherapies in advanced cystadenocarcinoma (1, 11–13).
Programmed death ligand 1 (PD-L1) expression in SGC tumor cells is frequently observed, indicating that it may play an important role in the immune tolerance and progression of SGC (14). On examining PD-L1 expression, it was detected in more than 5% of the tumor cells of the recurrent cystadenocarcinoma although not in the metastatic melanoma (Figure 2E). In contrast, Ross et al. analyzed tumor mutation burden (TMB), which is known to be associated with favorable tumor response to ICIs, in 623 cases of SGC, and reported that the TMB of SGC was significantly lower than that of other tumor types for which ICIs were approved such as melanoma and breast cancer, although cases of cystadenocarcinoma were not included in this study (15). Consistently, recent studies demonstrated limited efficacy of anti-PD-1 monotherapy for advanced SGCs (16–18). However, there were no cases of cystadenocarcinoma within these studies, and there have been no reports of advanced cystadenocarcinoma of the salivary gland treated with ICIs. In our patient, the recurrent tumor of the parotid gland and cervical LN metastases of cystadenocarcinoma as well as the multiple lung nodules achieved CR with only a single course of combined nivolumab and ipilimumab therapy. Thus, our case suggests that ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
This patient has provided written, informed consent for publication. A copy of the signed consent form is available on request.
Author Contributions
YN, MN, and BN designed the study. NO, RT, YI, SM, and YF interpreted the results. YN and MN wrote the manuscript. All authors reviewed the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Dr. Thomas D. Mayers of the University of Tsukuba Medical English Communication Center for English editing of this manuscript. We also thank Yuriko Hirota (Department of Dermatology, Faculty of Medicine, University of Tsukuba) for the technical support. | 80 MILLIGRAM, SINGLE | DrugDosageText | CC BY | 33718174 | 19,095,795 | 2021 |
What was the outcome of reaction 'Liver injury'? | Case Report: Complete Response of Recurrent and Metastatic Cystadenocarcinoma of the Parotid Gland With a Single Course of Combined Nivolumab and Ipilimumab Therapy.
Although cystadenocarcinoma is classified as a low-grade histological subtype of salivary gland carcinoma (SGC), recurrence and metastases sometimes develop. However, standard treatments for advanced cases have not yet been established. Here, we present a case of unresectable local recurrence and cervical lymph node metastases of cystadenocarcinoma of the parotid gland with multiple lung nodules, all of which showed complete response with only a single course of combined nivolumab and ipilimumab therapy. The patient's medical history of metastatic melanoma roused our suspicions that the multiple lung nodules were cystadenocarcinoma metastases or malignant melanoma. Combination therapy was used based on our suspected diagnosis of lung metastases of melanoma although histological examination of the lung nodules could not be performed. While various chemotherapies are used for advanced SGCs including cystadenocarcinoma, overall, the results are unsatisfactory. In contrast, there have not yet been any reports of advanced cystadenocarcinoma of the salivary gland treated with immune checkpoint inhibitors (ICIs). Given that, in our case, a single course of combined ICI therapy induced a complete response in the unresectable and lymph node metastases from the cystadenocarcinoma and the multiple lung nodules, ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Introduction
Salivary gland carcinomas (SGCs) are relatively rare, and the most common histopathological SGC types are mucoepidermoid carcinoma and adenoid cystic carcinoma (1). In contrast, cystadenocarcinoma is extremely rare, with the estimated incidence being only 2% of all SGCs (2). Although cystadenocarcinoma is classified as a low-grade histological subtype of SGC, recurrence and metastases sometimes develop (2, 3). However, standard treatments for advanced cases have not been established (3). Here, we present a case of unresectable, metastatic cystadenocarcinoma of the parotid gland with multiple lung nodules suspected to be metastatic lesions of cystadenocarcinoma or malignant melanoma, all of which showed complete response (CR) with a single course of combined nivolumab and ipilimumab therapy.
Case Description
A 65-year old man noticed a cutaneous nodule on his left forearm, which had gradually grown. He had a medical history of diabetes mellitus and hypertension. The cutaneous nodule was resected, and was diagnosed to be malignant melanoma. He was referred to our hospital, and underwent wide resection with left axillar lymph node (LN) dissection. The surgical margin of the primary tumor was negative, and one out of the 11 dissected LNs showed metastases. 1 year after the surgery, computed tomography (CT) revealed a nodule in the right parotid gland. The nodule was resected, and histological analyses revealed multiple cysts of various sizes lined by cuboidal, eosinophilic cells with mild to moderate atypia (Figures 1A–C). The cyst lumen contained eosinophilic materials, and some of the cuboidal cells showed decapitation secretion (Figures 1A–C). There were no myoepithelial cells around the luminal cells. In some parts, the tumor cells showed microinvasion. From these findings, a diagnosis of cystadenocarcinoma was made. 4 months after the resection, a nodule with cystadenocarcinoma recurred in the right parotid gland, and right superficial parotidectomy was performed. The surgical margin was negative, and the patient received postoperative irradiation with 60Gy. At 4 and 6 years after the parotidectomy, resection was performed on two cutaneous nodules with metastatic melanoma that appeared on the left forearm (Figure 1D). PD-L1 expression level was <1%, and BRAF mutations were not detected. 9 years after the parotidectomy, positron emission tomography (PET)-CT revealed a 40 × 40 mm mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose (FDG) accumulation (Figure 1E). In addition, multiple small nodules appeared in the lung. The mass in the parotid gland was resected, and histological analyses revealed multiple cysts with frequent papillary projection consisting of a proliferation of cuboidal cells with pleomorphism, indicating recurrent cystadenocarcinoma (Figure 1F). Tumor nests had invaded into the fibrotic stroma and multiple perineural invasions were also observed (Figures 1G,H). Because the mass had extended widely, it could not be completely excised and large parts of the surgical margin remained positive. 8 months after the last surgery, PET-CT revealed an irregularly shaped mass with high FDG accumulation below the surgical wound of the parotid gland (Figure 2A). In addition, right upper deep cervical LNs also showed high FDG accumulation (Figure 2B), indicating local recurrence and cervical LN metastases of cystadenocarcinoma. The size and number of lung nodules had also increased (Figures 2C,D). Because the lung nodules and the mass of recurrent cystadenocarcinoma appeared simultaneously, the nodules may be lung metastases of the cystadenocarcinoma. However, the lung nodules were also suspected to be metastatic melanoma because of the patient's medical history of lymph node and multiple skin metastases of melanoma. The patient would not agree to proposed partial lung resection for histological examination of the nodules. Therefore, based on our suspected diagnosis of lung metastases of melanoma, we proposed treatment with either anti-PD-1 antibody monotherapy or nivolumab and ipilimumab combination therapy. He selected the combination therapy, and was treated with combined nivolumab (80 mg/body) and ipilimumab (3 mg/kg) therapy. 2 weeks after the first administration of these antibodies, he developed Grade 4 liver injury, which required cessation of the treatment and a high-dose oral steroid with mycophenolate mofetil followed by steroid pulse therapy for improvement of the liver injury. However, PET-CT 4 months after the single course of the combination therapy showed that the FDG accumulation of both the mass below the surgical wound of the parotid gland and the cervical LNs had disappeared (Figures 2A,B). In addition, all of the lung nodules had disappeared (Figures 2C,D), suggesting that the combination therapy induced CR. At 10 months' follow-up after the immune checkpoint inhibitor (ICI) treatment, there was no recurrence.
Figure 1 (A) Multiple cysts of various size lined by cuboidal, eosinophilic cells, which contained eosinophilic materials (Hematoxylin and eosin [HE], ×40). (B) The tumor cells showed mild to moderate atypia (HE, ×400). (C) Some of the tumor cells showed decapitation secretion (HE, ×400). (D) The cutaneous nodules revealed proliferation of large atypical epithelioid cell with melanin pigmentation, suggesting metastatic melanoma (HE, ×400). (E) Positron emission tomography-computed tomography revealed a mass in the deep lobe of the right parotid gland with high fluorodeoxyglucose accumulation. (F) Multiple cysts with frequent papillary projection consisting of the proliferation of cuboidal cells with pleomorphism (HE, ×200). (G,H). Tumor nests invaded into the fibrotic stroma, and multiple perineural invasions were also observed (HE, ×200).
Figure 2 (A–D) Fluorodeoxyglucose (FDG) accumulation of the mass below the surgical wound of the parotid gland (A) and right upper deep cervical lymph nodes (LNs) (B), and multiple lung nodules (C,D) disappeared after a single course of combined nivolumab and ipilimumab therapy. Left and right panels indicate positron emission tomography-computed tomography (PET-CT) (A,B) or CT (C,D) before and 4 months after a single course of combined therapy, respectively. Arrow heads indicate the mass below the surgical wound of the parotid gland (A) and the cervical LNs (B) with high FDG accumulation, respectively. (E) Some of the tumor cells of the recurrent cystadenocarcinoma were positive for PD-L1 (clone: sp142, ×200).
Discussion
In our case, the mass below the surgical wound and the cervical LNs with high FDG accumulation were regarded as local recurrence and metastases of the cystadenocarcinoma, respectively. However, it was unclear whether the multiple lung nodules were metastases of cystadenocarcinoma or melanoma. Management of advanced melanoma is rapidly evolving, and recent clinical trials revealed that ICIs, such as anti-PD-1 antibody (nivolumab, pembrolizumab) and anti-CTLA-4 antibody (ipilimumab), significantly prolonged the survival of melanoma patients (4–6). Despite having higher rates of adverse events (AEs), nivolumab and ipilimumab combination therapy is known to show higher efficacy compared with either agent alone (7). Based on the suspected diagnosis of metastatic melanoma of the lung and according to the patient's intent, we treated the lesions with this combination therapy. As a result, despite the occurrence of severe liver AE, only a single course of the therapy induced CR.
Cystadenocarcinoma is characterized by prominent cystic structures lined with cuboidal, columnar or mucus-secreting cells, but lacking features of other specific SGC types (8). Although most cases of cystadenocarcinoma show an indolent behavior, recurrence and LN metastases may also develop (9, 10). In addition, cases showing distant metastases such as lung and bone metastases have been reported (3). While various chemotherapies are used for advanced SGCs and their efficacy may be dependent on histological type, overall, the results are unsatisfactory and there have been no reports of significant tumor responses to systemic chemotherapies in advanced cystadenocarcinoma (1, 11–13).
Programmed death ligand 1 (PD-L1) expression in SGC tumor cells is frequently observed, indicating that it may play an important role in the immune tolerance and progression of SGC (14). On examining PD-L1 expression, it was detected in more than 5% of the tumor cells of the recurrent cystadenocarcinoma although not in the metastatic melanoma (Figure 2E). In contrast, Ross et al. analyzed tumor mutation burden (TMB), which is known to be associated with favorable tumor response to ICIs, in 623 cases of SGC, and reported that the TMB of SGC was significantly lower than that of other tumor types for which ICIs were approved such as melanoma and breast cancer, although cases of cystadenocarcinoma were not included in this study (15). Consistently, recent studies demonstrated limited efficacy of anti-PD-1 monotherapy for advanced SGCs (16–18). However, there were no cases of cystadenocarcinoma within these studies, and there have been no reports of advanced cystadenocarcinoma of the salivary gland treated with ICIs. In our patient, the recurrent tumor of the parotid gland and cervical LN metastases of cystadenocarcinoma as well as the multiple lung nodules achieved CR with only a single course of combined nivolumab and ipilimumab therapy. Thus, our case suggests that ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
This patient has provided written, informed consent for publication. A copy of the signed consent form is available on request.
Author Contributions
YN, MN, and BN designed the study. NO, RT, YI, SM, and YF interpreted the results. YN and MN wrote the manuscript. All authors reviewed the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank Dr. Thomas D. Mayers of the University of Tsukuba Medical English Communication Center for English editing of this manuscript. We also thank Yuriko Hirota (Department of Dermatology, Faculty of Medicine, University of Tsukuba) for the technical support. | Recovering | ReactionOutcome | CC BY | 33718174 | 19,095,795 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute leukaemia'. | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | ACETAMINOPHEN, ALBUMIN HUMAN, AMPHOTERICIN B, BLINATUMOMAB, CILASTATIN SODIUM\IMIPENEM, CLONAZEPAM, CYCLOPHOSPHAMIDE, CYTARABINE, GEMTUZUMAB OZOGAMICIN, HUMAN IMMUNOGLOBULIN G, MERCAPTOPURINE, MEROPENEM, METHOTREXATE, METHYLPREDNISOLONE, METHYLPREDNISOLONE ACETATE, ONDANSETRON, PEGASPARGASE, PHLOROGLUCINOL, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISONE, PROBIOTICS NOS, SULFAMETHOXAZOLE\TRIMETHOPRIM, VANCOMYCIN | DrugsGivenReaction | CC BY | 33718232 | 19,058,055 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'C-reactive protein increased'. | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | ACETAMINOPHEN, ALBUMIN HUMAN, AMPHOTERICIN B, BLINATUMOMAB, CILASTATIN SODIUM\IMIPENEM, CLONAZEPAM, CYCLOPHOSPHAMIDE, CYTARABINE, GEMTUZUMAB OZOGAMICIN, HUMAN IMMUNOGLOBULIN G, MERCAPTOPURINE, MEROPENEM, METHOTREXATE, METHYLPREDNISOLONE, METHYLPREDNISOLONE ACETATE, ONDANSETRON, PEGASPARGASE, PHLOROGLUCINOL, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISONE, PROBIOTICS NOS, SULFAMETHOXAZOLE\TRIMETHOPRIM, VANCOMYCIN | DrugsGivenReaction | CC BY | 33718232 | 19,058,055 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Device breakage'. | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | ACETAMINOPHEN, ALBUMIN HUMAN, AMPHOTERICIN B, BLINATUMOMAB, CILASTATIN SODIUM\IMIPENEM, CLONAZEPAM, CYCLOPHOSPHAMIDE, CYTARABINE, GEMTUZUMAB OZOGAMICIN, HUMAN IMMUNOGLOBULIN G, MERCAPTOPURINE, MEROPENEM, METHOTREXATE, METHYLPREDNISOLONE, METHYLPREDNISOLONE ACETATE, ONDANSETRON, PEGASPARGASE, PHLOROGLUCINOL, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISONE, PROBIOTICS NOS, SULFAMETHOXAZOLE\TRIMETHOPRIM, VANCOMYCIN | DrugsGivenReaction | CC BY | 33718232 | 19,058,055 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile convulsion'. | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | ACETAMINOPHEN, ALBUMIN HUMAN, AMPHOTERICIN B, BLINATUMOMAB, CILASTATIN SODIUM\IMIPENEM, CLONAZEPAM, CYCLOPHOSPHAMIDE, CYTARABINE, GEMTUZUMAB OZOGAMICIN, HUMAN IMMUNOGLOBULIN G, MERCAPTOPURINE, MEROPENEM, METHOTREXATE, METHYLPREDNISOLONE, METHYLPREDNISOLONE ACETATE, ONDANSETRON, PEGASPARGASE, PHLOROGLUCINOL, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISONE, PROBIOTICS NOS, SULFAMETHOXAZOLE\TRIMETHOPRIM, VANCOMYCIN | DrugsGivenReaction | CC BY | 33718232 | 19,058,055 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | ACETAMINOPHEN, ALBUMIN HUMAN, AMPHOTERICIN B, BLINATUMOMAB, CILASTATIN SODIUM\IMIPENEM, CLONAZEPAM, CYCLOPHOSPHAMIDE, CYTARABINE, GEMTUZUMAB OZOGAMICIN, HUMAN IMMUNOGLOBULIN G, MERCAPTOPURINE, MEROPENEM, METHOTREXATE, METHYLPREDNISOLONE, METHYLPREDNISOLONE ACETATE, ONDANSETRON, PEGASPARGASE, PHLOROGLUCINOL, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISONE, PROBIOTICS NOS, SULFAMETHOXAZOLE\TRIMETHOPRIM, VANCOMYCIN | DrugsGivenReaction | CC BY | 33718232 | 19,058,055 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | ACETAMINOPHEN, ALBUMIN HUMAN, AMPHOTERICIN B, BLINATUMOMAB, CILASTATIN SODIUM\IMIPENEM, CLONAZEPAM, CYCLOPHOSPHAMIDE, CYTARABINE, GEMTUZUMAB OZOGAMICIN, HUMAN IMMUNOGLOBULIN G, MERCAPTOPURINE, MEROPENEM, METHOTREXATE, METHYLPREDNISOLONE, METHYLPREDNISOLONE ACETATE, ONDANSETRON, PEGASPARGASE, PHLOROGLUCINOL, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISONE, PROBIOTICS NOS, SULFAMETHOXAZOLE\TRIMETHOPRIM, VANCOMYCIN | DrugsGivenReaction | CC BY | 33718232 | 19,058,055 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Weight gain poor'. | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | ACETAMINOPHEN, ALBUMIN HUMAN, AMPHOTERICIN B, BLINATUMOMAB, CILASTATIN SODIUM\IMIPENEM, CLONAZEPAM, CYCLOPHOSPHAMIDE, CYTARABINE, GEMTUZUMAB OZOGAMICIN, HUMAN IMMUNOGLOBULIN G, MERCAPTOPURINE, MEROPENEM, METHOTREXATE, METHYLPREDNISOLONE, METHYLPREDNISOLONE ACETATE, ONDANSETRON, PEGASPARGASE, PHLOROGLUCINOL, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISONE, PROBIOTICS NOS, SULFAMETHOXAZOLE\TRIMETHOPRIM, VANCOMYCIN | DrugsGivenReaction | CC BY | 33718232 | 19,058,055 | 2021 |
What is the weight of the patient? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 2.98 kg. | Weight | CC BY | 33718232 | 19,058,055 | 2021 |
What was the administration route of drug 'BLINATUMOMAB'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33718232 | 19,058,055 | 2021 |
What was the administration route of drug 'METHOTREXATE'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Intrathecal | DrugAdministrationRoute | CC BY | 33718232 | 19,058,055 | 2021 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Intrathecal | DrugAdministrationRoute | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'ACETAMINOPHEN'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 1 DOSE/WEIGHT (7 KG) EVERY 6 HOURS | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'CLONAZEPAM'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 0.02 MILLIGRAM/KILOGRAM | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'GEMTUZUMAB OZOGAMICIN'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 3 MILLIGRAM/SQ. METER | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'HUMAN IMMUNOGLOBULIN G'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 0.4 GRAM PER KILOGRAM | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'METHYLPREDNISOLONE ACETATE'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 6 MILLIGRAM | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 6 MILLIGRAM | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'ONDANSETRON'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 2 MILLIGRAM, TWICE A DAY, AS NECESSARY | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'PEGASPARGASE'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 2500 IU INTERNATIONAL UNIT PER SQAURE METER | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'PHLOROGLUCINOL'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 1/4 TABLET, TWICE A DAY AS NECESSARY | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'PREDNISONE'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 60 MILLIGRAM/SQ. METER, QD | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'PROBIOTICS NOS'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 4 DROP, QD | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the dosage of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 4 MILLILITER, TID | DrugDosageText | CC BY | 33718232 | 19,058,055 | 2021 |
What was the outcome of reaction 'Febrile convulsion'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33718232 | 19,058,055 | 2021 |
What was the outcome of reaction 'Weight gain poor'? | Case Report: Targeting 2 Antigens as a Promising Strategy in Mixed Phenotype Acute Leukemia: Combination of Blinatumomab With Gemtuzumab Ozogamicin in an Infant With a KMT2A-Rearranged Leukemia.
Mixed phenotype acute leukemia (MPAL) accounts for 2-5% of leukemia in children. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. The prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children. A lymphoid-type therapeutic approach appears to be more effective but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75-80% of leukemia in infants under one year of age and remains a major pejorative prognostic factor in the Interfant-06 protocol with a 6 years EFS of only 36%. The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue. We describe here the feasibility and tolerance of the combination of two targeted immunotherapies, blinatumomab and Gemtuzumab Ozogamicin, in a 4-year-old infant with a primary refractory KTM2A-rearranged MPAL. Our main concern was to determine how to associate these two immunotherapies and we describe how we decided to do it with the parents' agreement. The good MRD response on the two clones made it possible to continue the curative intent with a hematopoietic stem cell transplant at 9 months of age. Despite a relapse at M11 post-transplant because of the recurrence of a pro-B clone retaining the initial lymphoid phenotype, the child is now 36 months old, in persistent negative MRD CR2 for 12 months after a salvage chemotherapy and an autologous CAR T cells infusion, with no known sequelae to date. This case study can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Introduction
Mixed phenotype acute leukemia (MPAL) accounts for 2%–5% of leukemia in children (1). It is a heterogeneous group of diseases whose immunophenotypic definition has changed over time (2–4). The current WHO classification recognizes two subclassifications of MPAL (biphenotypic and bilineal) with mostly similar clinical and genetics characteristics. MPAL are at higher risk of induction failure. Lineage switch (B to M or vice versa) or persistence of only the lymphoid or myeloid clone is frequently observed in biphenotypic/bilineal cases, highlighting their lineage plasticity. Prognosis of MPAL remains bleak, with an event-free survival (EFS) of less than 50% in children (1, 5–7). A lymphoid-type therapeutic approach appears to be more effective (6, 7) but failures to achieve complete remission (CR) remain significant. KMT2A fusions account for 75%–80% of leukemia in infants less than one year of age with typically an early pro-B CD10neg phenotype. Many cases express myeloid antigens (e.g., CD15/65, CD33, or weak MPO) but should not be considered MPAL unless unequivocal evidence of monoblastic differentiation (≥20% of blasts) or bright MPO expression, <5% of all cases; KTM2A rearrangement remains a major pejorative prognostic factor in the international Interfant-06 protocol and confers poor prognosis. The 6 years EFS for the low risk group (KMT2A germline patients) was 73.9% versus 36% for the KMT2A-rearranged group (8). The search for other therapeutic approaches, in particular immunotherapies that are able to eradicate all MPAL clones, is a major issue (9). We describe here the feasibility of the combination of two targeted immunotherapies in an infant with a primary refractory KTM2A-rearranged MPAL.
Case Report
Four-month-old little girl presented in February 2018 with asthenia, pallor, cutaneous hemorrhages, hepato-splenomegaly, and superior airways obstructive respiratory signs. Maximum white blood cells count was 762 G/L. Workup showed a spontaneous tumor lysis syndrome without renal failure with a grade 3 biological disseminated intravascular coagulation. HCoV-NL63 (non-SARS) coronavirus was found in the nasopharyngeal swab. Bone marrow was rich, infiltrated by 80% of lymphoblasts and 9% of resembling myeloblasts with fine granulations but peroxidase-negative. Atypical dysgranulopoiesis was also noted ( Figure 1 ). Flow cytometry (FCM) showed two distinct CD34+ CD135+ (FLT3-R) populations evoking a MPAL (B/myeloid) diagnosis according to the WHO 2016. Pro-B clone (70% of blasts) was CD19bright, CD22dim partial, cCD79a partial, CD20-, CD24dim without surface Kappa/Lambda or cytoplasmic mu-chain and co-expressed on some blasts (30% of CD19+) several myeloid antigens (CD11c/CD64/CD15/CD33). Monocytic clone (30%) was CD19-, cCD79a-, MPO-, CD33/11b/65/15/11c/64bright with partial CD14 (15%) and partial co-expression of lymphoid markers CD22 and CD24 showing a continuum of expression/differentiation between the “pure” lymphoid and myeloid clones ( Figure 2A ). FISH evidenced KTM2A rearrangement in 93% of the nuclei. The presence of a KMT2A-AFF1 (also known as MLL-AF4) fusion was confirmed using RT-PCR. A missense mutation of the FLT3 gene (43% allelic frequency) was found ( Figure 3A ). No deletion or duplication was found using MLPA (MRC HOLLAND kit P335-C1). Cerebrospinal fluid status was CNS3.
Figure 1 Cytological features of the bone marrow at diagnosis (May-Grünwald stain).
Figure 2 Immunophenotyping features at diagnosis (A), following courses (B, C), and relapse (D).
Figure 3 Expression of the FLT3 receptor (CD135) on the blast population at diagnosis and at relapse showing a six times more expression at relapse (B) than at diagnosis (A) (MFI, mean fluorescence intensity).
The child was treated according to the recommendations of the high-risk arm of the Interfant-06 protocol. A poor prednisone response was observed at D8 (blasts 127.9 G/L). The CSF was normalized after three intrathecal injections. Unfortunately, CR was not achieved at the end of induction with a M2 bone marrow (9% blasts), progressing to a M3 bone marrow (32% blasts) 15 days after beginning the IB consolidation phase (cyclophosphamide/cytarabine/6-mercaptopurine). A course of high-dose cytarabine-based chemotherapy (2.25 g/m2 bid for 3 days) with amsidine (75 mg/m2 per day for 3 days) failed with FCM showing the persistence of both B-lymphoid (80%) and myeloid (20%) blasts ( Figure 2B ).
After having obtained the informed consent of the parents and the authorization of the French national drug safety agency (ANSM), multidisciplinary team decision was to attack specifically each of the two phenotypically distinct leukemic clones with a combination of Blinatumomab (BLIN) and Gemtuzumab Ozogamicin (GO). BLIN was introduced first in May 2018 at a dose of 5 microg/m2/day for 7 days and then increased at 15 microg/m2/day. GO (3 mg/m2) was added at D11, D15, D18 with triple intrathecal injections every 15 days (methotrexate, cytarabine, methylprednisolone). At D25, generalized seizures appeared in a febrile context, lasting for 5 min to stop BLIN. All radiological, biological, and microbiological documentations were negative. BLIN was resumed at D30 and continued until D73. One additional dose of GO 3 mg/m2 was administered at D44 for consolidation. The only other grade 3/4 toxicity was an undocumented febrile neutropenia; no liver toxicity including sinusoidal obstructive syndrome (SOS) was seen. In terms of response, CR1 was obtained at D38 BLIN/GO. Minimal residual disease (MRD) as undetectable at the threshold of 10−4 by FCM and 10−5 using genomic PCR established on the KTM2A breakpoint. This was confirmed at the time of discontinuation of BLIN (administered for 68 days in total). At that time, there were still circulating T-lymphocytes (CD3+ 780/mm3, CD4+ at 603/mm3) but no B-lymphocytes were seen as expected. This good response made it possible to continue the curative intent with a hematopoietic stem cell transplant in August 2018, i.e., at 9 months of age, after a conditioning regimen combining busulfan, fludarabine, and thiotepa. SOS prophylaxis consisted in defibrotide. A full donor chimerism was seen at mo1 and mo2. There was no acute GVHD or hepatic SOS. Ciclosporin A was stopped at mo3. MRD was negative again at M6 with both technics.
Unfortunately, a combined relapse occurred 11 months after HCST (child aged 21 months), with invasion of sinuses and orbits, a CNS2 CSF with 54% of lymphoid blasts in the bone marrow. FCM confirmed the recurrence of a pro-B clone retaining initial phenotype (CD19bright, CD10-, partial CD33 but no monocytic antigens), with FLT3-R overexpression as in diagnosis ( Figure 2C ). KMT2A rearrangement and the initial FLT3 mutation were still detected with acquisition of a mono-allelic complete deletion of IKZF1 ( Figure 3B ). Salvage treatment consisted of intensive chemotherapy combined with midostaurine BID and triple intrathecal infusions. Bone marrow and extra-medullary CR2 was obtained with undetectable KTM2A breakpoint MRD at level 10−5. Autologous anti-CD19 CAR-T cells were administered 3 months after the relapse followed by a grade 2 cytokine release syndrome with hematological and neurological toxicities. The child is now 36 months old, in persistent negative MRD CR2 (at mo12 post-CAR T cells infusion), with no known sequelae to date.
Discussion
Pediatric MPALs are rare (<5% of pediatric AL cases), with up to 15% to 20% failures to achieve CR1. Very few data are available for children with KMT2A-rearranged MPAL ( Table 1 ). Among 28 children treated for a MPAL with lymphoid-type treatment between 1996 and 2006 in the Czech Republic, 3 had a KMT2A/AFF1 rearrangement, only one being alive after HSCT in CR2 (1). In a more recent series of 39 pediatric MPAL cases treated in Poland from 2007 to 2018, four cases presented with a KMT2A rearrangement but no details are provided regarding their specific treatment and outcome (7). An international cooperative study (18 centers participating in the iBFM-AMBI2012 study) looked at the therapeutic strategies and the outcome of 233 children with ambiguous lineage acute leukemia (ALAL) between 2002 and 2015 (176 single-population ALAL, 45 bilineal ALAL, 12 undifferentiated). Fifteen of 233 patients had a KMT2A/AFF1 rearrangement and 11 had another type of KMT2A rearrangement. These cases most often aggregate in the group of patients who received a lymphoid and myeloid oriented “hybrid” treatment with a 5y EFS of only 28% (6).
Table 1 KMT2A-rerranged MPAL cases from literature and their treatment approach.
References N of pts N of KMT2A-r pts Type of therapy Survival
Mejstrikova et al. (1)
Haematologica 28 3
(KMT2A/AFF1 : 3) Lymphoid type
(interfant 2003; POG9407) 1/3
Hrusak et al. (6)
Blood 233 26
(KMT2A/AFF1: 15 KMT2A-r other: 11) Hybrid
myeloid/lymphoid type 5 y EFS
28%+/−14%
Zając-Spychała et al. (7)
Haematologica 39 4 NA NA
New concepts and/or therapies and are thus needed for MPAL. BLIN is a commercialized bispecific CD19/CD3 monoclonal antibody. It has been tested for safety and efficacy in children with relapsed/refractory ALL with initial response rates of around 39%. Among 70 patients who received the recommended dosages (15 µg/m2/day after a week at 5 µg/m2/day), the CR rate was 56% among patients with <50% bone marrow blasts at baseline versus 33% among those with 50% or more blasts (10). In term or MRD response, among the 27 children who obtained a CR within the first two cycles, 14 (52%) achieved a complete MRD response, 13 (48%) by day 15 of cycle 1 (10). This was confirmed in a study comparing BLIN versus historical standard therapy in pediatric R/R Ph-negative B-cell precursor ALL (11). In infants less than 2 years of age, the response rate is 60% (6/10) with similar tolerance (10). GO is a commercialized humanized anti-CD33 monoclonal antibody coupled to the cytotoxic antibiotic calicheamicin causing DNA damage after endocytosis. This antibody has been shown to be effective in pediatric AML, including infants with similar and especially reasonable hepatic side effects (12, 13). Our main concern was to determine how to associate these two immunotherapies, one targeting the B lymphoid component, the other one targeting the myeloid component of the MPAL. BLIN allows the cytotoxic T lymphocytes to be engaged with malignant and benignant B cells, resulting in B cell lysis and T cell expansion. It needs preserved functional effector T-cells. GO, despite being a targeted chemotherapy, could precisely destroy those effectors. This is why we decided to first introduce BLIN alone, to induce the T–cell expansion and action on the B lineage component of the clone. Then GO was combined from D11 of the onset of BLIN, in a fractionated regimen we previously described as tolerated and effective in children with AML, at a dose of 3 mg/m2 three times in a week as monotherapy and in combination with cytarabine (14).
The history of our patient highlights the interest of a combined immunotherapy approach tailored to target immunophenotypic markers in MPAL. Indeed, lymphoid and myeloid clones, resistant to conventional chemotherapy, could be controlled by combining two drugs with a curative intent in this patient with a refractory disease. This case report can thus lead to the idea of a sequential combination of two immunotherapies targeting two distinct leukemic subclones (or even a single biphenotypic clone), as a potential one to be tested prospectively in children MPAL and even possibly all KMT2A-rearranged infant ALL.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author Contributions
BB reviewed the literature, collected, and analyzed data and wrote the manuscript. BB and AB designed the case report. EL, AC-E, and OF provided biological data. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33718232 | 19,058,055 | 2021 |
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