instruction stringlengths 34 186 | input stringlengths 2.02k 93.8k | output stringlengths 2 418 | meta_questiontype stringclasses 6 values | meta_inputlicense stringclasses 6 values | meta_pmid stringlengths 8 8 | meta_safetyreportid int64 9.51M 21M | meta_articlepubdate stringlengths 4 10 |
|---|---|---|---|---|---|---|---|
What was the administration route of drug 'FLECAINIDE'? | Vernakalant for Rapid Cardioversion of Recent-Onset Atrial Fibrillation: Results from the SPECTRUM Study.
Rapid restoration of sinus rhythm using pharmacological cardioversion is commonly indicated in patients with symptomatic recent-onset atrial fibrillation (AF). The objectives of this large, international, multicenter observational study were to determine the safety and effectiveness of intravenous (IV) vernakalant for conversion of AF to sinus rhythm in daily practice.
Consenting patients with symptomatic recent-onset AF (< 7 days) treated with IV vernakalant were enrolled and followed up to 24 h after the last infusion or until discharge, in order to determine the incidence of predefined serious adverse events (SAEs) and other observed SAEs and evaluate the conversion rate within the first 90 min. Overall, 2009 treatment episodes in 1778 patients were analyzed. The age of patients was 62.3 ± 13.0 years (mean ± standard deviation). Median AF duration before treatment was 11.1 h (IQR 5.4-27.0 h). A total of 28 SAEs occurred in 26 patients including 19 predefined SAEs, i.e., sinus arrest (n = 4, 0.2%), significant bradycardia (n = 11, 0.5%), significant hypotension (n = 2, 0.1%), and atrial flutter with 1:1 conduction (n = 2, 0.1%). There were no cases of sustained ventricular arrhythmias or deaths. All patients who experienced SAEs recovered fully (n = 25) or with sequelae (n = 1). Conversion rate to sinus rhythm was 70.2%, within a median of 12 min (IQR 8.0-28.0 min).
This large multicenter, international observational study confirms the good safety profile and the high effectiveness of vernakalant for the rapid cardioversion of recent-onset AF in daily hospital practice.
Introduction and Purpose of the Study
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with an estimated 33.5 million people affected worldwide [1]. One in four adults over 55 years of age in Europe and the USA develop AF, with greater prevalence in older populations [1, 2]. Patients with AF are at increased risk of stroke and heart failure [3, 4]. A significant number of patients with recent-onset AF seen in the emergency departments (EDs) undergo commonly in Europe pharmacological cardioversion.
Vernakalant is a partial atrial-selective antiarrhythmic agent by its action through IKur and IKACh channel inhibition [5]. However, it has a modest effect on the ventricle via Ina and IKr channels resulting in a limited effect on ventricular repolarization (QT interval) [5]. Vernakalant is contra-indicated in patients with prolonged QT interval.
Intravenous vernakalant has been approved by the European Medicine Agency [2010] for the rapid conversion of recent-onset AF [6]. To date, a number of studies have shown vernakalant to be well tolerated and effective for cardioversion of AF [7–18].
The FDA (Food and Drug Administration agency) decided in 2008 and in December 2019 not to approve to market vernakalant in the USA for safety concerns. In 2010, the EMA requested a post-authorization safety study to better define the risk benefit ratio in routine clinical practice. The objectives of SPECTRUM (Surveillance of Pharmacologic thErapy for Cardioversion in aTrial fibrillation Registry Using IV treatMent) (NCT01370629 and EUPAS2078) study were to assess the rates of adverse events and to estimate the effectiveness of the drug in a large cohort of patients with recent-onset AF.
Methods
Definitions
Recent-onset AF was defined as symptomatic episode within 7 days that will be undergoing cardioversion taking into account that about 70% of patients with symptomatic AF < 72 h were reported to convert spontaneously [19]. Beyond 7 days, AF is likely to persist and the chances of pharmacological cardioversion to be successful become low. Hypertension was reported when documented on the medical record or the patient report. Coronary artery disease (CAD) was diagnosed when the patient had a documented history of CAD and/or a history of coronary revascularization.
Patients and Procedures
Adult patients (≥ 18 years) with recent-onset AF occurring between September 1, 2011 and April 11, 2018 who received vernakalant for cardioversion were eligible for inclusion in this international, multicenter, observational, post-authorization study. Fifty-five hospitals in Austria, Denmark, Germany, Spain, Sweden, and Finland participated in the study, 53 of which enrolled patients. While administration of vernakalant was at the discretion of the treating physician, consecutively treated patients were enrolled and reasons for non-participation were documented. A preinfusion checklist and healthcare provider educational card were implemented during the study period to assist in identifying patients for treatment consistent with the approved indications and contraindications.
Patients were required to give informed consent for participation in the study and could be enrolled more than once if they presented on multiple occasions for AF episodes. Patients who had participated in an investigational drug/device clinical trial within 30 days prior to enrollment were not eligible. In order to enhance enrollment and reach the EMA required target of 2000 episodes, a protocol amendment was made in September 2016, which permitted retrospective inclusion of patients who had received vernakalant between April 2013 and the end of the study, provided that they fulfilled the established eligibility criteria. For prospectively enrolled patients, data were collected from both medical records and supplemental standardized data collection forms. For retrospectively enrolled patients, only medical records were available. The study period comprised a baseline assessment and up to 24-h follow-up after completion of the last infusion or until discharge. This study was mandated and approved by the European Committee for Medicinal Products for Human Use. The study protocol was approved by the appropriate local research ethics committees for all participating centers, and the study was conducted in accordance with applicable national and local regulations/guidelines, accepted standards for Good Clinical Practice, Guidelines for Good Pharmacoepidemiology Practices, and the Declaration of Helsinki [20].
Study Objectives and Endpoints
The primary objectives of the study was to estimate the incidence of clinically predefined serious adverse events (SAEs), i.e., significant hypotension (systolic blood pressure < 90 mmHg or requiring vasopressors); sustained (> 30 s) ventricular arrhythmias, Torsade de Pointes (>10 s) or ventricular fibrillation, atrial flutter with 1:1 conduction, bradycardia requiring temporary electrical pacing, or sinus arrest (> 3 s). Definition of these predefined SAEs was based on events from previous controlled studies on IV vernakalant [7, 8, 11, 12] and from the reported adverse events (AEs) on other antiarrhythmic agents. Secondary objectives included the rates of all other SAEs. Each SAE was reviewed and adjudicated by an independent expert Safety Review Committee (SRC). This study had also the objective to determine the conversion rate to sinus rhythm in a large population of patients outside the setting of controlled clinical trials.
The duration of the index AF episode was calculated as the time between the patient-reported time of symptom onset and the start of the first vernakalant infusion. Successful cardioversion was defined as conversion to sinus rhythm within 90 min of the start of vernakalant infusion. Conversion rate was calculated in all patients, as well as in an effectiveness population excluding all treatment episodes in which patients received another therapy for cardioversion within 90 min of the start of vernakalant administration (e.g., electrical or pharmacological cardioversion). Vernakalant is recommended to be administered in a step-dose fashion. Each treatment episode can comprise up to two infusions, separated by a 15-min observation period. The recommended doses for the first and second infusions are 3.0 mg/kg and 2.0 mg/kg, respectively, each administered over 10 min. For patients above 113 kg, vernakalant has a fixed initial dose of 339 mg. If conversion to sinus rhythm does not occur within 15 min after the end of the initial infusion, a second 10-min infusion of 226 mg may be administered.
Statistics and Analyses
A target sample size of 2000 vernakalant IV treatment episodes was chosen to allow adequate statistical precision, as expressed by a two-sided 95% confidence limit. Enrollment per site was capped at 10% of the total study population and 40% per country to minimize any potential bias in practice patterns. Categorical variable frequency, along with 95% confidence intervals (CIs), was determined for the summed treatment episodes. Continuous variables were summarized using descriptive statistics. Data were analyzed based on enrollment method (prospective vs retrospective) and reported as stratified and unstratified CIs. All analyses were performed using Statistical Analysis System v9.2, or later, software.
Results
Study Population
A total of 1778 patients who presented with 2009 treatment episodes were included: 1580 episodes were in prospectively enrolled patients and 429 in retrospectively enrolled patients (Table 1). The majority of patients were treated in the ED for 1289 (64.1%) AF episodes and 563 (28.0%) AF episodes in the coronary or intensive care units, with the remainder 157 (7.8%) episodes being treated in other hospital settings. As seen in Fig. 1, the main reason for non-inclusion in the study was lack of informed consent. In 1905 (94.7%) AF episodes, vernakalant was administered to non-surgery patients, and in 104 (5.2%) to post-cardiac surgery patients. The later are among the prospectively included patients. The mean age of the overall patient population at time of treatment was 62.3 ± 13.0 years (mean ± standard deviation [SD]), ranging from 18.0 to 94.0 years, and 1222 (60.8%) episodes occurred in men (Table 1). At baseline, systolic blood pressure (BP) was 132.5 ± 19.5 mmHg and heart rate (HR) was 112.9 ± 25.5/min (mean ± SD). The median duration of AF episode prior to treatment was 11.1 (5.4–27.0) hours (median [interquartile range, IQR]). In 88.9% of episodes, the patients were treated within 48 h of the onset of symptoms, and in 72.5% within 24 h. Duration of AF before treatment in 104 post-cardiac surgery patients was shorter than in the overall population, with 3.6 h (range 0.8–15.4) (median [IQR]). Baseline demographics and characteristics were similar between patients enrolled prospectively and retrospectively. Total length of ED stay was 7.5 (5.0–13.5) hours (median [IQR]). Only 167 (13.0%) of patients initially managed in the ED were in hospital for 24 h or longer. The number of vernakalant infusions was available in 1990 patients. Of these, 1201 (60.4%) received one vernakalant infusion and 789 (39.6) received a total of 2 infusions.Table 1 Clinical characteristics of patients
Total Prospective Retrospective
No. of patients 2009 1580 429
Age (years) mean ± SD 62.3 ± 13.0 61.9 ± 13.5 63.6 ± 11.2
Range (years) 18.0–94 18–93 30–94
Male, n (%) 1222 (60.8) 998 (63.2) 224 (52.2)
Body weight (kg) mean ± SD 84.1 ± 16.5 84.3 ± 16.5 83.1 (16.9)
Range (kg) 45.0–189.0 45.0–189.0 45.0–165.0
Body mass index (kg/m2) 27.8 ± 4.9 27.7 ± 4.8 28.2 ± 5.1
Associated conditions, n (%)
Hypertension 1103 (54.9) 884 (55.9) 219 (51.0)
Coronary artery disease 118 (5.9) 82 (5.2) 36 (8.4)
Cardiomyopathy 33 (1.6) 31 (2.0) 2 (0.5%)
Heart failure (history) 63 (3.1) 59 (3.7) 4 (0.9)
Diabetes 199 (9.9) 165 (10.4) 34 (7.9)
Stroke (history) 91 (4.5) 68 (4.3) 23 (5.4)
Pacemaker/ICD 36 (1.8) 24 (1.5) 12 (2.8)
Type of AF episode
First detected 477 (23.7) 393 (24.9) 84 (19.6)
Previous history of AF 1458 (72.6) 1115 (70.6) 343 (80.0)
Onset unknown/not assessed 5 (0.2) 3 (0.2) 2 (0.5)
Post-surgery 69 (3.4) 69 (4.4) 0 (0.0)
Symptoms on admission, n (%)
Palpitations, irregular heart beat 1749 (87.1) 1337 (84.6) 412 (96.0)
Dyspnea or shortness of breath 352 (17.5) 306 (19.4) 46 (10.7)
Dizziness, light-headedness 320 (15.9) 251 (15.9) 69 (16.1)
Chest pain 271 (13.5) 220 (13.9) 51 (11.9)
Syncope, near syncope 61 (3.0) 53 (3.4) 8 (1.9)
Duration of the index episode
Less than 24 h, n (%) 1438 (72.5) 1107 (70.2) 331 (81.5)
24–48 h, n (%) 347 (17.5) 288 (18.3) 59 (14.5)
More than 48 h 199 (10.0) 183 (11.6) 16 (3.9)
Mean duration ± SD (h) 23.2 ± 44.9 24.9 ± 45.8 16.8 ± 40.6
Median (IQR 25–75) (h) 11.1 (5.44–27.03) 11.9 (5.8–29.7) 8.2 (4.8–18.3)
Antiarrhythmic agents, n (%)
Betablockers 1055 (52.5) 800 (50.6) 255 (59.4)
Calcium channels blockers 22 (1.1) 20 (1.3) 2 (0.5)
Class I agents* 85 (4.2) 71 (4.5) 14 (3.3)
Class III agents* 98 (4.9) 89 (5.6) 9 (2.1)
Digitalis glycosides 22 (1.1) 18 (1.1) 4 (0.9)
*Using the Vaughan-Williams classification
Fig. 1 Study flow chart. Flow chart showing patient enrollment in the SPECTRUM study. The term patient here refers to individual treatment episodes (asterisk). Owing to lack of informed consent (n = 500) (dagger). Other reasons included patient enrollment in an investigational drug trial in the past 30 days, spontaneous conversion to sinus rhythm, ejection fraction 30–35%, electrical cardioversion preferred, missing information regarding start of atrial fibrillation, inclusion criteria not met, other, or no reason provided or known. Source data could not be verified to confirm that vernakalant IV was administered (double dagger). Spontaneous conversion to sinus rhythm before vernakalant IV administration (section sign). Patient decision and lack of follow-up after cardioversion in one case each (double vertical line). IV intravenous
Predefined Serious Adverse Events and Other Adverse Events
No deaths were recorded in our study. Nineteen predefined SAEs were reported during or after 17 treatment episodes (cumulative incidence 0.8%; CI 0.5–1.4%) (Table 2). Eighteen of the 19 events occurred within 2 h from the start of infusion. The remaining event was an episode of atrial flutter with 1:1 conduction which occurred 3.1 h after drug infusion and was terminated by electrical shock. Symptomatic bradycardia was the most common event occurring in 11 (0.5%; CI 0.4–1.2%) episodes (Table 2). Conversion to sinus rhythm occurred in 10 of these cases. A pause described as sinus arrest preceding the restoration of sinus rhythm occurred in 4 patients. In 2 patients, sinus arrest was associated with sinus bradycardia. In all bradycardia and sinus arrest cases, the vernakalant infusion was immediately discontinued. One of these 4 sinus arrests occurred in a 66-year-old man, sportive cyclist with no history of heart disease, admitted for a first episode of AF with a mean ventricular response of 95 beats/min. He received 300 mg orally of flecainide which failed to restore sinus rhythm. The treating physician decided 4 h later, to administer IV vernakalant. At the end of the infusion, a pause of 6 s, with a brief dizziness, occurred and resolved spontaneously, followed by a normal sinus rhythm with a HR of 47 beats/min which was patient usual HR and a BP of 120/85 mmHg. This event was considered a SAE although there was probably an interaction between oral flecainide still active and vernakalant in this event. One of the bradycardia events occurred in a retrospectively enrolled 69-year-old woman on bisoprolol with a history of hypertension and CAD, who developed 8 min after the second infusion of vernakalant a sinus bradycardia which rapidly resolved with IV atropine. Two bradycardia episodes occurred in post-cardiac surgery patients requiring temporary electrical pacing through the electrodes left in place by the surgeon. Both patients converted to sinus rhythm. None of the non-surgery patients required temporary electrical pacing. Significant hypotension occurred on two (0.1%; CI < 0.1–0.4%) occasions, associated with sinus bradycardia in both instances. Both events resolved with intravenous atropine and fluid. There were two cases of atrial flutter with 1:1 ventricular conduction terminated with electrical shock whereas no cases of sustained ventricular tachycardia (VT), ventricular fibrillation, or Torsade de Pointes were observed. In addition to the predefined SAEs, there were 9 other SAEs, one of which occurred in a retrospectively enrolled patient (Table 2). They included two instances of hypotension not requiring vasopressor agents, 2 non-sustained VT which deserve special attention. The first non-sustained VT occurred in a 48-year-old man with asthma admitted with fever, palpitations, dyspnea, and first episode of AF with a ventricular rate of 144 bpm. During vernakalant infusion, 5 beats of non-sustained VT was observed. Among the tests done, coronary angiography was reported as normal. The same run of 5 beats of non-sustained VT was observed 20 h after infusion (next day) making the causal effect of vernakalant unlikely. The other event occurred in a 57-year-old patient with a 6-year history of recurrent symptomatic AF and arterial hypertension with left ventricular hypertrophy. He was admitted with palpitations, irregular heartbeats, and dizziness. He was on dronedarone, and ECG showed AF with a ventricular rate of 135 bpm. During infusion of vernakalant, he had 6 s of non-sustained VT observed on the monitor and was given 5 mg of bisoprolol which reduced the heart rate to 120 beats/min and relieved patient symptoms. The Safety Review Committee considered that in the first case, the wide QRS complexes were due to aberrant conduction during rapid AF (Ashman phenomenon). Among the non-predefined SAEs, one supraventricular tachycardia (120 beats/min) and a single report each of angina pectoris, pericardial effusion, transient visual disturbance, and vernakalant overdose (Table 2). A total of 188 non-serious AEs were reported, the most common of which were dysgeusia (n = 35) and sneezing (n = 27). All patients with vernakalant-related AEs recovered without sequelae. All but 6 of the 28 SAEs were considered by the investigators and the SRC to be related to vernakalant administration.Table 2 Adverse events in 2009 episodes during treatment and observation periods
Event type Number of events Incidence (95% CI) Considered drug-related, n (%)
All SAEs 28 1.3% (0.8–1.9) 22 (78.6)
Predefined SAEs 19 0.8% (0.5–1.4) 18 (94.7)
Significant hypotension 2 0.1% (< 0.1–0.4) 2 (100.0)
Bradycardiaα 11 0.5% (0.3–10) 10 (93.3)
Sinus arrest (> 3 s)β 4 0.2% (< 0.1–0.4) 4 (100.0)
Atrial flutter with 1: 1 AV conduction 2 0.1% (0.1–0.4) 2 (100.0)
Ventricular tachycardia γ 0 0 0 (0.0)
Other than predefined SAEs 9 0.45% 5 (55.6)
Hypotension 2 0.1% 1 (50.0)
Supraventricular tachycardiaδ 1 < 0.1% 1 (100.0)
Non-sustained ventricular tachycardiaε 2 < 0.1% 1 (50.0)
Angina pectoris 1 (< 0.1) < 0.1% 0 (0.0)
Pericardial effusion 1 (< 0.1) < 0.1% 0 (0.0)
Visual disturbance 1 (< 0.1) < 0.1% 0 (0.0)
Vernakalant overdoseζ 1 (< 0.1) < 0.1% 1 (100.0)
αNine cases of sinus bradycardia and 2 reported as significant bradycardia
βOne patient had both sinus arrest followed by sinus bradycardia
γOne event reclassified as atrial flutter with 1:1 conduction
δAtrial arrhythmia other than atrial flutter
εSee text, exceeding 5% of the weight-based dosing recommendation. In this case, the administered dose was 51% in excess of the recommended dose
Rates of Conversion to Sinus Rhythm
Overall, conversion to sinus rhythm at any time following vernakalant infusion occurred in 1448 out of 2009 (72.1%) treatment episodes. Successful cardioversion was recorded in 70.2% (CI 68.1–72.2%) of the 1936 episodes of the effectiveness population excluding those in which either electrical cardioversion (n = 68) or an additional intravenous Class I/III antiarrhythmic drug (n = 6) was given within 90 min of infusion initiation. The rate of cardioversion was similar between the 1107 of 1580 (70.1%) episodes included prospectively and the 297 of 421 (70.5%) episodes of retrospectively enrolled patients. Successful cardioversion of AF was reported in 68 of 104 (65.4%) of treatment episodes in the post-cardiac surgery patients. Time to cardioversion was recorded in 1413 of 1448 episodes with successful conversion to sinus rhythm. The median time to conversion was 12.0 (8.0–28.0) minutes (median [IQR]) Fig. 2). One thousand one hundred eight of 1413 (78.4%) successful cardioversions were treated with only one drug infusion. The percentage of successful cardioversion was 70.1% in the prospective patients and 70.5% in the retrospective patients. The median hospital stay time in those treated in the ED was 7.5 h allowing patient discharges when their condition was clinically stable.Fig. 2 Time to conversion to sinus rhythm. Time to conversion to sinus rhythm with vernakalant IV in the effectiveness analysis population (N = 1936). Time to conversion was not recorded in 29 treatment episodes in which patients converted to sinus rhythm; these episodes are not displayed on the graph but are taken into account for the proportion calculation. IV intravenous
Anticoagulation
About a quarter of patients presenting with recent-onset AF at baseline were on vitamin K antagonists or direct oral anticoagulants. Investigators respected current guidelines [3] on anticoagulation both peri-procedurally and after hospital discharge.
Discussion
The SPECTRUM study included a large real-world patient population of 1778 patients with 2009 recent-onset AF episodes in whom pharmacological cardioversion was performed with vernakalant. About 70% of patients were cardioverted within 12 min from onset of infusion and 11 h from the AF onset. Our findings confirm the safety and efficacy of vernakalant reported in previous studies [7–18, 21–25] and extend their consistency to routine hospital use in large populations. To our knowledge, the present study provides the largest series of patients with recent-onset AF undergoing pharmacological cardioversion with a specific antiarrhythmic agent. The safety was the main objective of this study. We found the incidence of both predefined and other SAEs to be lower than expected. There were no death and no sustained ventricular arrhythmia. Overall, 28 SAEs (1.3%) were recorded. The majority of patients were AF treated in ED and intensive care units.
Pharmacological cardioversion is frequently indicated as part of a rhythm control strategy or as a tool to control patient symptoms and avoid hospitalization in clinically stable condition [25, 26]. It is often preferred to electrical cardioversion in patients with hemodynamically stable condition as it does not require general anesthesia or sedation. Among agents currently available for rapid termination of recent-onset AF, vernakalant represents an option [3]. However, there has been to our knowledge, no large study exploring the safety of vernakalant in daily practice.
There is no universal definition for recent-onset AF. In current literature, the duration limits of AF episodes range from < 24 [27] to < 48 h and even < 7 days [28, 29]. The prevalence of recent-onset AF among all AF subsets varies from 11% when restricted to the first detected episode (new onset) [30] to 26% [31]. The characteristics of patients were similar to those of other AF cohorts [31, 32].
As with electrical cardioversion, pharmacological cardioversion can be associated with post-cardioversion bradyarrhythmias, often unmasking pre-existing sinus node dysfunction or atrioventricular conduction abnormalities and can result in ventricular escape rhythms or prolonged ventricular pauses. Of interest, these pauses were first reported by Lown [33], following electrical cardioversion as the possible reflect of sinus dysfunction. Another possible mechanism for these sinus arrests is right atrial stunning [34]. The cumulative incidences of bradycardia (0.5%), sinus arrest (0.2%), and hypotension (0.1%) observed in this study were also low. The incidence of atrial flutter with 1:1 conduction was lower than that reported with oral Class Ic antiarrhythmics, such as flecainide or propafenone. The “pill in the pocket” approach requires initiation of therapy in hospital to verify its safety [35]. No cases of Torsade de Pointes or sustained VT was observed, which is in line with the low risk of ventricular proarrhythmia associated with vernakalant owing to its electrophysiological properties [5]. This contrasts with the reported incidence of Torsade de Pointes [24, 36, 37] in patients with AF/atrial flutter of 4.3% with intravenous ibutilide in the report of Kowey et al. including 1.7% of which required cardioversion [36]. Of note, all but one of the predefined SAEs in this study occurred within 2 h of the start of infusion. As aforementioned, the remaining patient had atrial flutter with 1:1 ventricular conduction which occurred 3.1 h following infusion initiation, indicating that close cardiac monitoring should be available during and after treatment in some patients.
Conversion to sinus rhythm with vernakalant was rapid (median time of 12.0 min) similar to what was previously reported [9–18]. The conversion median time of ibutilide was significantly longer than that of vernakalant (26 min versus 10 min, P = 0.01) in a randomized comparison [18]. Furthermore, in this particularly large real-world study, the median duration of AF episode was short (11.1 h) as there is important evidence, and relevant guidelines [3] suggesting that prompt cardioversion could be associated with benefits in terms of lower risk of thromboembolic events [4, 38, 39].
Although the baseline characteristics of the study population were consistent with AF population-based studies [31, 32] and clinical studies with vernakalant, the conversion rate was higher than that observed in recent review and meta-analysis (~ 50%) [22–25]. This seems likely to be due to patients being treated soon after symptom onset in European clinical practice. Other recent but smaller observational studies [13–15, 17, 18], which collectively included almost 1300 patients, have found similarly high conversion rates (65–86%) when vernakalant was administered soon after the onset of AF, particularly within the first 48 h [15, 17, 21]. Vernakalant has also been shown to induce a higher rate of cardioversion compared with flecainide (67% vs 46%) in a non-randomized cohort study [21]. Similarly, in randomized studies, vernakalant was more effective than amiodarone [12] (52% vs 5%; after 90 min) and ibutilide [18, 24] (69% vs 43%; within 90 min). The SPECTRUM results are consistent with previous reports that vernakalant is safe and effective for the rapid cardioversion of recent-onset AF and extends them to daily practice.
Owing to the rapid time to conversion with vernakalant, the median hospital stay time for those treated in the ED was 7.5 h. This is encouraging given that a study in France reported that hospitalization constitutes 60% of the cost of care for patients with AF [40].
Study Limitations
This multicenter international study was observational as the main objective was to determine the safety of vernakalant as used in daily hospital practice without interfering on the management of recent-onset AF by the treating physician. For these reasons, the adverse events were expected to be higher in an “uncontrolled” setting with no guidance on patient selection than those reported in controlled studies with strict protocols. In fact, SAEs were low in this study. Data collection for prospectively enrolled patients was comprehensive owing to use of both study-specific tools and medical records. However, for retrospectively enrolled patients, it was not possible to routinely collect all data of interest in a standardized manner. Nevertheless, baseline characteristics, medical histories, and SAEs in the retrospective cohort were similar to those in the prospective cohort, supporting the use of a retrospective analysis.
Conclusions
The results of this large multicenter study showed that vernakalant has a good safety profile and is effective in enabling rapid cardioversion in clinical practice. Moreover, the rates of serious complications were lower than those observed in early trials reflecting appropriate patient selection in clinical practice. In conclusion, vernakalant provides a rapid and effective means of pharmacological conversion in patients with recent-onset AF undergoing cardioversion undergoing cardioversion in daily hospital practice.
Appendix. List of Investigators
Austria: Michael Joannidis, Klemens Zotter Frank Hartig, Anton Sandhofer, Alois Süssenbacher, Bernd Eber, Elisabeth Lassnig, Ulrike Pfeifenberger, Michaela Steiner, Hans Domanovits, Alexander Simon, Alexander Spiel, Jan Niederdockl, Nikola Schuetz, Daniel Wehinger, Franz Xaver Roithinger, Isabella M. von Katzler, Katharina Bichler, Robert Schoenbauer, Lukas Fiedler, Michael Pfeffer, Markus Peck, Florian Benische, Michael Hackl, Susane Demschar, Astrid Ebner, Melanie Eder, Rainer Huditz, Arnulf Isak, Michael Moser, Georg Pinter, Thomas Singer, Claudia Waldhauser, Helmut Pürerfellner, Martin Martinek, Sandra Muellner, Andrea Ploechl, Tanja Koppler, Elisabeth Sigmund, Michael Derndorfer, Sabine Metz, Karin Streicher, Clemens Steinwender, Karim Saleh, Andreas Lueger, Petra Fladerer, Eiko Meister, Heinz Drexel, Alexandra Schuler, Susanne Waeger, Karl-Martin Ebner, Christine Heinzle, Arthur Mader, Peter Schwerzler, Berta Patsch, Abdurahman Said, Claudia Stoeckloecker, Daniela Zanolin, Jutta Bergler-Klein, Ljubica Mandic, Mariann Gyöngyösi, Neraida Cene, Zsuzsanna Szankai, Abelina Zimba.
Denmark: Henrik Nielsen, Bjerre Flemming, Michaelsen Michaelsen, Elisa Stokholm, Katja Holm, Charlotte Schmidt Skov, Pauline Gøgsig Johansen, Soren shjortshoj, Thomas Melchior, Ole Dyg Pedersen, Sanne Heinsvig, Inge Larsen, Vibeke Perret-Gentil, Thomas Wagner Nielsen, Axel Brandes, Marianne Jensen, Ida Rosenlund, Liv Gøtzsche, Heidi Munk Andersen.
Germany: Andreas Götte, Matthias Hammwohner, Britta Möehring, Jutta Schaertl, Daniel Steven, Iris Berg, Alexandra Kuehn, Hannes Reuter, Elena Terentieva, Christian Loges, Christine Lindner, Hendrik Bonnemeier, Christan Wulff, Thomas Demming, Svenja Gediehn, Johanna Parlitz, Wilhelm Haverkamp, Buehner Kathrin, Hubert Katja, Iacovella Ines, Bernhard Korbmacher, Marc Thone, Hannan Dalyanoglu, Da Un Chung, Naujoks Angela, Dirk Weismann, Björn Lengenfelder, Jan Becher, Klaus Meyer, Irina Turkin, Sebastian Maier, Marcus Koller, Alban Glaser, Lisa Gebele, Jale Goezuebueyuek, Ralph Hampe, Barbara Ruemmler, Hagen Schrötter, Manja Hubald, Cornelia Fritz, Martin Domhardt, Kathrin Haacke, Nicole Schmiedehausen, Ruth Strasser, Kristof Graf, Lidia Fischer, Roland Thieme, Karlheinz Seidl, Martin Kulzer, Monika Zackel, Gerian Grönefeld, Christina Paitazoglou, Simone Müller, ThoraBotschafter Britta Goldmann, Andrea Moeller, Sindy Bartel, Joern Schmitt, Damir Erkapic, Gabriele Hellwig-Bahavar, Ritvan Chasan, Christopher Gemein, Victoria Johnson, Christiane Kelm, Kay Weipert, Johannes Brachmann, Michael Held, Andrea Höhn, Ute Goebel, Andrea Linss, Swetlana Rube, Ahmed Saleh, Steffen Schnupp, Yeong-Hoon Choi, Vera Wolf, Andrea Plate, Anton Sabashnikov, Antje-Christin Deppe, Petra Krause.
Spain: Ignacio Fernandez Lozano, Manuel Sánchez, Francisco Hernández, Alfonso Martin Martinez, Pedro Vazquez, Esther Alvarez, Pascual Lopez, Raquel Torres, José Carbajosa Dalmau, Laura Parades, Nestor Hernandez, Inmaculada Jimenez Ruiz, Ana Maria Lopez, Luis López-Andujar, Alexandre Noguera, Francisco Roman Cerdan, Carmen del Arco Galan, Daniel Afonso, Raquel Caminero, Manual Lunquera, Monica Negro, Cristina Santiago, Nestor Villalba, José Manuel Garrido Castilla, Roberto Martinez Asenjo, Elena Mejia Martinez, José Luís Merino Llorens, Maria Jesus Diaz-Pintado, Jorge Alejandro Figueroa, Alberto Borobia Perez, Sergio Castrejon Castrejon, David Filgueiras Rama, Manuel Quintana Diaz, Maria Angelica Ribera Nunez, Miguel Angel Ramirez Marrero, Antonio Martin, José Miguel Ormaetxe Merodio, Mercedes Varona Peinador, Maria Fe Arcocha, Larraitz Gaztañaga, F. Xavier Palom Rico, Javier Jacob Rodriguez, Pascual Piñera Salmeron, Juan Cosin Sales, Isabel Navarro, Francisco Buendia Funetes.
Sweden: Henrik Wallentin, Kerstin Roos, Arash Mokhtari, Hans-Jörgen Nilsson, Peter Vasko, Terese Nyström, Martina Gustensson, Susanne Johansson, Inga Uggeldahl, Göran Andersson, Olle Bergström, Thomas Aronsson, Mehmet Hamid, Kerstin Giocondi, Deborah Svanerö, Qassim Awad, Tord Juhlin, Hjördis Jernhed, Stefan Berglund, Magnus Forsgren, Michael Guggi, Pär-Lennart Agren, Kristina Eriksson, Kristina Karlsson, Per Blomström, Alejandro Utreras, Caroline Lundgren, Maria Soderlund, Frederik Buijs, Solveig Östberg, Johan-Emil Bager, Ingrid Hendequist, Maria Just, Siv Heden, Liselott Lisjo, Chrichan Mansson, Helen Svanstrom, Mikael Dellborg, Helena Dellborg, Gorel Hultsberg Olsson, Linus Hansson.
Finland: Hannu Sulonen, Hanna Suurmunne, Anna Petrovskaja, Johanna Markkanen, Juha Hartikainen, Lari Kujanen, Antti Heikkola, Hanna Pohjantahti MaarooS.
Safety Review Committee
Lars Kober, MD, Samuel Lévy, MD (Chair), Cristina Varas-Lorenzo, MD, MSc, PhD, Manel Pladevall-Vila MD, MS.
The authors wish to thank Nathalie Dunkel and her team for their help in accessing the data of SPECTRUM and providing information and documents upon our request.
The authors would like to thank all of the investigators involved in the SPECTRUM study.
Funding
This study was funded by Correvio International Sàrl, Geneva, Switzerland. The authors received no funding for their participation in this manuscript.
Data Availability
The data underlying this article will be shared on reasonable request to the corresponding author.
Compliance with Ethical Standards
Conflict of Interest
Professor Levy reports no conflicts of interest. Professor Hartikainen has been an investigator in studies sponsored by AstraZeneca, Biosense Webster, Boehringer Ingelheim, Correvio International Sàrl, Medtronic, and St. Jude Medical. Dr. Ritz is an employee of Correvio International Sàrl, Geneva, Switzerland. Dr. Juhlin has received speaker honoraria from Correvio International Sàrl. Professor Domanovits reports no conflicts of interest. Dr. Carbajosa-Dalmau has received speaker honoraria from Correvio International Sàrl.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Oral | DrugAdministrationRoute | CC BY | 33206300 | 19,695,564 | 2021-04 |
What was the outcome of reaction 'Dizziness'? | Vernakalant for Rapid Cardioversion of Recent-Onset Atrial Fibrillation: Results from the SPECTRUM Study.
Rapid restoration of sinus rhythm using pharmacological cardioversion is commonly indicated in patients with symptomatic recent-onset atrial fibrillation (AF). The objectives of this large, international, multicenter observational study were to determine the safety and effectiveness of intravenous (IV) vernakalant for conversion of AF to sinus rhythm in daily practice.
Consenting patients with symptomatic recent-onset AF (< 7 days) treated with IV vernakalant were enrolled and followed up to 24 h after the last infusion or until discharge, in order to determine the incidence of predefined serious adverse events (SAEs) and other observed SAEs and evaluate the conversion rate within the first 90 min. Overall, 2009 treatment episodes in 1778 patients were analyzed. The age of patients was 62.3 ± 13.0 years (mean ± standard deviation). Median AF duration before treatment was 11.1 h (IQR 5.4-27.0 h). A total of 28 SAEs occurred in 26 patients including 19 predefined SAEs, i.e., sinus arrest (n = 4, 0.2%), significant bradycardia (n = 11, 0.5%), significant hypotension (n = 2, 0.1%), and atrial flutter with 1:1 conduction (n = 2, 0.1%). There were no cases of sustained ventricular arrhythmias or deaths. All patients who experienced SAEs recovered fully (n = 25) or with sequelae (n = 1). Conversion rate to sinus rhythm was 70.2%, within a median of 12 min (IQR 8.0-28.0 min).
This large multicenter, international observational study confirms the good safety profile and the high effectiveness of vernakalant for the rapid cardioversion of recent-onset AF in daily hospital practice.
Introduction and Purpose of the Study
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with an estimated 33.5 million people affected worldwide [1]. One in four adults over 55 years of age in Europe and the USA develop AF, with greater prevalence in older populations [1, 2]. Patients with AF are at increased risk of stroke and heart failure [3, 4]. A significant number of patients with recent-onset AF seen in the emergency departments (EDs) undergo commonly in Europe pharmacological cardioversion.
Vernakalant is a partial atrial-selective antiarrhythmic agent by its action through IKur and IKACh channel inhibition [5]. However, it has a modest effect on the ventricle via Ina and IKr channels resulting in a limited effect on ventricular repolarization (QT interval) [5]. Vernakalant is contra-indicated in patients with prolonged QT interval.
Intravenous vernakalant has been approved by the European Medicine Agency [2010] for the rapid conversion of recent-onset AF [6]. To date, a number of studies have shown vernakalant to be well tolerated and effective for cardioversion of AF [7–18].
The FDA (Food and Drug Administration agency) decided in 2008 and in December 2019 not to approve to market vernakalant in the USA for safety concerns. In 2010, the EMA requested a post-authorization safety study to better define the risk benefit ratio in routine clinical practice. The objectives of SPECTRUM (Surveillance of Pharmacologic thErapy for Cardioversion in aTrial fibrillation Registry Using IV treatMent) (NCT01370629 and EUPAS2078) study were to assess the rates of adverse events and to estimate the effectiveness of the drug in a large cohort of patients with recent-onset AF.
Methods
Definitions
Recent-onset AF was defined as symptomatic episode within 7 days that will be undergoing cardioversion taking into account that about 70% of patients with symptomatic AF < 72 h were reported to convert spontaneously [19]. Beyond 7 days, AF is likely to persist and the chances of pharmacological cardioversion to be successful become low. Hypertension was reported when documented on the medical record or the patient report. Coronary artery disease (CAD) was diagnosed when the patient had a documented history of CAD and/or a history of coronary revascularization.
Patients and Procedures
Adult patients (≥ 18 years) with recent-onset AF occurring between September 1, 2011 and April 11, 2018 who received vernakalant for cardioversion were eligible for inclusion in this international, multicenter, observational, post-authorization study. Fifty-five hospitals in Austria, Denmark, Germany, Spain, Sweden, and Finland participated in the study, 53 of which enrolled patients. While administration of vernakalant was at the discretion of the treating physician, consecutively treated patients were enrolled and reasons for non-participation were documented. A preinfusion checklist and healthcare provider educational card were implemented during the study period to assist in identifying patients for treatment consistent with the approved indications and contraindications.
Patients were required to give informed consent for participation in the study and could be enrolled more than once if they presented on multiple occasions for AF episodes. Patients who had participated in an investigational drug/device clinical trial within 30 days prior to enrollment were not eligible. In order to enhance enrollment and reach the EMA required target of 2000 episodes, a protocol amendment was made in September 2016, which permitted retrospective inclusion of patients who had received vernakalant between April 2013 and the end of the study, provided that they fulfilled the established eligibility criteria. For prospectively enrolled patients, data were collected from both medical records and supplemental standardized data collection forms. For retrospectively enrolled patients, only medical records were available. The study period comprised a baseline assessment and up to 24-h follow-up after completion of the last infusion or until discharge. This study was mandated and approved by the European Committee for Medicinal Products for Human Use. The study protocol was approved by the appropriate local research ethics committees for all participating centers, and the study was conducted in accordance with applicable national and local regulations/guidelines, accepted standards for Good Clinical Practice, Guidelines for Good Pharmacoepidemiology Practices, and the Declaration of Helsinki [20].
Study Objectives and Endpoints
The primary objectives of the study was to estimate the incidence of clinically predefined serious adverse events (SAEs), i.e., significant hypotension (systolic blood pressure < 90 mmHg or requiring vasopressors); sustained (> 30 s) ventricular arrhythmias, Torsade de Pointes (>10 s) or ventricular fibrillation, atrial flutter with 1:1 conduction, bradycardia requiring temporary electrical pacing, or sinus arrest (> 3 s). Definition of these predefined SAEs was based on events from previous controlled studies on IV vernakalant [7, 8, 11, 12] and from the reported adverse events (AEs) on other antiarrhythmic agents. Secondary objectives included the rates of all other SAEs. Each SAE was reviewed and adjudicated by an independent expert Safety Review Committee (SRC). This study had also the objective to determine the conversion rate to sinus rhythm in a large population of patients outside the setting of controlled clinical trials.
The duration of the index AF episode was calculated as the time between the patient-reported time of symptom onset and the start of the first vernakalant infusion. Successful cardioversion was defined as conversion to sinus rhythm within 90 min of the start of vernakalant infusion. Conversion rate was calculated in all patients, as well as in an effectiveness population excluding all treatment episodes in which patients received another therapy for cardioversion within 90 min of the start of vernakalant administration (e.g., electrical or pharmacological cardioversion). Vernakalant is recommended to be administered in a step-dose fashion. Each treatment episode can comprise up to two infusions, separated by a 15-min observation period. The recommended doses for the first and second infusions are 3.0 mg/kg and 2.0 mg/kg, respectively, each administered over 10 min. For patients above 113 kg, vernakalant has a fixed initial dose of 339 mg. If conversion to sinus rhythm does not occur within 15 min after the end of the initial infusion, a second 10-min infusion of 226 mg may be administered.
Statistics and Analyses
A target sample size of 2000 vernakalant IV treatment episodes was chosen to allow adequate statistical precision, as expressed by a two-sided 95% confidence limit. Enrollment per site was capped at 10% of the total study population and 40% per country to minimize any potential bias in practice patterns. Categorical variable frequency, along with 95% confidence intervals (CIs), was determined for the summed treatment episodes. Continuous variables were summarized using descriptive statistics. Data were analyzed based on enrollment method (prospective vs retrospective) and reported as stratified and unstratified CIs. All analyses were performed using Statistical Analysis System v9.2, or later, software.
Results
Study Population
A total of 1778 patients who presented with 2009 treatment episodes were included: 1580 episodes were in prospectively enrolled patients and 429 in retrospectively enrolled patients (Table 1). The majority of patients were treated in the ED for 1289 (64.1%) AF episodes and 563 (28.0%) AF episodes in the coronary or intensive care units, with the remainder 157 (7.8%) episodes being treated in other hospital settings. As seen in Fig. 1, the main reason for non-inclusion in the study was lack of informed consent. In 1905 (94.7%) AF episodes, vernakalant was administered to non-surgery patients, and in 104 (5.2%) to post-cardiac surgery patients. The later are among the prospectively included patients. The mean age of the overall patient population at time of treatment was 62.3 ± 13.0 years (mean ± standard deviation [SD]), ranging from 18.0 to 94.0 years, and 1222 (60.8%) episodes occurred in men (Table 1). At baseline, systolic blood pressure (BP) was 132.5 ± 19.5 mmHg and heart rate (HR) was 112.9 ± 25.5/min (mean ± SD). The median duration of AF episode prior to treatment was 11.1 (5.4–27.0) hours (median [interquartile range, IQR]). In 88.9% of episodes, the patients were treated within 48 h of the onset of symptoms, and in 72.5% within 24 h. Duration of AF before treatment in 104 post-cardiac surgery patients was shorter than in the overall population, with 3.6 h (range 0.8–15.4) (median [IQR]). Baseline demographics and characteristics were similar between patients enrolled prospectively and retrospectively. Total length of ED stay was 7.5 (5.0–13.5) hours (median [IQR]). Only 167 (13.0%) of patients initially managed in the ED were in hospital for 24 h or longer. The number of vernakalant infusions was available in 1990 patients. Of these, 1201 (60.4%) received one vernakalant infusion and 789 (39.6) received a total of 2 infusions.Table 1 Clinical characteristics of patients
Total Prospective Retrospective
No. of patients 2009 1580 429
Age (years) mean ± SD 62.3 ± 13.0 61.9 ± 13.5 63.6 ± 11.2
Range (years) 18.0–94 18–93 30–94
Male, n (%) 1222 (60.8) 998 (63.2) 224 (52.2)
Body weight (kg) mean ± SD 84.1 ± 16.5 84.3 ± 16.5 83.1 (16.9)
Range (kg) 45.0–189.0 45.0–189.0 45.0–165.0
Body mass index (kg/m2) 27.8 ± 4.9 27.7 ± 4.8 28.2 ± 5.1
Associated conditions, n (%)
Hypertension 1103 (54.9) 884 (55.9) 219 (51.0)
Coronary artery disease 118 (5.9) 82 (5.2) 36 (8.4)
Cardiomyopathy 33 (1.6) 31 (2.0) 2 (0.5%)
Heart failure (history) 63 (3.1) 59 (3.7) 4 (0.9)
Diabetes 199 (9.9) 165 (10.4) 34 (7.9)
Stroke (history) 91 (4.5) 68 (4.3) 23 (5.4)
Pacemaker/ICD 36 (1.8) 24 (1.5) 12 (2.8)
Type of AF episode
First detected 477 (23.7) 393 (24.9) 84 (19.6)
Previous history of AF 1458 (72.6) 1115 (70.6) 343 (80.0)
Onset unknown/not assessed 5 (0.2) 3 (0.2) 2 (0.5)
Post-surgery 69 (3.4) 69 (4.4) 0 (0.0)
Symptoms on admission, n (%)
Palpitations, irregular heart beat 1749 (87.1) 1337 (84.6) 412 (96.0)
Dyspnea or shortness of breath 352 (17.5) 306 (19.4) 46 (10.7)
Dizziness, light-headedness 320 (15.9) 251 (15.9) 69 (16.1)
Chest pain 271 (13.5) 220 (13.9) 51 (11.9)
Syncope, near syncope 61 (3.0) 53 (3.4) 8 (1.9)
Duration of the index episode
Less than 24 h, n (%) 1438 (72.5) 1107 (70.2) 331 (81.5)
24–48 h, n (%) 347 (17.5) 288 (18.3) 59 (14.5)
More than 48 h 199 (10.0) 183 (11.6) 16 (3.9)
Mean duration ± SD (h) 23.2 ± 44.9 24.9 ± 45.8 16.8 ± 40.6
Median (IQR 25–75) (h) 11.1 (5.44–27.03) 11.9 (5.8–29.7) 8.2 (4.8–18.3)
Antiarrhythmic agents, n (%)
Betablockers 1055 (52.5) 800 (50.6) 255 (59.4)
Calcium channels blockers 22 (1.1) 20 (1.3) 2 (0.5)
Class I agents* 85 (4.2) 71 (4.5) 14 (3.3)
Class III agents* 98 (4.9) 89 (5.6) 9 (2.1)
Digitalis glycosides 22 (1.1) 18 (1.1) 4 (0.9)
*Using the Vaughan-Williams classification
Fig. 1 Study flow chart. Flow chart showing patient enrollment in the SPECTRUM study. The term patient here refers to individual treatment episodes (asterisk). Owing to lack of informed consent (n = 500) (dagger). Other reasons included patient enrollment in an investigational drug trial in the past 30 days, spontaneous conversion to sinus rhythm, ejection fraction 30–35%, electrical cardioversion preferred, missing information regarding start of atrial fibrillation, inclusion criteria not met, other, or no reason provided or known. Source data could not be verified to confirm that vernakalant IV was administered (double dagger). Spontaneous conversion to sinus rhythm before vernakalant IV administration (section sign). Patient decision and lack of follow-up after cardioversion in one case each (double vertical line). IV intravenous
Predefined Serious Adverse Events and Other Adverse Events
No deaths were recorded in our study. Nineteen predefined SAEs were reported during or after 17 treatment episodes (cumulative incidence 0.8%; CI 0.5–1.4%) (Table 2). Eighteen of the 19 events occurred within 2 h from the start of infusion. The remaining event was an episode of atrial flutter with 1:1 conduction which occurred 3.1 h after drug infusion and was terminated by electrical shock. Symptomatic bradycardia was the most common event occurring in 11 (0.5%; CI 0.4–1.2%) episodes (Table 2). Conversion to sinus rhythm occurred in 10 of these cases. A pause described as sinus arrest preceding the restoration of sinus rhythm occurred in 4 patients. In 2 patients, sinus arrest was associated with sinus bradycardia. In all bradycardia and sinus arrest cases, the vernakalant infusion was immediately discontinued. One of these 4 sinus arrests occurred in a 66-year-old man, sportive cyclist with no history of heart disease, admitted for a first episode of AF with a mean ventricular response of 95 beats/min. He received 300 mg orally of flecainide which failed to restore sinus rhythm. The treating physician decided 4 h later, to administer IV vernakalant. At the end of the infusion, a pause of 6 s, with a brief dizziness, occurred and resolved spontaneously, followed by a normal sinus rhythm with a HR of 47 beats/min which was patient usual HR and a BP of 120/85 mmHg. This event was considered a SAE although there was probably an interaction between oral flecainide still active and vernakalant in this event. One of the bradycardia events occurred in a retrospectively enrolled 69-year-old woman on bisoprolol with a history of hypertension and CAD, who developed 8 min after the second infusion of vernakalant a sinus bradycardia which rapidly resolved with IV atropine. Two bradycardia episodes occurred in post-cardiac surgery patients requiring temporary electrical pacing through the electrodes left in place by the surgeon. Both patients converted to sinus rhythm. None of the non-surgery patients required temporary electrical pacing. Significant hypotension occurred on two (0.1%; CI < 0.1–0.4%) occasions, associated with sinus bradycardia in both instances. Both events resolved with intravenous atropine and fluid. There were two cases of atrial flutter with 1:1 ventricular conduction terminated with electrical shock whereas no cases of sustained ventricular tachycardia (VT), ventricular fibrillation, or Torsade de Pointes were observed. In addition to the predefined SAEs, there were 9 other SAEs, one of which occurred in a retrospectively enrolled patient (Table 2). They included two instances of hypotension not requiring vasopressor agents, 2 non-sustained VT which deserve special attention. The first non-sustained VT occurred in a 48-year-old man with asthma admitted with fever, palpitations, dyspnea, and first episode of AF with a ventricular rate of 144 bpm. During vernakalant infusion, 5 beats of non-sustained VT was observed. Among the tests done, coronary angiography was reported as normal. The same run of 5 beats of non-sustained VT was observed 20 h after infusion (next day) making the causal effect of vernakalant unlikely. The other event occurred in a 57-year-old patient with a 6-year history of recurrent symptomatic AF and arterial hypertension with left ventricular hypertrophy. He was admitted with palpitations, irregular heartbeats, and dizziness. He was on dronedarone, and ECG showed AF with a ventricular rate of 135 bpm. During infusion of vernakalant, he had 6 s of non-sustained VT observed on the monitor and was given 5 mg of bisoprolol which reduced the heart rate to 120 beats/min and relieved patient symptoms. The Safety Review Committee considered that in the first case, the wide QRS complexes were due to aberrant conduction during rapid AF (Ashman phenomenon). Among the non-predefined SAEs, one supraventricular tachycardia (120 beats/min) and a single report each of angina pectoris, pericardial effusion, transient visual disturbance, and vernakalant overdose (Table 2). A total of 188 non-serious AEs were reported, the most common of which were dysgeusia (n = 35) and sneezing (n = 27). All patients with vernakalant-related AEs recovered without sequelae. All but 6 of the 28 SAEs were considered by the investigators and the SRC to be related to vernakalant administration.Table 2 Adverse events in 2009 episodes during treatment and observation periods
Event type Number of events Incidence (95% CI) Considered drug-related, n (%)
All SAEs 28 1.3% (0.8–1.9) 22 (78.6)
Predefined SAEs 19 0.8% (0.5–1.4) 18 (94.7)
Significant hypotension 2 0.1% (< 0.1–0.4) 2 (100.0)
Bradycardiaα 11 0.5% (0.3–10) 10 (93.3)
Sinus arrest (> 3 s)β 4 0.2% (< 0.1–0.4) 4 (100.0)
Atrial flutter with 1: 1 AV conduction 2 0.1% (0.1–0.4) 2 (100.0)
Ventricular tachycardia γ 0 0 0 (0.0)
Other than predefined SAEs 9 0.45% 5 (55.6)
Hypotension 2 0.1% 1 (50.0)
Supraventricular tachycardiaδ 1 < 0.1% 1 (100.0)
Non-sustained ventricular tachycardiaε 2 < 0.1% 1 (50.0)
Angina pectoris 1 (< 0.1) < 0.1% 0 (0.0)
Pericardial effusion 1 (< 0.1) < 0.1% 0 (0.0)
Visual disturbance 1 (< 0.1) < 0.1% 0 (0.0)
Vernakalant overdoseζ 1 (< 0.1) < 0.1% 1 (100.0)
αNine cases of sinus bradycardia and 2 reported as significant bradycardia
βOne patient had both sinus arrest followed by sinus bradycardia
γOne event reclassified as atrial flutter with 1:1 conduction
δAtrial arrhythmia other than atrial flutter
εSee text, exceeding 5% of the weight-based dosing recommendation. In this case, the administered dose was 51% in excess of the recommended dose
Rates of Conversion to Sinus Rhythm
Overall, conversion to sinus rhythm at any time following vernakalant infusion occurred in 1448 out of 2009 (72.1%) treatment episodes. Successful cardioversion was recorded in 70.2% (CI 68.1–72.2%) of the 1936 episodes of the effectiveness population excluding those in which either electrical cardioversion (n = 68) or an additional intravenous Class I/III antiarrhythmic drug (n = 6) was given within 90 min of infusion initiation. The rate of cardioversion was similar between the 1107 of 1580 (70.1%) episodes included prospectively and the 297 of 421 (70.5%) episodes of retrospectively enrolled patients. Successful cardioversion of AF was reported in 68 of 104 (65.4%) of treatment episodes in the post-cardiac surgery patients. Time to cardioversion was recorded in 1413 of 1448 episodes with successful conversion to sinus rhythm. The median time to conversion was 12.0 (8.0–28.0) minutes (median [IQR]) Fig. 2). One thousand one hundred eight of 1413 (78.4%) successful cardioversions were treated with only one drug infusion. The percentage of successful cardioversion was 70.1% in the prospective patients and 70.5% in the retrospective patients. The median hospital stay time in those treated in the ED was 7.5 h allowing patient discharges when their condition was clinically stable.Fig. 2 Time to conversion to sinus rhythm. Time to conversion to sinus rhythm with vernakalant IV in the effectiveness analysis population (N = 1936). Time to conversion was not recorded in 29 treatment episodes in which patients converted to sinus rhythm; these episodes are not displayed on the graph but are taken into account for the proportion calculation. IV intravenous
Anticoagulation
About a quarter of patients presenting with recent-onset AF at baseline were on vitamin K antagonists or direct oral anticoagulants. Investigators respected current guidelines [3] on anticoagulation both peri-procedurally and after hospital discharge.
Discussion
The SPECTRUM study included a large real-world patient population of 1778 patients with 2009 recent-onset AF episodes in whom pharmacological cardioversion was performed with vernakalant. About 70% of patients were cardioverted within 12 min from onset of infusion and 11 h from the AF onset. Our findings confirm the safety and efficacy of vernakalant reported in previous studies [7–18, 21–25] and extend their consistency to routine hospital use in large populations. To our knowledge, the present study provides the largest series of patients with recent-onset AF undergoing pharmacological cardioversion with a specific antiarrhythmic agent. The safety was the main objective of this study. We found the incidence of both predefined and other SAEs to be lower than expected. There were no death and no sustained ventricular arrhythmia. Overall, 28 SAEs (1.3%) were recorded. The majority of patients were AF treated in ED and intensive care units.
Pharmacological cardioversion is frequently indicated as part of a rhythm control strategy or as a tool to control patient symptoms and avoid hospitalization in clinically stable condition [25, 26]. It is often preferred to electrical cardioversion in patients with hemodynamically stable condition as it does not require general anesthesia or sedation. Among agents currently available for rapid termination of recent-onset AF, vernakalant represents an option [3]. However, there has been to our knowledge, no large study exploring the safety of vernakalant in daily practice.
There is no universal definition for recent-onset AF. In current literature, the duration limits of AF episodes range from < 24 [27] to < 48 h and even < 7 days [28, 29]. The prevalence of recent-onset AF among all AF subsets varies from 11% when restricted to the first detected episode (new onset) [30] to 26% [31]. The characteristics of patients were similar to those of other AF cohorts [31, 32].
As with electrical cardioversion, pharmacological cardioversion can be associated with post-cardioversion bradyarrhythmias, often unmasking pre-existing sinus node dysfunction or atrioventricular conduction abnormalities and can result in ventricular escape rhythms or prolonged ventricular pauses. Of interest, these pauses were first reported by Lown [33], following electrical cardioversion as the possible reflect of sinus dysfunction. Another possible mechanism for these sinus arrests is right atrial stunning [34]. The cumulative incidences of bradycardia (0.5%), sinus arrest (0.2%), and hypotension (0.1%) observed in this study were also low. The incidence of atrial flutter with 1:1 conduction was lower than that reported with oral Class Ic antiarrhythmics, such as flecainide or propafenone. The “pill in the pocket” approach requires initiation of therapy in hospital to verify its safety [35]. No cases of Torsade de Pointes or sustained VT was observed, which is in line with the low risk of ventricular proarrhythmia associated with vernakalant owing to its electrophysiological properties [5]. This contrasts with the reported incidence of Torsade de Pointes [24, 36, 37] in patients with AF/atrial flutter of 4.3% with intravenous ibutilide in the report of Kowey et al. including 1.7% of which required cardioversion [36]. Of note, all but one of the predefined SAEs in this study occurred within 2 h of the start of infusion. As aforementioned, the remaining patient had atrial flutter with 1:1 ventricular conduction which occurred 3.1 h following infusion initiation, indicating that close cardiac monitoring should be available during and after treatment in some patients.
Conversion to sinus rhythm with vernakalant was rapid (median time of 12.0 min) similar to what was previously reported [9–18]. The conversion median time of ibutilide was significantly longer than that of vernakalant (26 min versus 10 min, P = 0.01) in a randomized comparison [18]. Furthermore, in this particularly large real-world study, the median duration of AF episode was short (11.1 h) as there is important evidence, and relevant guidelines [3] suggesting that prompt cardioversion could be associated with benefits in terms of lower risk of thromboembolic events [4, 38, 39].
Although the baseline characteristics of the study population were consistent with AF population-based studies [31, 32] and clinical studies with vernakalant, the conversion rate was higher than that observed in recent review and meta-analysis (~ 50%) [22–25]. This seems likely to be due to patients being treated soon after symptom onset in European clinical practice. Other recent but smaller observational studies [13–15, 17, 18], which collectively included almost 1300 patients, have found similarly high conversion rates (65–86%) when vernakalant was administered soon after the onset of AF, particularly within the first 48 h [15, 17, 21]. Vernakalant has also been shown to induce a higher rate of cardioversion compared with flecainide (67% vs 46%) in a non-randomized cohort study [21]. Similarly, in randomized studies, vernakalant was more effective than amiodarone [12] (52% vs 5%; after 90 min) and ibutilide [18, 24] (69% vs 43%; within 90 min). The SPECTRUM results are consistent with previous reports that vernakalant is safe and effective for the rapid cardioversion of recent-onset AF and extends them to daily practice.
Owing to the rapid time to conversion with vernakalant, the median hospital stay time for those treated in the ED was 7.5 h. This is encouraging given that a study in France reported that hospitalization constitutes 60% of the cost of care for patients with AF [40].
Study Limitations
This multicenter international study was observational as the main objective was to determine the safety of vernakalant as used in daily hospital practice without interfering on the management of recent-onset AF by the treating physician. For these reasons, the adverse events were expected to be higher in an “uncontrolled” setting with no guidance on patient selection than those reported in controlled studies with strict protocols. In fact, SAEs were low in this study. Data collection for prospectively enrolled patients was comprehensive owing to use of both study-specific tools and medical records. However, for retrospectively enrolled patients, it was not possible to routinely collect all data of interest in a standardized manner. Nevertheless, baseline characteristics, medical histories, and SAEs in the retrospective cohort were similar to those in the prospective cohort, supporting the use of a retrospective analysis.
Conclusions
The results of this large multicenter study showed that vernakalant has a good safety profile and is effective in enabling rapid cardioversion in clinical practice. Moreover, the rates of serious complications were lower than those observed in early trials reflecting appropriate patient selection in clinical practice. In conclusion, vernakalant provides a rapid and effective means of pharmacological conversion in patients with recent-onset AF undergoing cardioversion undergoing cardioversion in daily hospital practice.
Appendix. List of Investigators
Austria: Michael Joannidis, Klemens Zotter Frank Hartig, Anton Sandhofer, Alois Süssenbacher, Bernd Eber, Elisabeth Lassnig, Ulrike Pfeifenberger, Michaela Steiner, Hans Domanovits, Alexander Simon, Alexander Spiel, Jan Niederdockl, Nikola Schuetz, Daniel Wehinger, Franz Xaver Roithinger, Isabella M. von Katzler, Katharina Bichler, Robert Schoenbauer, Lukas Fiedler, Michael Pfeffer, Markus Peck, Florian Benische, Michael Hackl, Susane Demschar, Astrid Ebner, Melanie Eder, Rainer Huditz, Arnulf Isak, Michael Moser, Georg Pinter, Thomas Singer, Claudia Waldhauser, Helmut Pürerfellner, Martin Martinek, Sandra Muellner, Andrea Ploechl, Tanja Koppler, Elisabeth Sigmund, Michael Derndorfer, Sabine Metz, Karin Streicher, Clemens Steinwender, Karim Saleh, Andreas Lueger, Petra Fladerer, Eiko Meister, Heinz Drexel, Alexandra Schuler, Susanne Waeger, Karl-Martin Ebner, Christine Heinzle, Arthur Mader, Peter Schwerzler, Berta Patsch, Abdurahman Said, Claudia Stoeckloecker, Daniela Zanolin, Jutta Bergler-Klein, Ljubica Mandic, Mariann Gyöngyösi, Neraida Cene, Zsuzsanna Szankai, Abelina Zimba.
Denmark: Henrik Nielsen, Bjerre Flemming, Michaelsen Michaelsen, Elisa Stokholm, Katja Holm, Charlotte Schmidt Skov, Pauline Gøgsig Johansen, Soren shjortshoj, Thomas Melchior, Ole Dyg Pedersen, Sanne Heinsvig, Inge Larsen, Vibeke Perret-Gentil, Thomas Wagner Nielsen, Axel Brandes, Marianne Jensen, Ida Rosenlund, Liv Gøtzsche, Heidi Munk Andersen.
Germany: Andreas Götte, Matthias Hammwohner, Britta Möehring, Jutta Schaertl, Daniel Steven, Iris Berg, Alexandra Kuehn, Hannes Reuter, Elena Terentieva, Christian Loges, Christine Lindner, Hendrik Bonnemeier, Christan Wulff, Thomas Demming, Svenja Gediehn, Johanna Parlitz, Wilhelm Haverkamp, Buehner Kathrin, Hubert Katja, Iacovella Ines, Bernhard Korbmacher, Marc Thone, Hannan Dalyanoglu, Da Un Chung, Naujoks Angela, Dirk Weismann, Björn Lengenfelder, Jan Becher, Klaus Meyer, Irina Turkin, Sebastian Maier, Marcus Koller, Alban Glaser, Lisa Gebele, Jale Goezuebueyuek, Ralph Hampe, Barbara Ruemmler, Hagen Schrötter, Manja Hubald, Cornelia Fritz, Martin Domhardt, Kathrin Haacke, Nicole Schmiedehausen, Ruth Strasser, Kristof Graf, Lidia Fischer, Roland Thieme, Karlheinz Seidl, Martin Kulzer, Monika Zackel, Gerian Grönefeld, Christina Paitazoglou, Simone Müller, ThoraBotschafter Britta Goldmann, Andrea Moeller, Sindy Bartel, Joern Schmitt, Damir Erkapic, Gabriele Hellwig-Bahavar, Ritvan Chasan, Christopher Gemein, Victoria Johnson, Christiane Kelm, Kay Weipert, Johannes Brachmann, Michael Held, Andrea Höhn, Ute Goebel, Andrea Linss, Swetlana Rube, Ahmed Saleh, Steffen Schnupp, Yeong-Hoon Choi, Vera Wolf, Andrea Plate, Anton Sabashnikov, Antje-Christin Deppe, Petra Krause.
Spain: Ignacio Fernandez Lozano, Manuel Sánchez, Francisco Hernández, Alfonso Martin Martinez, Pedro Vazquez, Esther Alvarez, Pascual Lopez, Raquel Torres, José Carbajosa Dalmau, Laura Parades, Nestor Hernandez, Inmaculada Jimenez Ruiz, Ana Maria Lopez, Luis López-Andujar, Alexandre Noguera, Francisco Roman Cerdan, Carmen del Arco Galan, Daniel Afonso, Raquel Caminero, Manual Lunquera, Monica Negro, Cristina Santiago, Nestor Villalba, José Manuel Garrido Castilla, Roberto Martinez Asenjo, Elena Mejia Martinez, José Luís Merino Llorens, Maria Jesus Diaz-Pintado, Jorge Alejandro Figueroa, Alberto Borobia Perez, Sergio Castrejon Castrejon, David Filgueiras Rama, Manuel Quintana Diaz, Maria Angelica Ribera Nunez, Miguel Angel Ramirez Marrero, Antonio Martin, José Miguel Ormaetxe Merodio, Mercedes Varona Peinador, Maria Fe Arcocha, Larraitz Gaztañaga, F. Xavier Palom Rico, Javier Jacob Rodriguez, Pascual Piñera Salmeron, Juan Cosin Sales, Isabel Navarro, Francisco Buendia Funetes.
Sweden: Henrik Wallentin, Kerstin Roos, Arash Mokhtari, Hans-Jörgen Nilsson, Peter Vasko, Terese Nyström, Martina Gustensson, Susanne Johansson, Inga Uggeldahl, Göran Andersson, Olle Bergström, Thomas Aronsson, Mehmet Hamid, Kerstin Giocondi, Deborah Svanerö, Qassim Awad, Tord Juhlin, Hjördis Jernhed, Stefan Berglund, Magnus Forsgren, Michael Guggi, Pär-Lennart Agren, Kristina Eriksson, Kristina Karlsson, Per Blomström, Alejandro Utreras, Caroline Lundgren, Maria Soderlund, Frederik Buijs, Solveig Östberg, Johan-Emil Bager, Ingrid Hendequist, Maria Just, Siv Heden, Liselott Lisjo, Chrichan Mansson, Helen Svanstrom, Mikael Dellborg, Helena Dellborg, Gorel Hultsberg Olsson, Linus Hansson.
Finland: Hannu Sulonen, Hanna Suurmunne, Anna Petrovskaja, Johanna Markkanen, Juha Hartikainen, Lari Kujanen, Antti Heikkola, Hanna Pohjantahti MaarooS.
Safety Review Committee
Lars Kober, MD, Samuel Lévy, MD (Chair), Cristina Varas-Lorenzo, MD, MSc, PhD, Manel Pladevall-Vila MD, MS.
The authors wish to thank Nathalie Dunkel and her team for their help in accessing the data of SPECTRUM and providing information and documents upon our request.
The authors would like to thank all of the investigators involved in the SPECTRUM study.
Funding
This study was funded by Correvio International Sàrl, Geneva, Switzerland. The authors received no funding for their participation in this manuscript.
Data Availability
The data underlying this article will be shared on reasonable request to the corresponding author.
Compliance with Ethical Standards
Conflict of Interest
Professor Levy reports no conflicts of interest. Professor Hartikainen has been an investigator in studies sponsored by AstraZeneca, Biosense Webster, Boehringer Ingelheim, Correvio International Sàrl, Medtronic, and St. Jude Medical. Dr. Ritz is an employee of Correvio International Sàrl, Geneva, Switzerland. Dr. Juhlin has received speaker honoraria from Correvio International Sàrl. Professor Domanovits reports no conflicts of interest. Dr. Carbajosa-Dalmau has received speaker honoraria from Correvio International Sàrl.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33206300 | 19,673,350 | 2021-04 |
What was the outcome of reaction 'Sinus arrest'? | Vernakalant for Rapid Cardioversion of Recent-Onset Atrial Fibrillation: Results from the SPECTRUM Study.
Rapid restoration of sinus rhythm using pharmacological cardioversion is commonly indicated in patients with symptomatic recent-onset atrial fibrillation (AF). The objectives of this large, international, multicenter observational study were to determine the safety and effectiveness of intravenous (IV) vernakalant for conversion of AF to sinus rhythm in daily practice.
Consenting patients with symptomatic recent-onset AF (< 7 days) treated with IV vernakalant were enrolled and followed up to 24 h after the last infusion or until discharge, in order to determine the incidence of predefined serious adverse events (SAEs) and other observed SAEs and evaluate the conversion rate within the first 90 min. Overall, 2009 treatment episodes in 1778 patients were analyzed. The age of patients was 62.3 ± 13.0 years (mean ± standard deviation). Median AF duration before treatment was 11.1 h (IQR 5.4-27.0 h). A total of 28 SAEs occurred in 26 patients including 19 predefined SAEs, i.e., sinus arrest (n = 4, 0.2%), significant bradycardia (n = 11, 0.5%), significant hypotension (n = 2, 0.1%), and atrial flutter with 1:1 conduction (n = 2, 0.1%). There were no cases of sustained ventricular arrhythmias or deaths. All patients who experienced SAEs recovered fully (n = 25) or with sequelae (n = 1). Conversion rate to sinus rhythm was 70.2%, within a median of 12 min (IQR 8.0-28.0 min).
This large multicenter, international observational study confirms the good safety profile and the high effectiveness of vernakalant for the rapid cardioversion of recent-onset AF in daily hospital practice.
Introduction and Purpose of the Study
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with an estimated 33.5 million people affected worldwide [1]. One in four adults over 55 years of age in Europe and the USA develop AF, with greater prevalence in older populations [1, 2]. Patients with AF are at increased risk of stroke and heart failure [3, 4]. A significant number of patients with recent-onset AF seen in the emergency departments (EDs) undergo commonly in Europe pharmacological cardioversion.
Vernakalant is a partial atrial-selective antiarrhythmic agent by its action through IKur and IKACh channel inhibition [5]. However, it has a modest effect on the ventricle via Ina and IKr channels resulting in a limited effect on ventricular repolarization (QT interval) [5]. Vernakalant is contra-indicated in patients with prolonged QT interval.
Intravenous vernakalant has been approved by the European Medicine Agency [2010] for the rapid conversion of recent-onset AF [6]. To date, a number of studies have shown vernakalant to be well tolerated and effective for cardioversion of AF [7–18].
The FDA (Food and Drug Administration agency) decided in 2008 and in December 2019 not to approve to market vernakalant in the USA for safety concerns. In 2010, the EMA requested a post-authorization safety study to better define the risk benefit ratio in routine clinical practice. The objectives of SPECTRUM (Surveillance of Pharmacologic thErapy for Cardioversion in aTrial fibrillation Registry Using IV treatMent) (NCT01370629 and EUPAS2078) study were to assess the rates of adverse events and to estimate the effectiveness of the drug in a large cohort of patients with recent-onset AF.
Methods
Definitions
Recent-onset AF was defined as symptomatic episode within 7 days that will be undergoing cardioversion taking into account that about 70% of patients with symptomatic AF < 72 h were reported to convert spontaneously [19]. Beyond 7 days, AF is likely to persist and the chances of pharmacological cardioversion to be successful become low. Hypertension was reported when documented on the medical record or the patient report. Coronary artery disease (CAD) was diagnosed when the patient had a documented history of CAD and/or a history of coronary revascularization.
Patients and Procedures
Adult patients (≥ 18 years) with recent-onset AF occurring between September 1, 2011 and April 11, 2018 who received vernakalant for cardioversion were eligible for inclusion in this international, multicenter, observational, post-authorization study. Fifty-five hospitals in Austria, Denmark, Germany, Spain, Sweden, and Finland participated in the study, 53 of which enrolled patients. While administration of vernakalant was at the discretion of the treating physician, consecutively treated patients were enrolled and reasons for non-participation were documented. A preinfusion checklist and healthcare provider educational card were implemented during the study period to assist in identifying patients for treatment consistent with the approved indications and contraindications.
Patients were required to give informed consent for participation in the study and could be enrolled more than once if they presented on multiple occasions for AF episodes. Patients who had participated in an investigational drug/device clinical trial within 30 days prior to enrollment were not eligible. In order to enhance enrollment and reach the EMA required target of 2000 episodes, a protocol amendment was made in September 2016, which permitted retrospective inclusion of patients who had received vernakalant between April 2013 and the end of the study, provided that they fulfilled the established eligibility criteria. For prospectively enrolled patients, data were collected from both medical records and supplemental standardized data collection forms. For retrospectively enrolled patients, only medical records were available. The study period comprised a baseline assessment and up to 24-h follow-up after completion of the last infusion or until discharge. This study was mandated and approved by the European Committee for Medicinal Products for Human Use. The study protocol was approved by the appropriate local research ethics committees for all participating centers, and the study was conducted in accordance with applicable national and local regulations/guidelines, accepted standards for Good Clinical Practice, Guidelines for Good Pharmacoepidemiology Practices, and the Declaration of Helsinki [20].
Study Objectives and Endpoints
The primary objectives of the study was to estimate the incidence of clinically predefined serious adverse events (SAEs), i.e., significant hypotension (systolic blood pressure < 90 mmHg or requiring vasopressors); sustained (> 30 s) ventricular arrhythmias, Torsade de Pointes (>10 s) or ventricular fibrillation, atrial flutter with 1:1 conduction, bradycardia requiring temporary electrical pacing, or sinus arrest (> 3 s). Definition of these predefined SAEs was based on events from previous controlled studies on IV vernakalant [7, 8, 11, 12] and from the reported adverse events (AEs) on other antiarrhythmic agents. Secondary objectives included the rates of all other SAEs. Each SAE was reviewed and adjudicated by an independent expert Safety Review Committee (SRC). This study had also the objective to determine the conversion rate to sinus rhythm in a large population of patients outside the setting of controlled clinical trials.
The duration of the index AF episode was calculated as the time between the patient-reported time of symptom onset and the start of the first vernakalant infusion. Successful cardioversion was defined as conversion to sinus rhythm within 90 min of the start of vernakalant infusion. Conversion rate was calculated in all patients, as well as in an effectiveness population excluding all treatment episodes in which patients received another therapy for cardioversion within 90 min of the start of vernakalant administration (e.g., electrical or pharmacological cardioversion). Vernakalant is recommended to be administered in a step-dose fashion. Each treatment episode can comprise up to two infusions, separated by a 15-min observation period. The recommended doses for the first and second infusions are 3.0 mg/kg and 2.0 mg/kg, respectively, each administered over 10 min. For patients above 113 kg, vernakalant has a fixed initial dose of 339 mg. If conversion to sinus rhythm does not occur within 15 min after the end of the initial infusion, a second 10-min infusion of 226 mg may be administered.
Statistics and Analyses
A target sample size of 2000 vernakalant IV treatment episodes was chosen to allow adequate statistical precision, as expressed by a two-sided 95% confidence limit. Enrollment per site was capped at 10% of the total study population and 40% per country to minimize any potential bias in practice patterns. Categorical variable frequency, along with 95% confidence intervals (CIs), was determined for the summed treatment episodes. Continuous variables were summarized using descriptive statistics. Data were analyzed based on enrollment method (prospective vs retrospective) and reported as stratified and unstratified CIs. All analyses were performed using Statistical Analysis System v9.2, or later, software.
Results
Study Population
A total of 1778 patients who presented with 2009 treatment episodes were included: 1580 episodes were in prospectively enrolled patients and 429 in retrospectively enrolled patients (Table 1). The majority of patients were treated in the ED for 1289 (64.1%) AF episodes and 563 (28.0%) AF episodes in the coronary or intensive care units, with the remainder 157 (7.8%) episodes being treated in other hospital settings. As seen in Fig. 1, the main reason for non-inclusion in the study was lack of informed consent. In 1905 (94.7%) AF episodes, vernakalant was administered to non-surgery patients, and in 104 (5.2%) to post-cardiac surgery patients. The later are among the prospectively included patients. The mean age of the overall patient population at time of treatment was 62.3 ± 13.0 years (mean ± standard deviation [SD]), ranging from 18.0 to 94.0 years, and 1222 (60.8%) episodes occurred in men (Table 1). At baseline, systolic blood pressure (BP) was 132.5 ± 19.5 mmHg and heart rate (HR) was 112.9 ± 25.5/min (mean ± SD). The median duration of AF episode prior to treatment was 11.1 (5.4–27.0) hours (median [interquartile range, IQR]). In 88.9% of episodes, the patients were treated within 48 h of the onset of symptoms, and in 72.5% within 24 h. Duration of AF before treatment in 104 post-cardiac surgery patients was shorter than in the overall population, with 3.6 h (range 0.8–15.4) (median [IQR]). Baseline demographics and characteristics were similar between patients enrolled prospectively and retrospectively. Total length of ED stay was 7.5 (5.0–13.5) hours (median [IQR]). Only 167 (13.0%) of patients initially managed in the ED were in hospital for 24 h or longer. The number of vernakalant infusions was available in 1990 patients. Of these, 1201 (60.4%) received one vernakalant infusion and 789 (39.6) received a total of 2 infusions.Table 1 Clinical characteristics of patients
Total Prospective Retrospective
No. of patients 2009 1580 429
Age (years) mean ± SD 62.3 ± 13.0 61.9 ± 13.5 63.6 ± 11.2
Range (years) 18.0–94 18–93 30–94
Male, n (%) 1222 (60.8) 998 (63.2) 224 (52.2)
Body weight (kg) mean ± SD 84.1 ± 16.5 84.3 ± 16.5 83.1 (16.9)
Range (kg) 45.0–189.0 45.0–189.0 45.0–165.0
Body mass index (kg/m2) 27.8 ± 4.9 27.7 ± 4.8 28.2 ± 5.1
Associated conditions, n (%)
Hypertension 1103 (54.9) 884 (55.9) 219 (51.0)
Coronary artery disease 118 (5.9) 82 (5.2) 36 (8.4)
Cardiomyopathy 33 (1.6) 31 (2.0) 2 (0.5%)
Heart failure (history) 63 (3.1) 59 (3.7) 4 (0.9)
Diabetes 199 (9.9) 165 (10.4) 34 (7.9)
Stroke (history) 91 (4.5) 68 (4.3) 23 (5.4)
Pacemaker/ICD 36 (1.8) 24 (1.5) 12 (2.8)
Type of AF episode
First detected 477 (23.7) 393 (24.9) 84 (19.6)
Previous history of AF 1458 (72.6) 1115 (70.6) 343 (80.0)
Onset unknown/not assessed 5 (0.2) 3 (0.2) 2 (0.5)
Post-surgery 69 (3.4) 69 (4.4) 0 (0.0)
Symptoms on admission, n (%)
Palpitations, irregular heart beat 1749 (87.1) 1337 (84.6) 412 (96.0)
Dyspnea or shortness of breath 352 (17.5) 306 (19.4) 46 (10.7)
Dizziness, light-headedness 320 (15.9) 251 (15.9) 69 (16.1)
Chest pain 271 (13.5) 220 (13.9) 51 (11.9)
Syncope, near syncope 61 (3.0) 53 (3.4) 8 (1.9)
Duration of the index episode
Less than 24 h, n (%) 1438 (72.5) 1107 (70.2) 331 (81.5)
24–48 h, n (%) 347 (17.5) 288 (18.3) 59 (14.5)
More than 48 h 199 (10.0) 183 (11.6) 16 (3.9)
Mean duration ± SD (h) 23.2 ± 44.9 24.9 ± 45.8 16.8 ± 40.6
Median (IQR 25–75) (h) 11.1 (5.44–27.03) 11.9 (5.8–29.7) 8.2 (4.8–18.3)
Antiarrhythmic agents, n (%)
Betablockers 1055 (52.5) 800 (50.6) 255 (59.4)
Calcium channels blockers 22 (1.1) 20 (1.3) 2 (0.5)
Class I agents* 85 (4.2) 71 (4.5) 14 (3.3)
Class III agents* 98 (4.9) 89 (5.6) 9 (2.1)
Digitalis glycosides 22 (1.1) 18 (1.1) 4 (0.9)
*Using the Vaughan-Williams classification
Fig. 1 Study flow chart. Flow chart showing patient enrollment in the SPECTRUM study. The term patient here refers to individual treatment episodes (asterisk). Owing to lack of informed consent (n = 500) (dagger). Other reasons included patient enrollment in an investigational drug trial in the past 30 days, spontaneous conversion to sinus rhythm, ejection fraction 30–35%, electrical cardioversion preferred, missing information regarding start of atrial fibrillation, inclusion criteria not met, other, or no reason provided or known. Source data could not be verified to confirm that vernakalant IV was administered (double dagger). Spontaneous conversion to sinus rhythm before vernakalant IV administration (section sign). Patient decision and lack of follow-up after cardioversion in one case each (double vertical line). IV intravenous
Predefined Serious Adverse Events and Other Adverse Events
No deaths were recorded in our study. Nineteen predefined SAEs were reported during or after 17 treatment episodes (cumulative incidence 0.8%; CI 0.5–1.4%) (Table 2). Eighteen of the 19 events occurred within 2 h from the start of infusion. The remaining event was an episode of atrial flutter with 1:1 conduction which occurred 3.1 h after drug infusion and was terminated by electrical shock. Symptomatic bradycardia was the most common event occurring in 11 (0.5%; CI 0.4–1.2%) episodes (Table 2). Conversion to sinus rhythm occurred in 10 of these cases. A pause described as sinus arrest preceding the restoration of sinus rhythm occurred in 4 patients. In 2 patients, sinus arrest was associated with sinus bradycardia. In all bradycardia and sinus arrest cases, the vernakalant infusion was immediately discontinued. One of these 4 sinus arrests occurred in a 66-year-old man, sportive cyclist with no history of heart disease, admitted for a first episode of AF with a mean ventricular response of 95 beats/min. He received 300 mg orally of flecainide which failed to restore sinus rhythm. The treating physician decided 4 h later, to administer IV vernakalant. At the end of the infusion, a pause of 6 s, with a brief dizziness, occurred and resolved spontaneously, followed by a normal sinus rhythm with a HR of 47 beats/min which was patient usual HR and a BP of 120/85 mmHg. This event was considered a SAE although there was probably an interaction between oral flecainide still active and vernakalant in this event. One of the bradycardia events occurred in a retrospectively enrolled 69-year-old woman on bisoprolol with a history of hypertension and CAD, who developed 8 min after the second infusion of vernakalant a sinus bradycardia which rapidly resolved with IV atropine. Two bradycardia episodes occurred in post-cardiac surgery patients requiring temporary electrical pacing through the electrodes left in place by the surgeon. Both patients converted to sinus rhythm. None of the non-surgery patients required temporary electrical pacing. Significant hypotension occurred on two (0.1%; CI < 0.1–0.4%) occasions, associated with sinus bradycardia in both instances. Both events resolved with intravenous atropine and fluid. There were two cases of atrial flutter with 1:1 ventricular conduction terminated with electrical shock whereas no cases of sustained ventricular tachycardia (VT), ventricular fibrillation, or Torsade de Pointes were observed. In addition to the predefined SAEs, there were 9 other SAEs, one of which occurred in a retrospectively enrolled patient (Table 2). They included two instances of hypotension not requiring vasopressor agents, 2 non-sustained VT which deserve special attention. The first non-sustained VT occurred in a 48-year-old man with asthma admitted with fever, palpitations, dyspnea, and first episode of AF with a ventricular rate of 144 bpm. During vernakalant infusion, 5 beats of non-sustained VT was observed. Among the tests done, coronary angiography was reported as normal. The same run of 5 beats of non-sustained VT was observed 20 h after infusion (next day) making the causal effect of vernakalant unlikely. The other event occurred in a 57-year-old patient with a 6-year history of recurrent symptomatic AF and arterial hypertension with left ventricular hypertrophy. He was admitted with palpitations, irregular heartbeats, and dizziness. He was on dronedarone, and ECG showed AF with a ventricular rate of 135 bpm. During infusion of vernakalant, he had 6 s of non-sustained VT observed on the monitor and was given 5 mg of bisoprolol which reduced the heart rate to 120 beats/min and relieved patient symptoms. The Safety Review Committee considered that in the first case, the wide QRS complexes were due to aberrant conduction during rapid AF (Ashman phenomenon). Among the non-predefined SAEs, one supraventricular tachycardia (120 beats/min) and a single report each of angina pectoris, pericardial effusion, transient visual disturbance, and vernakalant overdose (Table 2). A total of 188 non-serious AEs were reported, the most common of which were dysgeusia (n = 35) and sneezing (n = 27). All patients with vernakalant-related AEs recovered without sequelae. All but 6 of the 28 SAEs were considered by the investigators and the SRC to be related to vernakalant administration.Table 2 Adverse events in 2009 episodes during treatment and observation periods
Event type Number of events Incidence (95% CI) Considered drug-related, n (%)
All SAEs 28 1.3% (0.8–1.9) 22 (78.6)
Predefined SAEs 19 0.8% (0.5–1.4) 18 (94.7)
Significant hypotension 2 0.1% (< 0.1–0.4) 2 (100.0)
Bradycardiaα 11 0.5% (0.3–10) 10 (93.3)
Sinus arrest (> 3 s)β 4 0.2% (< 0.1–0.4) 4 (100.0)
Atrial flutter with 1: 1 AV conduction 2 0.1% (0.1–0.4) 2 (100.0)
Ventricular tachycardia γ 0 0 0 (0.0)
Other than predefined SAEs 9 0.45% 5 (55.6)
Hypotension 2 0.1% 1 (50.0)
Supraventricular tachycardiaδ 1 < 0.1% 1 (100.0)
Non-sustained ventricular tachycardiaε 2 < 0.1% 1 (50.0)
Angina pectoris 1 (< 0.1) < 0.1% 0 (0.0)
Pericardial effusion 1 (< 0.1) < 0.1% 0 (0.0)
Visual disturbance 1 (< 0.1) < 0.1% 0 (0.0)
Vernakalant overdoseζ 1 (< 0.1) < 0.1% 1 (100.0)
αNine cases of sinus bradycardia and 2 reported as significant bradycardia
βOne patient had both sinus arrest followed by sinus bradycardia
γOne event reclassified as atrial flutter with 1:1 conduction
δAtrial arrhythmia other than atrial flutter
εSee text, exceeding 5% of the weight-based dosing recommendation. In this case, the administered dose was 51% in excess of the recommended dose
Rates of Conversion to Sinus Rhythm
Overall, conversion to sinus rhythm at any time following vernakalant infusion occurred in 1448 out of 2009 (72.1%) treatment episodes. Successful cardioversion was recorded in 70.2% (CI 68.1–72.2%) of the 1936 episodes of the effectiveness population excluding those in which either electrical cardioversion (n = 68) or an additional intravenous Class I/III antiarrhythmic drug (n = 6) was given within 90 min of infusion initiation. The rate of cardioversion was similar between the 1107 of 1580 (70.1%) episodes included prospectively and the 297 of 421 (70.5%) episodes of retrospectively enrolled patients. Successful cardioversion of AF was reported in 68 of 104 (65.4%) of treatment episodes in the post-cardiac surgery patients. Time to cardioversion was recorded in 1413 of 1448 episodes with successful conversion to sinus rhythm. The median time to conversion was 12.0 (8.0–28.0) minutes (median [IQR]) Fig. 2). One thousand one hundred eight of 1413 (78.4%) successful cardioversions were treated with only one drug infusion. The percentage of successful cardioversion was 70.1% in the prospective patients and 70.5% in the retrospective patients. The median hospital stay time in those treated in the ED was 7.5 h allowing patient discharges when their condition was clinically stable.Fig. 2 Time to conversion to sinus rhythm. Time to conversion to sinus rhythm with vernakalant IV in the effectiveness analysis population (N = 1936). Time to conversion was not recorded in 29 treatment episodes in which patients converted to sinus rhythm; these episodes are not displayed on the graph but are taken into account for the proportion calculation. IV intravenous
Anticoagulation
About a quarter of patients presenting with recent-onset AF at baseline were on vitamin K antagonists or direct oral anticoagulants. Investigators respected current guidelines [3] on anticoagulation both peri-procedurally and after hospital discharge.
Discussion
The SPECTRUM study included a large real-world patient population of 1778 patients with 2009 recent-onset AF episodes in whom pharmacological cardioversion was performed with vernakalant. About 70% of patients were cardioverted within 12 min from onset of infusion and 11 h from the AF onset. Our findings confirm the safety and efficacy of vernakalant reported in previous studies [7–18, 21–25] and extend their consistency to routine hospital use in large populations. To our knowledge, the present study provides the largest series of patients with recent-onset AF undergoing pharmacological cardioversion with a specific antiarrhythmic agent. The safety was the main objective of this study. We found the incidence of both predefined and other SAEs to be lower than expected. There were no death and no sustained ventricular arrhythmia. Overall, 28 SAEs (1.3%) were recorded. The majority of patients were AF treated in ED and intensive care units.
Pharmacological cardioversion is frequently indicated as part of a rhythm control strategy or as a tool to control patient symptoms and avoid hospitalization in clinically stable condition [25, 26]. It is often preferred to electrical cardioversion in patients with hemodynamically stable condition as it does not require general anesthesia or sedation. Among agents currently available for rapid termination of recent-onset AF, vernakalant represents an option [3]. However, there has been to our knowledge, no large study exploring the safety of vernakalant in daily practice.
There is no universal definition for recent-onset AF. In current literature, the duration limits of AF episodes range from < 24 [27] to < 48 h and even < 7 days [28, 29]. The prevalence of recent-onset AF among all AF subsets varies from 11% when restricted to the first detected episode (new onset) [30] to 26% [31]. The characteristics of patients were similar to those of other AF cohorts [31, 32].
As with electrical cardioversion, pharmacological cardioversion can be associated with post-cardioversion bradyarrhythmias, often unmasking pre-existing sinus node dysfunction or atrioventricular conduction abnormalities and can result in ventricular escape rhythms or prolonged ventricular pauses. Of interest, these pauses were first reported by Lown [33], following electrical cardioversion as the possible reflect of sinus dysfunction. Another possible mechanism for these sinus arrests is right atrial stunning [34]. The cumulative incidences of bradycardia (0.5%), sinus arrest (0.2%), and hypotension (0.1%) observed in this study were also low. The incidence of atrial flutter with 1:1 conduction was lower than that reported with oral Class Ic antiarrhythmics, such as flecainide or propafenone. The “pill in the pocket” approach requires initiation of therapy in hospital to verify its safety [35]. No cases of Torsade de Pointes or sustained VT was observed, which is in line with the low risk of ventricular proarrhythmia associated with vernakalant owing to its electrophysiological properties [5]. This contrasts with the reported incidence of Torsade de Pointes [24, 36, 37] in patients with AF/atrial flutter of 4.3% with intravenous ibutilide in the report of Kowey et al. including 1.7% of which required cardioversion [36]. Of note, all but one of the predefined SAEs in this study occurred within 2 h of the start of infusion. As aforementioned, the remaining patient had atrial flutter with 1:1 ventricular conduction which occurred 3.1 h following infusion initiation, indicating that close cardiac monitoring should be available during and after treatment in some patients.
Conversion to sinus rhythm with vernakalant was rapid (median time of 12.0 min) similar to what was previously reported [9–18]. The conversion median time of ibutilide was significantly longer than that of vernakalant (26 min versus 10 min, P = 0.01) in a randomized comparison [18]. Furthermore, in this particularly large real-world study, the median duration of AF episode was short (11.1 h) as there is important evidence, and relevant guidelines [3] suggesting that prompt cardioversion could be associated with benefits in terms of lower risk of thromboembolic events [4, 38, 39].
Although the baseline characteristics of the study population were consistent with AF population-based studies [31, 32] and clinical studies with vernakalant, the conversion rate was higher than that observed in recent review and meta-analysis (~ 50%) [22–25]. This seems likely to be due to patients being treated soon after symptom onset in European clinical practice. Other recent but smaller observational studies [13–15, 17, 18], which collectively included almost 1300 patients, have found similarly high conversion rates (65–86%) when vernakalant was administered soon after the onset of AF, particularly within the first 48 h [15, 17, 21]. Vernakalant has also been shown to induce a higher rate of cardioversion compared with flecainide (67% vs 46%) in a non-randomized cohort study [21]. Similarly, in randomized studies, vernakalant was more effective than amiodarone [12] (52% vs 5%; after 90 min) and ibutilide [18, 24] (69% vs 43%; within 90 min). The SPECTRUM results are consistent with previous reports that vernakalant is safe and effective for the rapid cardioversion of recent-onset AF and extends them to daily practice.
Owing to the rapid time to conversion with vernakalant, the median hospital stay time for those treated in the ED was 7.5 h. This is encouraging given that a study in France reported that hospitalization constitutes 60% of the cost of care for patients with AF [40].
Study Limitations
This multicenter international study was observational as the main objective was to determine the safety of vernakalant as used in daily hospital practice without interfering on the management of recent-onset AF by the treating physician. For these reasons, the adverse events were expected to be higher in an “uncontrolled” setting with no guidance on patient selection than those reported in controlled studies with strict protocols. In fact, SAEs were low in this study. Data collection for prospectively enrolled patients was comprehensive owing to use of both study-specific tools and medical records. However, for retrospectively enrolled patients, it was not possible to routinely collect all data of interest in a standardized manner. Nevertheless, baseline characteristics, medical histories, and SAEs in the retrospective cohort were similar to those in the prospective cohort, supporting the use of a retrospective analysis.
Conclusions
The results of this large multicenter study showed that vernakalant has a good safety profile and is effective in enabling rapid cardioversion in clinical practice. Moreover, the rates of serious complications were lower than those observed in early trials reflecting appropriate patient selection in clinical practice. In conclusion, vernakalant provides a rapid and effective means of pharmacological conversion in patients with recent-onset AF undergoing cardioversion undergoing cardioversion in daily hospital practice.
Appendix. List of Investigators
Austria: Michael Joannidis, Klemens Zotter Frank Hartig, Anton Sandhofer, Alois Süssenbacher, Bernd Eber, Elisabeth Lassnig, Ulrike Pfeifenberger, Michaela Steiner, Hans Domanovits, Alexander Simon, Alexander Spiel, Jan Niederdockl, Nikola Schuetz, Daniel Wehinger, Franz Xaver Roithinger, Isabella M. von Katzler, Katharina Bichler, Robert Schoenbauer, Lukas Fiedler, Michael Pfeffer, Markus Peck, Florian Benische, Michael Hackl, Susane Demschar, Astrid Ebner, Melanie Eder, Rainer Huditz, Arnulf Isak, Michael Moser, Georg Pinter, Thomas Singer, Claudia Waldhauser, Helmut Pürerfellner, Martin Martinek, Sandra Muellner, Andrea Ploechl, Tanja Koppler, Elisabeth Sigmund, Michael Derndorfer, Sabine Metz, Karin Streicher, Clemens Steinwender, Karim Saleh, Andreas Lueger, Petra Fladerer, Eiko Meister, Heinz Drexel, Alexandra Schuler, Susanne Waeger, Karl-Martin Ebner, Christine Heinzle, Arthur Mader, Peter Schwerzler, Berta Patsch, Abdurahman Said, Claudia Stoeckloecker, Daniela Zanolin, Jutta Bergler-Klein, Ljubica Mandic, Mariann Gyöngyösi, Neraida Cene, Zsuzsanna Szankai, Abelina Zimba.
Denmark: Henrik Nielsen, Bjerre Flemming, Michaelsen Michaelsen, Elisa Stokholm, Katja Holm, Charlotte Schmidt Skov, Pauline Gøgsig Johansen, Soren shjortshoj, Thomas Melchior, Ole Dyg Pedersen, Sanne Heinsvig, Inge Larsen, Vibeke Perret-Gentil, Thomas Wagner Nielsen, Axel Brandes, Marianne Jensen, Ida Rosenlund, Liv Gøtzsche, Heidi Munk Andersen.
Germany: Andreas Götte, Matthias Hammwohner, Britta Möehring, Jutta Schaertl, Daniel Steven, Iris Berg, Alexandra Kuehn, Hannes Reuter, Elena Terentieva, Christian Loges, Christine Lindner, Hendrik Bonnemeier, Christan Wulff, Thomas Demming, Svenja Gediehn, Johanna Parlitz, Wilhelm Haverkamp, Buehner Kathrin, Hubert Katja, Iacovella Ines, Bernhard Korbmacher, Marc Thone, Hannan Dalyanoglu, Da Un Chung, Naujoks Angela, Dirk Weismann, Björn Lengenfelder, Jan Becher, Klaus Meyer, Irina Turkin, Sebastian Maier, Marcus Koller, Alban Glaser, Lisa Gebele, Jale Goezuebueyuek, Ralph Hampe, Barbara Ruemmler, Hagen Schrötter, Manja Hubald, Cornelia Fritz, Martin Domhardt, Kathrin Haacke, Nicole Schmiedehausen, Ruth Strasser, Kristof Graf, Lidia Fischer, Roland Thieme, Karlheinz Seidl, Martin Kulzer, Monika Zackel, Gerian Grönefeld, Christina Paitazoglou, Simone Müller, ThoraBotschafter Britta Goldmann, Andrea Moeller, Sindy Bartel, Joern Schmitt, Damir Erkapic, Gabriele Hellwig-Bahavar, Ritvan Chasan, Christopher Gemein, Victoria Johnson, Christiane Kelm, Kay Weipert, Johannes Brachmann, Michael Held, Andrea Höhn, Ute Goebel, Andrea Linss, Swetlana Rube, Ahmed Saleh, Steffen Schnupp, Yeong-Hoon Choi, Vera Wolf, Andrea Plate, Anton Sabashnikov, Antje-Christin Deppe, Petra Krause.
Spain: Ignacio Fernandez Lozano, Manuel Sánchez, Francisco Hernández, Alfonso Martin Martinez, Pedro Vazquez, Esther Alvarez, Pascual Lopez, Raquel Torres, José Carbajosa Dalmau, Laura Parades, Nestor Hernandez, Inmaculada Jimenez Ruiz, Ana Maria Lopez, Luis López-Andujar, Alexandre Noguera, Francisco Roman Cerdan, Carmen del Arco Galan, Daniel Afonso, Raquel Caminero, Manual Lunquera, Monica Negro, Cristina Santiago, Nestor Villalba, José Manuel Garrido Castilla, Roberto Martinez Asenjo, Elena Mejia Martinez, José Luís Merino Llorens, Maria Jesus Diaz-Pintado, Jorge Alejandro Figueroa, Alberto Borobia Perez, Sergio Castrejon Castrejon, David Filgueiras Rama, Manuel Quintana Diaz, Maria Angelica Ribera Nunez, Miguel Angel Ramirez Marrero, Antonio Martin, José Miguel Ormaetxe Merodio, Mercedes Varona Peinador, Maria Fe Arcocha, Larraitz Gaztañaga, F. Xavier Palom Rico, Javier Jacob Rodriguez, Pascual Piñera Salmeron, Juan Cosin Sales, Isabel Navarro, Francisco Buendia Funetes.
Sweden: Henrik Wallentin, Kerstin Roos, Arash Mokhtari, Hans-Jörgen Nilsson, Peter Vasko, Terese Nyström, Martina Gustensson, Susanne Johansson, Inga Uggeldahl, Göran Andersson, Olle Bergström, Thomas Aronsson, Mehmet Hamid, Kerstin Giocondi, Deborah Svanerö, Qassim Awad, Tord Juhlin, Hjördis Jernhed, Stefan Berglund, Magnus Forsgren, Michael Guggi, Pär-Lennart Agren, Kristina Eriksson, Kristina Karlsson, Per Blomström, Alejandro Utreras, Caroline Lundgren, Maria Soderlund, Frederik Buijs, Solveig Östberg, Johan-Emil Bager, Ingrid Hendequist, Maria Just, Siv Heden, Liselott Lisjo, Chrichan Mansson, Helen Svanstrom, Mikael Dellborg, Helena Dellborg, Gorel Hultsberg Olsson, Linus Hansson.
Finland: Hannu Sulonen, Hanna Suurmunne, Anna Petrovskaja, Johanna Markkanen, Juha Hartikainen, Lari Kujanen, Antti Heikkola, Hanna Pohjantahti MaarooS.
Safety Review Committee
Lars Kober, MD, Samuel Lévy, MD (Chair), Cristina Varas-Lorenzo, MD, MSc, PhD, Manel Pladevall-Vila MD, MS.
The authors wish to thank Nathalie Dunkel and her team for their help in accessing the data of SPECTRUM and providing information and documents upon our request.
The authors would like to thank all of the investigators involved in the SPECTRUM study.
Funding
This study was funded by Correvio International Sàrl, Geneva, Switzerland. The authors received no funding for their participation in this manuscript.
Data Availability
The data underlying this article will be shared on reasonable request to the corresponding author.
Compliance with Ethical Standards
Conflict of Interest
Professor Levy reports no conflicts of interest. Professor Hartikainen has been an investigator in studies sponsored by AstraZeneca, Biosense Webster, Boehringer Ingelheim, Correvio International Sàrl, Medtronic, and St. Jude Medical. Dr. Ritz is an employee of Correvio International Sàrl, Geneva, Switzerland. Dr. Juhlin has received speaker honoraria from Correvio International Sàrl. Professor Domanovits reports no conflicts of interest. Dr. Carbajosa-Dalmau has received speaker honoraria from Correvio International Sàrl.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33206300 | 19,695,564 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Combination Therapy Using Prothrombin Complex Concentrate and Vitamin K in Anticoagulated Patients with Traumatic Intracranial Hemorrhage Prevents Progressive Hemorrhagic Injury: A Historically Controlled Study.
Warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk. However, warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) through progressive hemorrhagic injury (PHI). Therefore, a rapid anticoagulation reversal could be required in patients with TICH to prevent PHI. Differences in the warfarin reversal effect between combination therapy of prothrombin complex concentrate (PCC) with vitamin K (VK) and VK monotherapy remain unclear. However, studies have reported that PCC has greater effectiveness and safety for warfarin reversal compared with fresh frozen plasma (FFP). This retrospective study aimed to evaluate the warfarin reversal effects of combination therapy of PCC with VK and VK monotherapy on TICH. We compared the clinical outcomes between the periods before and after the PCC introduction in our hospital. There were 13 and 7 patients who received VK monotherapy and PCC with VK, respectively. PHI predictors were evaluated using univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00-0.41, P = 0.004). None of the patients presented with thrombotic complications. Warfarin reversal through a combination of PCC with VK could be more effective for inhibiting post-trauma PHI compared with VK monotherapy. This could be attributed to a rapid and stable warfarin reversal. PCC should be administered to patients with TICH taking warfarin for PHI prevention.
Introduction
With increasing life expectancy, there has been a concomitant increase in the number of patients requiring long-term anticoagulation to prevent arterial fibrillation-associated cerebral or systemic embolism and deep venous thrombosis.1) These patients receive oral anticoagulants, including warfarin as a vitamin K (VK) antagonist or direct oral anticoagulants (DOAC). A previous large-scale randomized clinical trial reported that DOAC and warfarin had similar efficacy and safety.2–5) Furthermore, DOAC has predictable pharmacokinetics and does not require routine monitoring since their anticoagulating effect does not interact with VK and interacts less frequently with other drugs. Therefore, DOAC has been preferably used for thromboembolic disease prevention recently. However, warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk, including those with an artificial valve, mitral stenosis, etc.2) Furthermore, warfarin is administered to patients with severe renal impairment who cannot be treated with DOAC.
Head trauma could cause an acute subdural hematoma, acute epidural hematoma, cerebral contusion, and traumatic subarachnoid hematoma. Progressive hemorrhagic injury (PHI) could cause a worsening of neurological conditions.3) Warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) since it inhibits hemostasis.6–8) Therefore, a rapid anticoagulation reversal in patients with TICH might be required for PHI prevention.
VK, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) are available for warfarin reversal in emergencies.2) PCC, which is the most recent to become clinically available, could have greater advantages compared with FFP. This is because it does not require blood typing and cross-matching; moreover, it eliminates the risk of FFP-related volume overload. Furthermore, compared with VK, PCC normalizes prothrombin time/international normalized ratio (PT-INR) more rapidly.9,10) Studies have reported that PCC for warfarin reversal could have greater effectiveness and safety than FFP.11) However, prior to PCC becoming clinically available, warfarin reversal was commonly achieved using VK alone rather than FFP infusion followed by VK. This could be because patients on warfarin treatment often present poor cardiac function and FFP could cause volume-overload associated with congestive heart failure.2,12) There is a need to study differences in the warfarin reversal effect in patients with head trauma between combination therapy of PCC with VK and VK monotherapy.
This retrospective study aimed to evaluate the warfarin reversal effects of a combination of PCC with VK and VK monotherapy in patients with TICH. Furthermore, we aimed to compare the clinical outcomes between the periods before and after the PCC introduction in our hospital.
Methods
The protocol for this retrospective study was approved by the ethics committee at our institution, which waived the requirement for patient consent (No. 3758). We retrospectively reviewed the medical records of 498 adult patients (≥18 years old) admitted at our hospital between February 2016 and November 2019 due to TICH within 12 post-injury hours (Fig. 1). Among them, 35 patients underwent warfarin treatment with a PT-INR of ≥1.4. Seven patients were infused with FFP to treat coincidental systemic massive hemorrhage due to aortic, hepatic, or pulmonary injuries. They were excluded from the study population because the clinical status is different from the others. In our hospital, four-factor PCC (4F-PCC) (Kcentra), which is among the clinically available PCC, was introduced for warfarin reversal from December 2017. We considered the periods before and after November 2017 as the VK era and PCC era, respectively. There 18 and 10 patients in the VK and PCC eras, respectively.
We excluded patients with mild head injury or excessively severe trauma on admission who did not receive treatment for warfarin reversal effect. The treatment outcome was evaluated in the remaining 20 patients (13 and 7 patients in the VK and PCC era, respectively). Immediately after TICH identification, all patients in the VK and PCC era were treated using intravenous administration of VK and PCC in combination with VK, respectively. Regarding the patients’ demographic and clinical characteristics, only time from injury to admission showed a significant between-group difference where it was longer in the VK era than in the PCC era (Table 1).
All the patients underwent a computer tomography (CT) scan on admission and repeat scans at least twice within 3 and 4-24 hours after admission. PHI was evaluated on the repeat CT scans and defined as follows: the appearance of a new intracranial hematoma, including intracerebral, intraventricular, subdural, epidural, or subarachnoid hemorrhage not caused by redistributed hemorrhage or expansion of pre-existing hematoma indicated by a qualitative increase in the volume by 1.4 times greater than the volume on the admission CT.13)
For warfarin reversal with and without PCC, the target PT-INR level was <1.40. Regarding reversal using PCC, PCC was intravenously administered immediately followed by intravenous VK administration (10–20 mg). The administered PCC dose was determined according to our institutional protocol, which was approved by the medical safety commission of our hospital, as follows: 25 IU/kg, 35 IU/kg, and 50 IU/kg were given to patients with INR 1.4–4, 4.0–6.0, and >6, respectively. PCC was only administered once. Contrastingly, 10 mg VK was repeatedly administered in case the PT-INR was ≥1.4 in the follow-up test at 8–12 post-admission hours. We performed between-reversal comparisons of the rates of reaching the target PT-INR at half a day after hospitalization.
The PHI incidence was evaluated in all the patients who underwent reversal treatment. Furthermore, we performed between-reversal comparisons of the in-hospital death; modified Rankin Scale (mRS) at discharge; and adverse events, including myocardial infarction, ischemic stroke, pulmonary embolism, and deep vein thrombosis.
Table 1 presents the patients’ baseline and clinical characteristics. Hypertension was defined as a pre-injury or pre-treatment systolic and/or diastolic blood pressure of ≥140 mmHg and ≥90 mmHg, respectively. Patients were considered to have diabetes if their glycosylated hemoglobin A1C level exceeded 6.5% or if they were being treated with insulin and/or oral hypoglycemic medications. The used antiplatelet drugs included aspirin, cilostazol, and clopidogrel with none of the patients taking prasugrel and ticlopidine hydrochloride.
Continuous variables were express as mean ± SD or median (interquartile range [IQR]). Categorical variables were expressed as number (%). All statistical analyses were performed using JMP version 15 software (SAS Institute, Tokyo, Japan). Statistical significance was set at P <0.05. Between-group comparisons were performed using Fisher's exact test or Mann–Whitney U test. Univariable logistic regression analyses were performed to determine PHI predictors.
Results
Figure 2 shows the time course of PT-INR in the seven patients who underwent combination therapy of PCC with VK. There was a rapid decrease in PT-INR, which reached its target (<1.40) at 1 hour after the start of warfarin reversal in all patients. PT-INR at half a day after reversal remained <1.40 in most patients except one who presented a PT-INR of 1.41.
There were no patients who had new bleeding at other sites and all of the PHI was identified as an expansion of pre-existing hematomas. Patients who underwent warfarin therapy had a high PHI incidence. Among the 20 patients, 12 (60%) patients presented with PHI. The PHI incidence was significantly lower in patients who underwent PCC therapy than VK monotherapy (84.6% vs. 14.3%, P = 0.004; Table 2). There were numerically, but not significantly, more patients who underwent PCC therapy with a PT-INR <1.40 at half a day after warfarin reversal induction compared with those who underwent VK monotherapy (85.7% vs 30.8%). There were no significant between-reversal differences in the hospitalization period, mRS at discharge, mortality, and rate of surgical treatment by craniotomy.
As shown in Table 3, PHI predictors were evaluated by univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00–0.41, P = 0.004). Contrastingly, other demographic and patient characteristics were not associated with PHI. Hemostasis-related factors, including antiplatelet therapy and tranexamic acid administration, did not affect PHI. Severely impaired consciousness (Glasgow Coma Scale [GCS] <12) and delayed admission (time from injury to admission >4 hours) did not affect PHI. Higher PT-INR (>2.0) at admission was not associated with PHI. Patients who reached the target-PT-INR (<1.4) at half a day tended to have less PHI but it was not statistically significant.
Discussion
There have been numerous reports that warfarin reversal using PCC is effective in patients with non-TICH or TICH.11,14–28) However, these studies compared warfarin reversal using PCC and FFP11,14–28) with none of the studies comparing the treatment outcome of warfarin reversal using combination therapy of PCC with VK and VK monotherapy. The use of FFP is associated with a greater risk of volume overload and heart failure.9) In some clinical settings, FFP administration for warfarin reversal is difficult since patients on anticoagulant therapy present with a high risk of heart failure, and the complication rate of atrial fibrillation increases in proportion to the severity of heart failure.29) Moreover, heart failure has been reported in 37% of newly developed atrial fibrillation.30) Therefore, there is a need to directly compare the recent warfarin reversal using a combination therapy of PCC and conventional reversal using VK monotherapy. In this novel study, we found that warfarin reversal by PCC significantly suppressed PHI compared with VK monotherapy.
Warfarin treatment is associated with poor prognosis of patients with TICH. Ivascu et al. reported that oral warfarin increased the mortality rate in patients with TICH (48%), which is approximately five times higher than that in patients without anticoagulant therapy.31) The observed poor outcome under warfarin treatment could be attributed to the anticoagulation causing PHI.7,32–34) Oral anticoagulation is associated with PHI even in patients with minor head trauma.31) Therefore, there is a need to improve the prognosis of patients with head trauma under anticoagulant therapy by rapidly neutralizing the anticoagulant effect. Furthermore, risk factors for PHI have been shown to include older age, male gender, and larger initial lesions.35–40) However, these findings were not observed in our study given its small sample size.
For warfarin reversal, the use of PCC, rather than FFP, was associated with a more rapid decrease in the PT-INR17,18,22) and a higher rate of achieving the target PT-INR value without a cardiovascular volume load.9) VK, which induces production of warfarin-inhibiting coagulant factors in the liver, takes about 24 hours to fully exert its effect to modulate prolonged PT-INR by warfarin.41) PCC intravenous administration is to compensate for the shortage of coagulant factor and shows a more rapid decrease in PT-INR levels than VK intravenous administration alone.42) Rapid PT-INR correction by PCC is considered to suppress PHI more effectively than VK alone in patients taking warfarin. To neutralize a warfarin effect by PCC, the short-lasting effect of PCC should be paid attention to. PCC without VK may result in a re-increase in PT-INR and clinical deterioration.43) Therefore, to maintain the rapidly corrected PT-INR by PCC, VK plays an important role. These were consistent with our findings that, in the present study, most of the patients who underwent the combination therapy using PCC and VK had normalized values of PT-INR rapidly (at 1 hour after PCC administration) and remained within or close to the reference values after 12 hours. Immediate and stable effect of the combination of PCC and VK is considered to prevent PHI.
Anticoagulant therapy neutralization is associated with thrombosis risk.44,45) There have been reports on adverse events of PCC, including ischemic stroke, anaphylactic shock, disseminated intravascular coagulation, and deep vein thrombosis.43,46–50) However, none of our patients presented with complications in the present study. Given the association of warfarin with PHI, which could increase the mortality rate,51) we suggest that anticoagulation neutralization should be performed as early as possible in patients with traumatic head injury under anticoagulant therapy.
PCC contains concentrated VK-dependent coagulation factors (factors II, VII, IX, and X) extracted from large donor-pooled plasma and stored as a lyophilized powder. Currently, PCC is available in two forms: 4F-PCC11,14–16,24) and three-factor PCC (3F-PCC),18–21,23) which have both been used in previous studies. Compared with 3F-PCC, 4F-PCC contains higher levels of factor VII, as well as some anticoagulant proteins (Protein C, Protein S, Antithrombin, and heparin),52) and is associated with rapid INR reversal and a reduction in transfusion requirement without the risk of thromboembolic events.53) However, it remains unclear whether 4F-PCC is better than 3F-PCC.
This study has several limitations. First, this was a retrospective study with a small number of patients. Furthermore, there could have been patient selection bias. However, this was minimized by comparing warfarin-reversal using PCC with historical control. Second, although PCC may improve the prognosis of patients with TICH, this was not assessed. There is a need for further studies to confirm our findings and the PCC effect on the prognosis.
Conclusion
Warfarin reversal using combination therapy of PCC with VK after head trauma might be more effective for PIH inhibition than using VK monotherapy. This could be attributed to the rapid and stable neutralization of the warfarin anticoagulant effect. Furthermore, treatment with PCC was not associated with major thrombotic complications. PCC should be administered to patients with TICH taking warfarin to prevent PHI.
Conflicts of Interest Disclosure
All authors declare that they have no conflicts of interest.
Fig. 1 Study profile. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, TICH: traumatic intracranial hemorrhage.
Fig. 2 Time course of PT-INR in patients with combination therapy of PCC with VK. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 1 Patient baseline and clinical characteristics
Total VK monotherapy (n = 13) Combination with PCC (n = 7) P value
Age 79.1 ± 7.08 78.6 ± 7.2 80 ± 6.6 0.72
Female gender 7 (35%) 5 (38.5%) 2 (28.6%) >0.99
Hypertension 14 (70%) 13 (69.2%) 5 (71.4%) >0.99
Diabetes mellitus 9 (45%) 6 (46.2%) 3 (42.9%) >0.99
Antiplatelet therapy 6 (30%) 5 (38.5%) 1 (14.3%) 0.35
mRS before injury 3 (1–3) 5 (4–6) 4 (3.5–5.5) 0.93
GCS on admission 12 (11–14.3) 12 (8.5–14) 12 (11–15) 0.54
PT-INR at admission 2.33 (1.70–3.18) 2.52 (1.78–3.17) 1.83 (1.67–3.39) >0.99
Time from injury to admission (hour) 3.7 ± 2.6 4.5 ± 2.8 2.1 ± 1.3 0.02*
Use of tranexamic acid 60 (%) 7 (53.9%) 5 (71.4%) 0.64
Data are presented as mean (SD), number (%), or median (IQR). *Indicates statistical significance. GCS: Glasgow Coma Scale, IQR: interquartile range, mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 2 Patient characteristics of the hematoma expansion positive and negative groups
Total (n = 20) VK monotherapy (n = 13) Combination with PCC (n = 7) P value
PHI 12 (60) 11 (84.6) 1 (14.3) 0.004*
Reached target-PT-INR after a half day 10 (50) 4 (30.8) 6 (85.7) 0.057
Hospitalization (day) 22.6 ± 30.2 15.1 ± 15.0 36.4 ± 45.7 0.27
mRS at discharge 4.5 (3–6) 5 (4–6) 4 (3.5–5.5) 0.46
Death 8 (40) 6 (46.2) 2 (28.6) 0.48
Craniotomy 3 (15) 2 (15.3) 1 (14.3) >0.99
Data are shown as mean (SD), number (%), or median (IQR). *Shows statistical significance. mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PHI: progressive hemorrhagic injury, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 3 Univariable analysis of predictors of hematoma expansion
Predictor Odds ratio 95% Confidence interval P value
Age >80 0.43 0.07–2.68 0.65
Female sex 0.84 0.092–8.32 >0.99
Hypertension 1.8 0.26–12.5 0.62
Diabetes mellitus 0.3 0.05–1.94 0.36
Antiplatelet therapy 4.9 0.46–54.5 0.32
Tranexamic acid 2.1 0.32–12.5 0.65
GCS score at admission <12 3.1 0.422–21.3 0.37
Delayed admission† 1.19 0.19–7.46 >0.99
Higher PT-INR (>2.0) at admission 0.84 0.134–5.26 >0.99
Reaching target-PT-INR after a half day 0.17 0.0225–1.23 0.17
Reversal using PCC 0.03 0.00–0.41 0.004*
†Time from injury to admission was >4 hours. *Shows a statistical significance. GCS: Glasgow Coma Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio. | ASPIRIN, COAGULATION FACTOR IX HUMAN\COAGULATION FACTOR VII HUMAN\COAGULATION FACTOR X HUMAN\PROTEIN C\PROTEIN S HUMAN\PROTHROMBIN, PHYTONADIONE, WARFARIN POTASSIUM | DrugsGivenReaction | CC BY-NC-ND | 33208582 | 18,674,277 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'. | Combination Therapy Using Prothrombin Complex Concentrate and Vitamin K in Anticoagulated Patients with Traumatic Intracranial Hemorrhage Prevents Progressive Hemorrhagic Injury: A Historically Controlled Study.
Warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk. However, warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) through progressive hemorrhagic injury (PHI). Therefore, a rapid anticoagulation reversal could be required in patients with TICH to prevent PHI. Differences in the warfarin reversal effect between combination therapy of prothrombin complex concentrate (PCC) with vitamin K (VK) and VK monotherapy remain unclear. However, studies have reported that PCC has greater effectiveness and safety for warfarin reversal compared with fresh frozen plasma (FFP). This retrospective study aimed to evaluate the warfarin reversal effects of combination therapy of PCC with VK and VK monotherapy on TICH. We compared the clinical outcomes between the periods before and after the PCC introduction in our hospital. There were 13 and 7 patients who received VK monotherapy and PCC with VK, respectively. PHI predictors were evaluated using univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00-0.41, P = 0.004). None of the patients presented with thrombotic complications. Warfarin reversal through a combination of PCC with VK could be more effective for inhibiting post-trauma PHI compared with VK monotherapy. This could be attributed to a rapid and stable warfarin reversal. PCC should be administered to patients with TICH taking warfarin for PHI prevention.
Introduction
With increasing life expectancy, there has been a concomitant increase in the number of patients requiring long-term anticoagulation to prevent arterial fibrillation-associated cerebral or systemic embolism and deep venous thrombosis.1) These patients receive oral anticoagulants, including warfarin as a vitamin K (VK) antagonist or direct oral anticoagulants (DOAC). A previous large-scale randomized clinical trial reported that DOAC and warfarin had similar efficacy and safety.2–5) Furthermore, DOAC has predictable pharmacokinetics and does not require routine monitoring since their anticoagulating effect does not interact with VK and interacts less frequently with other drugs. Therefore, DOAC has been preferably used for thromboembolic disease prevention recently. However, warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk, including those with an artificial valve, mitral stenosis, etc.2) Furthermore, warfarin is administered to patients with severe renal impairment who cannot be treated with DOAC.
Head trauma could cause an acute subdural hematoma, acute epidural hematoma, cerebral contusion, and traumatic subarachnoid hematoma. Progressive hemorrhagic injury (PHI) could cause a worsening of neurological conditions.3) Warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) since it inhibits hemostasis.6–8) Therefore, a rapid anticoagulation reversal in patients with TICH might be required for PHI prevention.
VK, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) are available for warfarin reversal in emergencies.2) PCC, which is the most recent to become clinically available, could have greater advantages compared with FFP. This is because it does not require blood typing and cross-matching; moreover, it eliminates the risk of FFP-related volume overload. Furthermore, compared with VK, PCC normalizes prothrombin time/international normalized ratio (PT-INR) more rapidly.9,10) Studies have reported that PCC for warfarin reversal could have greater effectiveness and safety than FFP.11) However, prior to PCC becoming clinically available, warfarin reversal was commonly achieved using VK alone rather than FFP infusion followed by VK. This could be because patients on warfarin treatment often present poor cardiac function and FFP could cause volume-overload associated with congestive heart failure.2,12) There is a need to study differences in the warfarin reversal effect in patients with head trauma between combination therapy of PCC with VK and VK monotherapy.
This retrospective study aimed to evaluate the warfarin reversal effects of a combination of PCC with VK and VK monotherapy in patients with TICH. Furthermore, we aimed to compare the clinical outcomes between the periods before and after the PCC introduction in our hospital.
Methods
The protocol for this retrospective study was approved by the ethics committee at our institution, which waived the requirement for patient consent (No. 3758). We retrospectively reviewed the medical records of 498 adult patients (≥18 years old) admitted at our hospital between February 2016 and November 2019 due to TICH within 12 post-injury hours (Fig. 1). Among them, 35 patients underwent warfarin treatment with a PT-INR of ≥1.4. Seven patients were infused with FFP to treat coincidental systemic massive hemorrhage due to aortic, hepatic, or pulmonary injuries. They were excluded from the study population because the clinical status is different from the others. In our hospital, four-factor PCC (4F-PCC) (Kcentra), which is among the clinically available PCC, was introduced for warfarin reversal from December 2017. We considered the periods before and after November 2017 as the VK era and PCC era, respectively. There 18 and 10 patients in the VK and PCC eras, respectively.
We excluded patients with mild head injury or excessively severe trauma on admission who did not receive treatment for warfarin reversal effect. The treatment outcome was evaluated in the remaining 20 patients (13 and 7 patients in the VK and PCC era, respectively). Immediately after TICH identification, all patients in the VK and PCC era were treated using intravenous administration of VK and PCC in combination with VK, respectively. Regarding the patients’ demographic and clinical characteristics, only time from injury to admission showed a significant between-group difference where it was longer in the VK era than in the PCC era (Table 1).
All the patients underwent a computer tomography (CT) scan on admission and repeat scans at least twice within 3 and 4-24 hours after admission. PHI was evaluated on the repeat CT scans and defined as follows: the appearance of a new intracranial hematoma, including intracerebral, intraventricular, subdural, epidural, or subarachnoid hemorrhage not caused by redistributed hemorrhage or expansion of pre-existing hematoma indicated by a qualitative increase in the volume by 1.4 times greater than the volume on the admission CT.13)
For warfarin reversal with and without PCC, the target PT-INR level was <1.40. Regarding reversal using PCC, PCC was intravenously administered immediately followed by intravenous VK administration (10–20 mg). The administered PCC dose was determined according to our institutional protocol, which was approved by the medical safety commission of our hospital, as follows: 25 IU/kg, 35 IU/kg, and 50 IU/kg were given to patients with INR 1.4–4, 4.0–6.0, and >6, respectively. PCC was only administered once. Contrastingly, 10 mg VK was repeatedly administered in case the PT-INR was ≥1.4 in the follow-up test at 8–12 post-admission hours. We performed between-reversal comparisons of the rates of reaching the target PT-INR at half a day after hospitalization.
The PHI incidence was evaluated in all the patients who underwent reversal treatment. Furthermore, we performed between-reversal comparisons of the in-hospital death; modified Rankin Scale (mRS) at discharge; and adverse events, including myocardial infarction, ischemic stroke, pulmonary embolism, and deep vein thrombosis.
Table 1 presents the patients’ baseline and clinical characteristics. Hypertension was defined as a pre-injury or pre-treatment systolic and/or diastolic blood pressure of ≥140 mmHg and ≥90 mmHg, respectively. Patients were considered to have diabetes if their glycosylated hemoglobin A1C level exceeded 6.5% or if they were being treated with insulin and/or oral hypoglycemic medications. The used antiplatelet drugs included aspirin, cilostazol, and clopidogrel with none of the patients taking prasugrel and ticlopidine hydrochloride.
Continuous variables were express as mean ± SD or median (interquartile range [IQR]). Categorical variables were expressed as number (%). All statistical analyses were performed using JMP version 15 software (SAS Institute, Tokyo, Japan). Statistical significance was set at P <0.05. Between-group comparisons were performed using Fisher's exact test or Mann–Whitney U test. Univariable logistic regression analyses were performed to determine PHI predictors.
Results
Figure 2 shows the time course of PT-INR in the seven patients who underwent combination therapy of PCC with VK. There was a rapid decrease in PT-INR, which reached its target (<1.40) at 1 hour after the start of warfarin reversal in all patients. PT-INR at half a day after reversal remained <1.40 in most patients except one who presented a PT-INR of 1.41.
There were no patients who had new bleeding at other sites and all of the PHI was identified as an expansion of pre-existing hematomas. Patients who underwent warfarin therapy had a high PHI incidence. Among the 20 patients, 12 (60%) patients presented with PHI. The PHI incidence was significantly lower in patients who underwent PCC therapy than VK monotherapy (84.6% vs. 14.3%, P = 0.004; Table 2). There were numerically, but not significantly, more patients who underwent PCC therapy with a PT-INR <1.40 at half a day after warfarin reversal induction compared with those who underwent VK monotherapy (85.7% vs 30.8%). There were no significant between-reversal differences in the hospitalization period, mRS at discharge, mortality, and rate of surgical treatment by craniotomy.
As shown in Table 3, PHI predictors were evaluated by univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00–0.41, P = 0.004). Contrastingly, other demographic and patient characteristics were not associated with PHI. Hemostasis-related factors, including antiplatelet therapy and tranexamic acid administration, did not affect PHI. Severely impaired consciousness (Glasgow Coma Scale [GCS] <12) and delayed admission (time from injury to admission >4 hours) did not affect PHI. Higher PT-INR (>2.0) at admission was not associated with PHI. Patients who reached the target-PT-INR (<1.4) at half a day tended to have less PHI but it was not statistically significant.
Discussion
There have been numerous reports that warfarin reversal using PCC is effective in patients with non-TICH or TICH.11,14–28) However, these studies compared warfarin reversal using PCC and FFP11,14–28) with none of the studies comparing the treatment outcome of warfarin reversal using combination therapy of PCC with VK and VK monotherapy. The use of FFP is associated with a greater risk of volume overload and heart failure.9) In some clinical settings, FFP administration for warfarin reversal is difficult since patients on anticoagulant therapy present with a high risk of heart failure, and the complication rate of atrial fibrillation increases in proportion to the severity of heart failure.29) Moreover, heart failure has been reported in 37% of newly developed atrial fibrillation.30) Therefore, there is a need to directly compare the recent warfarin reversal using a combination therapy of PCC and conventional reversal using VK monotherapy. In this novel study, we found that warfarin reversal by PCC significantly suppressed PHI compared with VK monotherapy.
Warfarin treatment is associated with poor prognosis of patients with TICH. Ivascu et al. reported that oral warfarin increased the mortality rate in patients with TICH (48%), which is approximately five times higher than that in patients without anticoagulant therapy.31) The observed poor outcome under warfarin treatment could be attributed to the anticoagulation causing PHI.7,32–34) Oral anticoagulation is associated with PHI even in patients with minor head trauma.31) Therefore, there is a need to improve the prognosis of patients with head trauma under anticoagulant therapy by rapidly neutralizing the anticoagulant effect. Furthermore, risk factors for PHI have been shown to include older age, male gender, and larger initial lesions.35–40) However, these findings were not observed in our study given its small sample size.
For warfarin reversal, the use of PCC, rather than FFP, was associated with a more rapid decrease in the PT-INR17,18,22) and a higher rate of achieving the target PT-INR value without a cardiovascular volume load.9) VK, which induces production of warfarin-inhibiting coagulant factors in the liver, takes about 24 hours to fully exert its effect to modulate prolonged PT-INR by warfarin.41) PCC intravenous administration is to compensate for the shortage of coagulant factor and shows a more rapid decrease in PT-INR levels than VK intravenous administration alone.42) Rapid PT-INR correction by PCC is considered to suppress PHI more effectively than VK alone in patients taking warfarin. To neutralize a warfarin effect by PCC, the short-lasting effect of PCC should be paid attention to. PCC without VK may result in a re-increase in PT-INR and clinical deterioration.43) Therefore, to maintain the rapidly corrected PT-INR by PCC, VK plays an important role. These were consistent with our findings that, in the present study, most of the patients who underwent the combination therapy using PCC and VK had normalized values of PT-INR rapidly (at 1 hour after PCC administration) and remained within or close to the reference values after 12 hours. Immediate and stable effect of the combination of PCC and VK is considered to prevent PHI.
Anticoagulant therapy neutralization is associated with thrombosis risk.44,45) There have been reports on adverse events of PCC, including ischemic stroke, anaphylactic shock, disseminated intravascular coagulation, and deep vein thrombosis.43,46–50) However, none of our patients presented with complications in the present study. Given the association of warfarin with PHI, which could increase the mortality rate,51) we suggest that anticoagulation neutralization should be performed as early as possible in patients with traumatic head injury under anticoagulant therapy.
PCC contains concentrated VK-dependent coagulation factors (factors II, VII, IX, and X) extracted from large donor-pooled plasma and stored as a lyophilized powder. Currently, PCC is available in two forms: 4F-PCC11,14–16,24) and three-factor PCC (3F-PCC),18–21,23) which have both been used in previous studies. Compared with 3F-PCC, 4F-PCC contains higher levels of factor VII, as well as some anticoagulant proteins (Protein C, Protein S, Antithrombin, and heparin),52) and is associated with rapid INR reversal and a reduction in transfusion requirement without the risk of thromboembolic events.53) However, it remains unclear whether 4F-PCC is better than 3F-PCC.
This study has several limitations. First, this was a retrospective study with a small number of patients. Furthermore, there could have been patient selection bias. However, this was minimized by comparing warfarin-reversal using PCC with historical control. Second, although PCC may improve the prognosis of patients with TICH, this was not assessed. There is a need for further studies to confirm our findings and the PCC effect on the prognosis.
Conclusion
Warfarin reversal using combination therapy of PCC with VK after head trauma might be more effective for PIH inhibition than using VK monotherapy. This could be attributed to the rapid and stable neutralization of the warfarin anticoagulant effect. Furthermore, treatment with PCC was not associated with major thrombotic complications. PCC should be administered to patients with TICH taking warfarin to prevent PHI.
Conflicts of Interest Disclosure
All authors declare that they have no conflicts of interest.
Fig. 1 Study profile. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, TICH: traumatic intracranial hemorrhage.
Fig. 2 Time course of PT-INR in patients with combination therapy of PCC with VK. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 1 Patient baseline and clinical characteristics
Total VK monotherapy (n = 13) Combination with PCC (n = 7) P value
Age 79.1 ± 7.08 78.6 ± 7.2 80 ± 6.6 0.72
Female gender 7 (35%) 5 (38.5%) 2 (28.6%) >0.99
Hypertension 14 (70%) 13 (69.2%) 5 (71.4%) >0.99
Diabetes mellitus 9 (45%) 6 (46.2%) 3 (42.9%) >0.99
Antiplatelet therapy 6 (30%) 5 (38.5%) 1 (14.3%) 0.35
mRS before injury 3 (1–3) 5 (4–6) 4 (3.5–5.5) 0.93
GCS on admission 12 (11–14.3) 12 (8.5–14) 12 (11–15) 0.54
PT-INR at admission 2.33 (1.70–3.18) 2.52 (1.78–3.17) 1.83 (1.67–3.39) >0.99
Time from injury to admission (hour) 3.7 ± 2.6 4.5 ± 2.8 2.1 ± 1.3 0.02*
Use of tranexamic acid 60 (%) 7 (53.9%) 5 (71.4%) 0.64
Data are presented as mean (SD), number (%), or median (IQR). *Indicates statistical significance. GCS: Glasgow Coma Scale, IQR: interquartile range, mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 2 Patient characteristics of the hematoma expansion positive and negative groups
Total (n = 20) VK monotherapy (n = 13) Combination with PCC (n = 7) P value
PHI 12 (60) 11 (84.6) 1 (14.3) 0.004*
Reached target-PT-INR after a half day 10 (50) 4 (30.8) 6 (85.7) 0.057
Hospitalization (day) 22.6 ± 30.2 15.1 ± 15.0 36.4 ± 45.7 0.27
mRS at discharge 4.5 (3–6) 5 (4–6) 4 (3.5–5.5) 0.46
Death 8 (40) 6 (46.2) 2 (28.6) 0.48
Craniotomy 3 (15) 2 (15.3) 1 (14.3) >0.99
Data are shown as mean (SD), number (%), or median (IQR). *Shows statistical significance. mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PHI: progressive hemorrhagic injury, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 3 Univariable analysis of predictors of hematoma expansion
Predictor Odds ratio 95% Confidence interval P value
Age >80 0.43 0.07–2.68 0.65
Female sex 0.84 0.092–8.32 >0.99
Hypertension 1.8 0.26–12.5 0.62
Diabetes mellitus 0.3 0.05–1.94 0.36
Antiplatelet therapy 4.9 0.46–54.5 0.32
Tranexamic acid 2.1 0.32–12.5 0.65
GCS score at admission <12 3.1 0.422–21.3 0.37
Delayed admission† 1.19 0.19–7.46 >0.99
Higher PT-INR (>2.0) at admission 0.84 0.134–5.26 >0.99
Reaching target-PT-INR after a half day 0.17 0.0225–1.23 0.17
Reversal using PCC 0.03 0.00–0.41 0.004*
†Time from injury to admission was >4 hours. *Shows a statistical significance. GCS: Glasgow Coma Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio. | ASPIRIN, COAGULATION FACTOR IX HUMAN\COAGULATION FACTOR VII HUMAN\COAGULATION FACTOR X HUMAN\PROTEIN C\PROTEIN S HUMAN\PROTHROMBIN, PHYTONADIONE, WARFARIN POTASSIUM | DrugsGivenReaction | CC BY-NC-ND | 33208582 | 18,674,277 | 2021-01-15 |
What is the weight of the patient? | Combination Therapy Using Prothrombin Complex Concentrate and Vitamin K in Anticoagulated Patients with Traumatic Intracranial Hemorrhage Prevents Progressive Hemorrhagic Injury: A Historically Controlled Study.
Warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk. However, warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) through progressive hemorrhagic injury (PHI). Therefore, a rapid anticoagulation reversal could be required in patients with TICH to prevent PHI. Differences in the warfarin reversal effect between combination therapy of prothrombin complex concentrate (PCC) with vitamin K (VK) and VK monotherapy remain unclear. However, studies have reported that PCC has greater effectiveness and safety for warfarin reversal compared with fresh frozen plasma (FFP). This retrospective study aimed to evaluate the warfarin reversal effects of combination therapy of PCC with VK and VK monotherapy on TICH. We compared the clinical outcomes between the periods before and after the PCC introduction in our hospital. There were 13 and 7 patients who received VK monotherapy and PCC with VK, respectively. PHI predictors were evaluated using univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00-0.41, P = 0.004). None of the patients presented with thrombotic complications. Warfarin reversal through a combination of PCC with VK could be more effective for inhibiting post-trauma PHI compared with VK monotherapy. This could be attributed to a rapid and stable warfarin reversal. PCC should be administered to patients with TICH taking warfarin for PHI prevention.
Introduction
With increasing life expectancy, there has been a concomitant increase in the number of patients requiring long-term anticoagulation to prevent arterial fibrillation-associated cerebral or systemic embolism and deep venous thrombosis.1) These patients receive oral anticoagulants, including warfarin as a vitamin K (VK) antagonist or direct oral anticoagulants (DOAC). A previous large-scale randomized clinical trial reported that DOAC and warfarin had similar efficacy and safety.2–5) Furthermore, DOAC has predictable pharmacokinetics and does not require routine monitoring since their anticoagulating effect does not interact with VK and interacts less frequently with other drugs. Therefore, DOAC has been preferably used for thromboembolic disease prevention recently. However, warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk, including those with an artificial valve, mitral stenosis, etc.2) Furthermore, warfarin is administered to patients with severe renal impairment who cannot be treated with DOAC.
Head trauma could cause an acute subdural hematoma, acute epidural hematoma, cerebral contusion, and traumatic subarachnoid hematoma. Progressive hemorrhagic injury (PHI) could cause a worsening of neurological conditions.3) Warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) since it inhibits hemostasis.6–8) Therefore, a rapid anticoagulation reversal in patients with TICH might be required for PHI prevention.
VK, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) are available for warfarin reversal in emergencies.2) PCC, which is the most recent to become clinically available, could have greater advantages compared with FFP. This is because it does not require blood typing and cross-matching; moreover, it eliminates the risk of FFP-related volume overload. Furthermore, compared with VK, PCC normalizes prothrombin time/international normalized ratio (PT-INR) more rapidly.9,10) Studies have reported that PCC for warfarin reversal could have greater effectiveness and safety than FFP.11) However, prior to PCC becoming clinically available, warfarin reversal was commonly achieved using VK alone rather than FFP infusion followed by VK. This could be because patients on warfarin treatment often present poor cardiac function and FFP could cause volume-overload associated with congestive heart failure.2,12) There is a need to study differences in the warfarin reversal effect in patients with head trauma between combination therapy of PCC with VK and VK monotherapy.
This retrospective study aimed to evaluate the warfarin reversal effects of a combination of PCC with VK and VK monotherapy in patients with TICH. Furthermore, we aimed to compare the clinical outcomes between the periods before and after the PCC introduction in our hospital.
Methods
The protocol for this retrospective study was approved by the ethics committee at our institution, which waived the requirement for patient consent (No. 3758). We retrospectively reviewed the medical records of 498 adult patients (≥18 years old) admitted at our hospital between February 2016 and November 2019 due to TICH within 12 post-injury hours (Fig. 1). Among them, 35 patients underwent warfarin treatment with a PT-INR of ≥1.4. Seven patients were infused with FFP to treat coincidental systemic massive hemorrhage due to aortic, hepatic, or pulmonary injuries. They were excluded from the study population because the clinical status is different from the others. In our hospital, four-factor PCC (4F-PCC) (Kcentra), which is among the clinically available PCC, was introduced for warfarin reversal from December 2017. We considered the periods before and after November 2017 as the VK era and PCC era, respectively. There 18 and 10 patients in the VK and PCC eras, respectively.
We excluded patients with mild head injury or excessively severe trauma on admission who did not receive treatment for warfarin reversal effect. The treatment outcome was evaluated in the remaining 20 patients (13 and 7 patients in the VK and PCC era, respectively). Immediately after TICH identification, all patients in the VK and PCC era were treated using intravenous administration of VK and PCC in combination with VK, respectively. Regarding the patients’ demographic and clinical characteristics, only time from injury to admission showed a significant between-group difference where it was longer in the VK era than in the PCC era (Table 1).
All the patients underwent a computer tomography (CT) scan on admission and repeat scans at least twice within 3 and 4-24 hours after admission. PHI was evaluated on the repeat CT scans and defined as follows: the appearance of a new intracranial hematoma, including intracerebral, intraventricular, subdural, epidural, or subarachnoid hemorrhage not caused by redistributed hemorrhage or expansion of pre-existing hematoma indicated by a qualitative increase in the volume by 1.4 times greater than the volume on the admission CT.13)
For warfarin reversal with and without PCC, the target PT-INR level was <1.40. Regarding reversal using PCC, PCC was intravenously administered immediately followed by intravenous VK administration (10–20 mg). The administered PCC dose was determined according to our institutional protocol, which was approved by the medical safety commission of our hospital, as follows: 25 IU/kg, 35 IU/kg, and 50 IU/kg were given to patients with INR 1.4–4, 4.0–6.0, and >6, respectively. PCC was only administered once. Contrastingly, 10 mg VK was repeatedly administered in case the PT-INR was ≥1.4 in the follow-up test at 8–12 post-admission hours. We performed between-reversal comparisons of the rates of reaching the target PT-INR at half a day after hospitalization.
The PHI incidence was evaluated in all the patients who underwent reversal treatment. Furthermore, we performed between-reversal comparisons of the in-hospital death; modified Rankin Scale (mRS) at discharge; and adverse events, including myocardial infarction, ischemic stroke, pulmonary embolism, and deep vein thrombosis.
Table 1 presents the patients’ baseline and clinical characteristics. Hypertension was defined as a pre-injury or pre-treatment systolic and/or diastolic blood pressure of ≥140 mmHg and ≥90 mmHg, respectively. Patients were considered to have diabetes if their glycosylated hemoglobin A1C level exceeded 6.5% or if they were being treated with insulin and/or oral hypoglycemic medications. The used antiplatelet drugs included aspirin, cilostazol, and clopidogrel with none of the patients taking prasugrel and ticlopidine hydrochloride.
Continuous variables were express as mean ± SD or median (interquartile range [IQR]). Categorical variables were expressed as number (%). All statistical analyses were performed using JMP version 15 software (SAS Institute, Tokyo, Japan). Statistical significance was set at P <0.05. Between-group comparisons were performed using Fisher's exact test or Mann–Whitney U test. Univariable logistic regression analyses were performed to determine PHI predictors.
Results
Figure 2 shows the time course of PT-INR in the seven patients who underwent combination therapy of PCC with VK. There was a rapid decrease in PT-INR, which reached its target (<1.40) at 1 hour after the start of warfarin reversal in all patients. PT-INR at half a day after reversal remained <1.40 in most patients except one who presented a PT-INR of 1.41.
There were no patients who had new bleeding at other sites and all of the PHI was identified as an expansion of pre-existing hematomas. Patients who underwent warfarin therapy had a high PHI incidence. Among the 20 patients, 12 (60%) patients presented with PHI. The PHI incidence was significantly lower in patients who underwent PCC therapy than VK monotherapy (84.6% vs. 14.3%, P = 0.004; Table 2). There were numerically, but not significantly, more patients who underwent PCC therapy with a PT-INR <1.40 at half a day after warfarin reversal induction compared with those who underwent VK monotherapy (85.7% vs 30.8%). There were no significant between-reversal differences in the hospitalization period, mRS at discharge, mortality, and rate of surgical treatment by craniotomy.
As shown in Table 3, PHI predictors were evaluated by univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00–0.41, P = 0.004). Contrastingly, other demographic and patient characteristics were not associated with PHI. Hemostasis-related factors, including antiplatelet therapy and tranexamic acid administration, did not affect PHI. Severely impaired consciousness (Glasgow Coma Scale [GCS] <12) and delayed admission (time from injury to admission >4 hours) did not affect PHI. Higher PT-INR (>2.0) at admission was not associated with PHI. Patients who reached the target-PT-INR (<1.4) at half a day tended to have less PHI but it was not statistically significant.
Discussion
There have been numerous reports that warfarin reversal using PCC is effective in patients with non-TICH or TICH.11,14–28) However, these studies compared warfarin reversal using PCC and FFP11,14–28) with none of the studies comparing the treatment outcome of warfarin reversal using combination therapy of PCC with VK and VK monotherapy. The use of FFP is associated with a greater risk of volume overload and heart failure.9) In some clinical settings, FFP administration for warfarin reversal is difficult since patients on anticoagulant therapy present with a high risk of heart failure, and the complication rate of atrial fibrillation increases in proportion to the severity of heart failure.29) Moreover, heart failure has been reported in 37% of newly developed atrial fibrillation.30) Therefore, there is a need to directly compare the recent warfarin reversal using a combination therapy of PCC and conventional reversal using VK monotherapy. In this novel study, we found that warfarin reversal by PCC significantly suppressed PHI compared with VK monotherapy.
Warfarin treatment is associated with poor prognosis of patients with TICH. Ivascu et al. reported that oral warfarin increased the mortality rate in patients with TICH (48%), which is approximately five times higher than that in patients without anticoagulant therapy.31) The observed poor outcome under warfarin treatment could be attributed to the anticoagulation causing PHI.7,32–34) Oral anticoagulation is associated with PHI even in patients with minor head trauma.31) Therefore, there is a need to improve the prognosis of patients with head trauma under anticoagulant therapy by rapidly neutralizing the anticoagulant effect. Furthermore, risk factors for PHI have been shown to include older age, male gender, and larger initial lesions.35–40) However, these findings were not observed in our study given its small sample size.
For warfarin reversal, the use of PCC, rather than FFP, was associated with a more rapid decrease in the PT-INR17,18,22) and a higher rate of achieving the target PT-INR value without a cardiovascular volume load.9) VK, which induces production of warfarin-inhibiting coagulant factors in the liver, takes about 24 hours to fully exert its effect to modulate prolonged PT-INR by warfarin.41) PCC intravenous administration is to compensate for the shortage of coagulant factor and shows a more rapid decrease in PT-INR levels than VK intravenous administration alone.42) Rapid PT-INR correction by PCC is considered to suppress PHI more effectively than VK alone in patients taking warfarin. To neutralize a warfarin effect by PCC, the short-lasting effect of PCC should be paid attention to. PCC without VK may result in a re-increase in PT-INR and clinical deterioration.43) Therefore, to maintain the rapidly corrected PT-INR by PCC, VK plays an important role. These were consistent with our findings that, in the present study, most of the patients who underwent the combination therapy using PCC and VK had normalized values of PT-INR rapidly (at 1 hour after PCC administration) and remained within or close to the reference values after 12 hours. Immediate and stable effect of the combination of PCC and VK is considered to prevent PHI.
Anticoagulant therapy neutralization is associated with thrombosis risk.44,45) There have been reports on adverse events of PCC, including ischemic stroke, anaphylactic shock, disseminated intravascular coagulation, and deep vein thrombosis.43,46–50) However, none of our patients presented with complications in the present study. Given the association of warfarin with PHI, which could increase the mortality rate,51) we suggest that anticoagulation neutralization should be performed as early as possible in patients with traumatic head injury under anticoagulant therapy.
PCC contains concentrated VK-dependent coagulation factors (factors II, VII, IX, and X) extracted from large donor-pooled plasma and stored as a lyophilized powder. Currently, PCC is available in two forms: 4F-PCC11,14–16,24) and three-factor PCC (3F-PCC),18–21,23) which have both been used in previous studies. Compared with 3F-PCC, 4F-PCC contains higher levels of factor VII, as well as some anticoagulant proteins (Protein C, Protein S, Antithrombin, and heparin),52) and is associated with rapid INR reversal and a reduction in transfusion requirement without the risk of thromboembolic events.53) However, it remains unclear whether 4F-PCC is better than 3F-PCC.
This study has several limitations. First, this was a retrospective study with a small number of patients. Furthermore, there could have been patient selection bias. However, this was minimized by comparing warfarin-reversal using PCC with historical control. Second, although PCC may improve the prognosis of patients with TICH, this was not assessed. There is a need for further studies to confirm our findings and the PCC effect on the prognosis.
Conclusion
Warfarin reversal using combination therapy of PCC with VK after head trauma might be more effective for PIH inhibition than using VK monotherapy. This could be attributed to the rapid and stable neutralization of the warfarin anticoagulant effect. Furthermore, treatment with PCC was not associated with major thrombotic complications. PCC should be administered to patients with TICH taking warfarin to prevent PHI.
Conflicts of Interest Disclosure
All authors declare that they have no conflicts of interest.
Fig. 1 Study profile. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, TICH: traumatic intracranial hemorrhage.
Fig. 2 Time course of PT-INR in patients with combination therapy of PCC with VK. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 1 Patient baseline and clinical characteristics
Total VK monotherapy (n = 13) Combination with PCC (n = 7) P value
Age 79.1 ± 7.08 78.6 ± 7.2 80 ± 6.6 0.72
Female gender 7 (35%) 5 (38.5%) 2 (28.6%) >0.99
Hypertension 14 (70%) 13 (69.2%) 5 (71.4%) >0.99
Diabetes mellitus 9 (45%) 6 (46.2%) 3 (42.9%) >0.99
Antiplatelet therapy 6 (30%) 5 (38.5%) 1 (14.3%) 0.35
mRS before injury 3 (1–3) 5 (4–6) 4 (3.5–5.5) 0.93
GCS on admission 12 (11–14.3) 12 (8.5–14) 12 (11–15) 0.54
PT-INR at admission 2.33 (1.70–3.18) 2.52 (1.78–3.17) 1.83 (1.67–3.39) >0.99
Time from injury to admission (hour) 3.7 ± 2.6 4.5 ± 2.8 2.1 ± 1.3 0.02*
Use of tranexamic acid 60 (%) 7 (53.9%) 5 (71.4%) 0.64
Data are presented as mean (SD), number (%), or median (IQR). *Indicates statistical significance. GCS: Glasgow Coma Scale, IQR: interquartile range, mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 2 Patient characteristics of the hematoma expansion positive and negative groups
Total (n = 20) VK monotherapy (n = 13) Combination with PCC (n = 7) P value
PHI 12 (60) 11 (84.6) 1 (14.3) 0.004*
Reached target-PT-INR after a half day 10 (50) 4 (30.8) 6 (85.7) 0.057
Hospitalization (day) 22.6 ± 30.2 15.1 ± 15.0 36.4 ± 45.7 0.27
mRS at discharge 4.5 (3–6) 5 (4–6) 4 (3.5–5.5) 0.46
Death 8 (40) 6 (46.2) 2 (28.6) 0.48
Craniotomy 3 (15) 2 (15.3) 1 (14.3) >0.99
Data are shown as mean (SD), number (%), or median (IQR). *Shows statistical significance. mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PHI: progressive hemorrhagic injury, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 3 Univariable analysis of predictors of hematoma expansion
Predictor Odds ratio 95% Confidence interval P value
Age >80 0.43 0.07–2.68 0.65
Female sex 0.84 0.092–8.32 >0.99
Hypertension 1.8 0.26–12.5 0.62
Diabetes mellitus 0.3 0.05–1.94 0.36
Antiplatelet therapy 4.9 0.46–54.5 0.32
Tranexamic acid 2.1 0.32–12.5 0.65
GCS score at admission <12 3.1 0.422–21.3 0.37
Delayed admission† 1.19 0.19–7.46 >0.99
Higher PT-INR (>2.0) at admission 0.84 0.134–5.26 >0.99
Reaching target-PT-INR after a half day 0.17 0.0225–1.23 0.17
Reversal using PCC 0.03 0.00–0.41 0.004*
†Time from injury to admission was >4 hours. *Shows a statistical significance. GCS: Glasgow Coma Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio. | 67 kg. | Weight | CC BY-NC-ND | 33208582 | 18,674,277 | 2021-01-15 |
What was the administration route of drug 'COAGULATION FACTOR IX HUMAN\COAGULATION FACTOR VII HUMAN\COAGULATION FACTOR X HUMAN\PROTEIN C\PROTEIN S HUMAN\PROTHROMBIN'? | Combination Therapy Using Prothrombin Complex Concentrate and Vitamin K in Anticoagulated Patients with Traumatic Intracranial Hemorrhage Prevents Progressive Hemorrhagic Injury: A Historically Controlled Study.
Warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk. However, warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) through progressive hemorrhagic injury (PHI). Therefore, a rapid anticoagulation reversal could be required in patients with TICH to prevent PHI. Differences in the warfarin reversal effect between combination therapy of prothrombin complex concentrate (PCC) with vitamin K (VK) and VK monotherapy remain unclear. However, studies have reported that PCC has greater effectiveness and safety for warfarin reversal compared with fresh frozen plasma (FFP). This retrospective study aimed to evaluate the warfarin reversal effects of combination therapy of PCC with VK and VK monotherapy on TICH. We compared the clinical outcomes between the periods before and after the PCC introduction in our hospital. There were 13 and 7 patients who received VK monotherapy and PCC with VK, respectively. PHI predictors were evaluated using univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00-0.41, P = 0.004). None of the patients presented with thrombotic complications. Warfarin reversal through a combination of PCC with VK could be more effective for inhibiting post-trauma PHI compared with VK monotherapy. This could be attributed to a rapid and stable warfarin reversal. PCC should be administered to patients with TICH taking warfarin for PHI prevention.
Introduction
With increasing life expectancy, there has been a concomitant increase in the number of patients requiring long-term anticoagulation to prevent arterial fibrillation-associated cerebral or systemic embolism and deep venous thrombosis.1) These patients receive oral anticoagulants, including warfarin as a vitamin K (VK) antagonist or direct oral anticoagulants (DOAC). A previous large-scale randomized clinical trial reported that DOAC and warfarin had similar efficacy and safety.2–5) Furthermore, DOAC has predictable pharmacokinetics and does not require routine monitoring since their anticoagulating effect does not interact with VK and interacts less frequently with other drugs. Therefore, DOAC has been preferably used for thromboembolic disease prevention recently. However, warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk, including those with an artificial valve, mitral stenosis, etc.2) Furthermore, warfarin is administered to patients with severe renal impairment who cannot be treated with DOAC.
Head trauma could cause an acute subdural hematoma, acute epidural hematoma, cerebral contusion, and traumatic subarachnoid hematoma. Progressive hemorrhagic injury (PHI) could cause a worsening of neurological conditions.3) Warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) since it inhibits hemostasis.6–8) Therefore, a rapid anticoagulation reversal in patients with TICH might be required for PHI prevention.
VK, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) are available for warfarin reversal in emergencies.2) PCC, which is the most recent to become clinically available, could have greater advantages compared with FFP. This is because it does not require blood typing and cross-matching; moreover, it eliminates the risk of FFP-related volume overload. Furthermore, compared with VK, PCC normalizes prothrombin time/international normalized ratio (PT-INR) more rapidly.9,10) Studies have reported that PCC for warfarin reversal could have greater effectiveness and safety than FFP.11) However, prior to PCC becoming clinically available, warfarin reversal was commonly achieved using VK alone rather than FFP infusion followed by VK. This could be because patients on warfarin treatment often present poor cardiac function and FFP could cause volume-overload associated with congestive heart failure.2,12) There is a need to study differences in the warfarin reversal effect in patients with head trauma between combination therapy of PCC with VK and VK monotherapy.
This retrospective study aimed to evaluate the warfarin reversal effects of a combination of PCC with VK and VK monotherapy in patients with TICH. Furthermore, we aimed to compare the clinical outcomes between the periods before and after the PCC introduction in our hospital.
Methods
The protocol for this retrospective study was approved by the ethics committee at our institution, which waived the requirement for patient consent (No. 3758). We retrospectively reviewed the medical records of 498 adult patients (≥18 years old) admitted at our hospital between February 2016 and November 2019 due to TICH within 12 post-injury hours (Fig. 1). Among them, 35 patients underwent warfarin treatment with a PT-INR of ≥1.4. Seven patients were infused with FFP to treat coincidental systemic massive hemorrhage due to aortic, hepatic, or pulmonary injuries. They were excluded from the study population because the clinical status is different from the others. In our hospital, four-factor PCC (4F-PCC) (Kcentra), which is among the clinically available PCC, was introduced for warfarin reversal from December 2017. We considered the periods before and after November 2017 as the VK era and PCC era, respectively. There 18 and 10 patients in the VK and PCC eras, respectively.
We excluded patients with mild head injury or excessively severe trauma on admission who did not receive treatment for warfarin reversal effect. The treatment outcome was evaluated in the remaining 20 patients (13 and 7 patients in the VK and PCC era, respectively). Immediately after TICH identification, all patients in the VK and PCC era were treated using intravenous administration of VK and PCC in combination with VK, respectively. Regarding the patients’ demographic and clinical characteristics, only time from injury to admission showed a significant between-group difference where it was longer in the VK era than in the PCC era (Table 1).
All the patients underwent a computer tomography (CT) scan on admission and repeat scans at least twice within 3 and 4-24 hours after admission. PHI was evaluated on the repeat CT scans and defined as follows: the appearance of a new intracranial hematoma, including intracerebral, intraventricular, subdural, epidural, or subarachnoid hemorrhage not caused by redistributed hemorrhage or expansion of pre-existing hematoma indicated by a qualitative increase in the volume by 1.4 times greater than the volume on the admission CT.13)
For warfarin reversal with and without PCC, the target PT-INR level was <1.40. Regarding reversal using PCC, PCC was intravenously administered immediately followed by intravenous VK administration (10–20 mg). The administered PCC dose was determined according to our institutional protocol, which was approved by the medical safety commission of our hospital, as follows: 25 IU/kg, 35 IU/kg, and 50 IU/kg were given to patients with INR 1.4–4, 4.0–6.0, and >6, respectively. PCC was only administered once. Contrastingly, 10 mg VK was repeatedly administered in case the PT-INR was ≥1.4 in the follow-up test at 8–12 post-admission hours. We performed between-reversal comparisons of the rates of reaching the target PT-INR at half a day after hospitalization.
The PHI incidence was evaluated in all the patients who underwent reversal treatment. Furthermore, we performed between-reversal comparisons of the in-hospital death; modified Rankin Scale (mRS) at discharge; and adverse events, including myocardial infarction, ischemic stroke, pulmonary embolism, and deep vein thrombosis.
Table 1 presents the patients’ baseline and clinical characteristics. Hypertension was defined as a pre-injury or pre-treatment systolic and/or diastolic blood pressure of ≥140 mmHg and ≥90 mmHg, respectively. Patients were considered to have diabetes if their glycosylated hemoglobin A1C level exceeded 6.5% or if they were being treated with insulin and/or oral hypoglycemic medications. The used antiplatelet drugs included aspirin, cilostazol, and clopidogrel with none of the patients taking prasugrel and ticlopidine hydrochloride.
Continuous variables were express as mean ± SD or median (interquartile range [IQR]). Categorical variables were expressed as number (%). All statistical analyses were performed using JMP version 15 software (SAS Institute, Tokyo, Japan). Statistical significance was set at P <0.05. Between-group comparisons were performed using Fisher's exact test or Mann–Whitney U test. Univariable logistic regression analyses were performed to determine PHI predictors.
Results
Figure 2 shows the time course of PT-INR in the seven patients who underwent combination therapy of PCC with VK. There was a rapid decrease in PT-INR, which reached its target (<1.40) at 1 hour after the start of warfarin reversal in all patients. PT-INR at half a day after reversal remained <1.40 in most patients except one who presented a PT-INR of 1.41.
There were no patients who had new bleeding at other sites and all of the PHI was identified as an expansion of pre-existing hematomas. Patients who underwent warfarin therapy had a high PHI incidence. Among the 20 patients, 12 (60%) patients presented with PHI. The PHI incidence was significantly lower in patients who underwent PCC therapy than VK monotherapy (84.6% vs. 14.3%, P = 0.004; Table 2). There were numerically, but not significantly, more patients who underwent PCC therapy with a PT-INR <1.40 at half a day after warfarin reversal induction compared with those who underwent VK monotherapy (85.7% vs 30.8%). There were no significant between-reversal differences in the hospitalization period, mRS at discharge, mortality, and rate of surgical treatment by craniotomy.
As shown in Table 3, PHI predictors were evaluated by univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00–0.41, P = 0.004). Contrastingly, other demographic and patient characteristics were not associated with PHI. Hemostasis-related factors, including antiplatelet therapy and tranexamic acid administration, did not affect PHI. Severely impaired consciousness (Glasgow Coma Scale [GCS] <12) and delayed admission (time from injury to admission >4 hours) did not affect PHI. Higher PT-INR (>2.0) at admission was not associated with PHI. Patients who reached the target-PT-INR (<1.4) at half a day tended to have less PHI but it was not statistically significant.
Discussion
There have been numerous reports that warfarin reversal using PCC is effective in patients with non-TICH or TICH.11,14–28) However, these studies compared warfarin reversal using PCC and FFP11,14–28) with none of the studies comparing the treatment outcome of warfarin reversal using combination therapy of PCC with VK and VK monotherapy. The use of FFP is associated with a greater risk of volume overload and heart failure.9) In some clinical settings, FFP administration for warfarin reversal is difficult since patients on anticoagulant therapy present with a high risk of heart failure, and the complication rate of atrial fibrillation increases in proportion to the severity of heart failure.29) Moreover, heart failure has been reported in 37% of newly developed atrial fibrillation.30) Therefore, there is a need to directly compare the recent warfarin reversal using a combination therapy of PCC and conventional reversal using VK monotherapy. In this novel study, we found that warfarin reversal by PCC significantly suppressed PHI compared with VK monotherapy.
Warfarin treatment is associated with poor prognosis of patients with TICH. Ivascu et al. reported that oral warfarin increased the mortality rate in patients with TICH (48%), which is approximately five times higher than that in patients without anticoagulant therapy.31) The observed poor outcome under warfarin treatment could be attributed to the anticoagulation causing PHI.7,32–34) Oral anticoagulation is associated with PHI even in patients with minor head trauma.31) Therefore, there is a need to improve the prognosis of patients with head trauma under anticoagulant therapy by rapidly neutralizing the anticoagulant effect. Furthermore, risk factors for PHI have been shown to include older age, male gender, and larger initial lesions.35–40) However, these findings were not observed in our study given its small sample size.
For warfarin reversal, the use of PCC, rather than FFP, was associated with a more rapid decrease in the PT-INR17,18,22) and a higher rate of achieving the target PT-INR value without a cardiovascular volume load.9) VK, which induces production of warfarin-inhibiting coagulant factors in the liver, takes about 24 hours to fully exert its effect to modulate prolonged PT-INR by warfarin.41) PCC intravenous administration is to compensate for the shortage of coagulant factor and shows a more rapid decrease in PT-INR levels than VK intravenous administration alone.42) Rapid PT-INR correction by PCC is considered to suppress PHI more effectively than VK alone in patients taking warfarin. To neutralize a warfarin effect by PCC, the short-lasting effect of PCC should be paid attention to. PCC without VK may result in a re-increase in PT-INR and clinical deterioration.43) Therefore, to maintain the rapidly corrected PT-INR by PCC, VK plays an important role. These were consistent with our findings that, in the present study, most of the patients who underwent the combination therapy using PCC and VK had normalized values of PT-INR rapidly (at 1 hour after PCC administration) and remained within or close to the reference values after 12 hours. Immediate and stable effect of the combination of PCC and VK is considered to prevent PHI.
Anticoagulant therapy neutralization is associated with thrombosis risk.44,45) There have been reports on adverse events of PCC, including ischemic stroke, anaphylactic shock, disseminated intravascular coagulation, and deep vein thrombosis.43,46–50) However, none of our patients presented with complications in the present study. Given the association of warfarin with PHI, which could increase the mortality rate,51) we suggest that anticoagulation neutralization should be performed as early as possible in patients with traumatic head injury under anticoagulant therapy.
PCC contains concentrated VK-dependent coagulation factors (factors II, VII, IX, and X) extracted from large donor-pooled plasma and stored as a lyophilized powder. Currently, PCC is available in two forms: 4F-PCC11,14–16,24) and three-factor PCC (3F-PCC),18–21,23) which have both been used in previous studies. Compared with 3F-PCC, 4F-PCC contains higher levels of factor VII, as well as some anticoagulant proteins (Protein C, Protein S, Antithrombin, and heparin),52) and is associated with rapid INR reversal and a reduction in transfusion requirement without the risk of thromboembolic events.53) However, it remains unclear whether 4F-PCC is better than 3F-PCC.
This study has several limitations. First, this was a retrospective study with a small number of patients. Furthermore, there could have been patient selection bias. However, this was minimized by comparing warfarin-reversal using PCC with historical control. Second, although PCC may improve the prognosis of patients with TICH, this was not assessed. There is a need for further studies to confirm our findings and the PCC effect on the prognosis.
Conclusion
Warfarin reversal using combination therapy of PCC with VK after head trauma might be more effective for PIH inhibition than using VK monotherapy. This could be attributed to the rapid and stable neutralization of the warfarin anticoagulant effect. Furthermore, treatment with PCC was not associated with major thrombotic complications. PCC should be administered to patients with TICH taking warfarin to prevent PHI.
Conflicts of Interest Disclosure
All authors declare that they have no conflicts of interest.
Fig. 1 Study profile. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, TICH: traumatic intracranial hemorrhage.
Fig. 2 Time course of PT-INR in patients with combination therapy of PCC with VK. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 1 Patient baseline and clinical characteristics
Total VK monotherapy (n = 13) Combination with PCC (n = 7) P value
Age 79.1 ± 7.08 78.6 ± 7.2 80 ± 6.6 0.72
Female gender 7 (35%) 5 (38.5%) 2 (28.6%) >0.99
Hypertension 14 (70%) 13 (69.2%) 5 (71.4%) >0.99
Diabetes mellitus 9 (45%) 6 (46.2%) 3 (42.9%) >0.99
Antiplatelet therapy 6 (30%) 5 (38.5%) 1 (14.3%) 0.35
mRS before injury 3 (1–3) 5 (4–6) 4 (3.5–5.5) 0.93
GCS on admission 12 (11–14.3) 12 (8.5–14) 12 (11–15) 0.54
PT-INR at admission 2.33 (1.70–3.18) 2.52 (1.78–3.17) 1.83 (1.67–3.39) >0.99
Time from injury to admission (hour) 3.7 ± 2.6 4.5 ± 2.8 2.1 ± 1.3 0.02*
Use of tranexamic acid 60 (%) 7 (53.9%) 5 (71.4%) 0.64
Data are presented as mean (SD), number (%), or median (IQR). *Indicates statistical significance. GCS: Glasgow Coma Scale, IQR: interquartile range, mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 2 Patient characteristics of the hematoma expansion positive and negative groups
Total (n = 20) VK monotherapy (n = 13) Combination with PCC (n = 7) P value
PHI 12 (60) 11 (84.6) 1 (14.3) 0.004*
Reached target-PT-INR after a half day 10 (50) 4 (30.8) 6 (85.7) 0.057
Hospitalization (day) 22.6 ± 30.2 15.1 ± 15.0 36.4 ± 45.7 0.27
mRS at discharge 4.5 (3–6) 5 (4–6) 4 (3.5–5.5) 0.46
Death 8 (40) 6 (46.2) 2 (28.6) 0.48
Craniotomy 3 (15) 2 (15.3) 1 (14.3) >0.99
Data are shown as mean (SD), number (%), or median (IQR). *Shows statistical significance. mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PHI: progressive hemorrhagic injury, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 3 Univariable analysis of predictors of hematoma expansion
Predictor Odds ratio 95% Confidence interval P value
Age >80 0.43 0.07–2.68 0.65
Female sex 0.84 0.092–8.32 >0.99
Hypertension 1.8 0.26–12.5 0.62
Diabetes mellitus 0.3 0.05–1.94 0.36
Antiplatelet therapy 4.9 0.46–54.5 0.32
Tranexamic acid 2.1 0.32–12.5 0.65
GCS score at admission <12 3.1 0.422–21.3 0.37
Delayed admission† 1.19 0.19–7.46 >0.99
Higher PT-INR (>2.0) at admission 0.84 0.134–5.26 >0.99
Reaching target-PT-INR after a half day 0.17 0.0225–1.23 0.17
Reversal using PCC 0.03 0.00–0.41 0.004*
†Time from injury to admission was >4 hours. *Shows a statistical significance. GCS: Glasgow Coma Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33208582 | 18,674,277 | 2021-01-15 |
What was the administration route of drug 'PHYTONADIONE'? | Combination Therapy Using Prothrombin Complex Concentrate and Vitamin K in Anticoagulated Patients with Traumatic Intracranial Hemorrhage Prevents Progressive Hemorrhagic Injury: A Historically Controlled Study.
Warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk. However, warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) through progressive hemorrhagic injury (PHI). Therefore, a rapid anticoagulation reversal could be required in patients with TICH to prevent PHI. Differences in the warfarin reversal effect between combination therapy of prothrombin complex concentrate (PCC) with vitamin K (VK) and VK monotherapy remain unclear. However, studies have reported that PCC has greater effectiveness and safety for warfarin reversal compared with fresh frozen plasma (FFP). This retrospective study aimed to evaluate the warfarin reversal effects of combination therapy of PCC with VK and VK monotherapy on TICH. We compared the clinical outcomes between the periods before and after the PCC introduction in our hospital. There were 13 and 7 patients who received VK monotherapy and PCC with VK, respectively. PHI predictors were evaluated using univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00-0.41, P = 0.004). None of the patients presented with thrombotic complications. Warfarin reversal through a combination of PCC with VK could be more effective for inhibiting post-trauma PHI compared with VK monotherapy. This could be attributed to a rapid and stable warfarin reversal. PCC should be administered to patients with TICH taking warfarin for PHI prevention.
Introduction
With increasing life expectancy, there has been a concomitant increase in the number of patients requiring long-term anticoagulation to prevent arterial fibrillation-associated cerebral or systemic embolism and deep venous thrombosis.1) These patients receive oral anticoagulants, including warfarin as a vitamin K (VK) antagonist or direct oral anticoagulants (DOAC). A previous large-scale randomized clinical trial reported that DOAC and warfarin had similar efficacy and safety.2–5) Furthermore, DOAC has predictable pharmacokinetics and does not require routine monitoring since their anticoagulating effect does not interact with VK and interacts less frequently with other drugs. Therefore, DOAC has been preferably used for thromboembolic disease prevention recently. However, warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk, including those with an artificial valve, mitral stenosis, etc.2) Furthermore, warfarin is administered to patients with severe renal impairment who cannot be treated with DOAC.
Head trauma could cause an acute subdural hematoma, acute epidural hematoma, cerebral contusion, and traumatic subarachnoid hematoma. Progressive hemorrhagic injury (PHI) could cause a worsening of neurological conditions.3) Warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) since it inhibits hemostasis.6–8) Therefore, a rapid anticoagulation reversal in patients with TICH might be required for PHI prevention.
VK, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) are available for warfarin reversal in emergencies.2) PCC, which is the most recent to become clinically available, could have greater advantages compared with FFP. This is because it does not require blood typing and cross-matching; moreover, it eliminates the risk of FFP-related volume overload. Furthermore, compared with VK, PCC normalizes prothrombin time/international normalized ratio (PT-INR) more rapidly.9,10) Studies have reported that PCC for warfarin reversal could have greater effectiveness and safety than FFP.11) However, prior to PCC becoming clinically available, warfarin reversal was commonly achieved using VK alone rather than FFP infusion followed by VK. This could be because patients on warfarin treatment often present poor cardiac function and FFP could cause volume-overload associated with congestive heart failure.2,12) There is a need to study differences in the warfarin reversal effect in patients with head trauma between combination therapy of PCC with VK and VK monotherapy.
This retrospective study aimed to evaluate the warfarin reversal effects of a combination of PCC with VK and VK monotherapy in patients with TICH. Furthermore, we aimed to compare the clinical outcomes between the periods before and after the PCC introduction in our hospital.
Methods
The protocol for this retrospective study was approved by the ethics committee at our institution, which waived the requirement for patient consent (No. 3758). We retrospectively reviewed the medical records of 498 adult patients (≥18 years old) admitted at our hospital between February 2016 and November 2019 due to TICH within 12 post-injury hours (Fig. 1). Among them, 35 patients underwent warfarin treatment with a PT-INR of ≥1.4. Seven patients were infused with FFP to treat coincidental systemic massive hemorrhage due to aortic, hepatic, or pulmonary injuries. They were excluded from the study population because the clinical status is different from the others. In our hospital, four-factor PCC (4F-PCC) (Kcentra), which is among the clinically available PCC, was introduced for warfarin reversal from December 2017. We considered the periods before and after November 2017 as the VK era and PCC era, respectively. There 18 and 10 patients in the VK and PCC eras, respectively.
We excluded patients with mild head injury or excessively severe trauma on admission who did not receive treatment for warfarin reversal effect. The treatment outcome was evaluated in the remaining 20 patients (13 and 7 patients in the VK and PCC era, respectively). Immediately after TICH identification, all patients in the VK and PCC era were treated using intravenous administration of VK and PCC in combination with VK, respectively. Regarding the patients’ demographic and clinical characteristics, only time from injury to admission showed a significant between-group difference where it was longer in the VK era than in the PCC era (Table 1).
All the patients underwent a computer tomography (CT) scan on admission and repeat scans at least twice within 3 and 4-24 hours after admission. PHI was evaluated on the repeat CT scans and defined as follows: the appearance of a new intracranial hematoma, including intracerebral, intraventricular, subdural, epidural, or subarachnoid hemorrhage not caused by redistributed hemorrhage or expansion of pre-existing hematoma indicated by a qualitative increase in the volume by 1.4 times greater than the volume on the admission CT.13)
For warfarin reversal with and without PCC, the target PT-INR level was <1.40. Regarding reversal using PCC, PCC was intravenously administered immediately followed by intravenous VK administration (10–20 mg). The administered PCC dose was determined according to our institutional protocol, which was approved by the medical safety commission of our hospital, as follows: 25 IU/kg, 35 IU/kg, and 50 IU/kg were given to patients with INR 1.4–4, 4.0–6.0, and >6, respectively. PCC was only administered once. Contrastingly, 10 mg VK was repeatedly administered in case the PT-INR was ≥1.4 in the follow-up test at 8–12 post-admission hours. We performed between-reversal comparisons of the rates of reaching the target PT-INR at half a day after hospitalization.
The PHI incidence was evaluated in all the patients who underwent reversal treatment. Furthermore, we performed between-reversal comparisons of the in-hospital death; modified Rankin Scale (mRS) at discharge; and adverse events, including myocardial infarction, ischemic stroke, pulmonary embolism, and deep vein thrombosis.
Table 1 presents the patients’ baseline and clinical characteristics. Hypertension was defined as a pre-injury or pre-treatment systolic and/or diastolic blood pressure of ≥140 mmHg and ≥90 mmHg, respectively. Patients were considered to have diabetes if their glycosylated hemoglobin A1C level exceeded 6.5% or if they were being treated with insulin and/or oral hypoglycemic medications. The used antiplatelet drugs included aspirin, cilostazol, and clopidogrel with none of the patients taking prasugrel and ticlopidine hydrochloride.
Continuous variables were express as mean ± SD or median (interquartile range [IQR]). Categorical variables were expressed as number (%). All statistical analyses were performed using JMP version 15 software (SAS Institute, Tokyo, Japan). Statistical significance was set at P <0.05. Between-group comparisons were performed using Fisher's exact test or Mann–Whitney U test. Univariable logistic regression analyses were performed to determine PHI predictors.
Results
Figure 2 shows the time course of PT-INR in the seven patients who underwent combination therapy of PCC with VK. There was a rapid decrease in PT-INR, which reached its target (<1.40) at 1 hour after the start of warfarin reversal in all patients. PT-INR at half a day after reversal remained <1.40 in most patients except one who presented a PT-INR of 1.41.
There were no patients who had new bleeding at other sites and all of the PHI was identified as an expansion of pre-existing hematomas. Patients who underwent warfarin therapy had a high PHI incidence. Among the 20 patients, 12 (60%) patients presented with PHI. The PHI incidence was significantly lower in patients who underwent PCC therapy than VK monotherapy (84.6% vs. 14.3%, P = 0.004; Table 2). There were numerically, but not significantly, more patients who underwent PCC therapy with a PT-INR <1.40 at half a day after warfarin reversal induction compared with those who underwent VK monotherapy (85.7% vs 30.8%). There were no significant between-reversal differences in the hospitalization period, mRS at discharge, mortality, and rate of surgical treatment by craniotomy.
As shown in Table 3, PHI predictors were evaluated by univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00–0.41, P = 0.004). Contrastingly, other demographic and patient characteristics were not associated with PHI. Hemostasis-related factors, including antiplatelet therapy and tranexamic acid administration, did not affect PHI. Severely impaired consciousness (Glasgow Coma Scale [GCS] <12) and delayed admission (time from injury to admission >4 hours) did not affect PHI. Higher PT-INR (>2.0) at admission was not associated with PHI. Patients who reached the target-PT-INR (<1.4) at half a day tended to have less PHI but it was not statistically significant.
Discussion
There have been numerous reports that warfarin reversal using PCC is effective in patients with non-TICH or TICH.11,14–28) However, these studies compared warfarin reversal using PCC and FFP11,14–28) with none of the studies comparing the treatment outcome of warfarin reversal using combination therapy of PCC with VK and VK monotherapy. The use of FFP is associated with a greater risk of volume overload and heart failure.9) In some clinical settings, FFP administration for warfarin reversal is difficult since patients on anticoagulant therapy present with a high risk of heart failure, and the complication rate of atrial fibrillation increases in proportion to the severity of heart failure.29) Moreover, heart failure has been reported in 37% of newly developed atrial fibrillation.30) Therefore, there is a need to directly compare the recent warfarin reversal using a combination therapy of PCC and conventional reversal using VK monotherapy. In this novel study, we found that warfarin reversal by PCC significantly suppressed PHI compared with VK monotherapy.
Warfarin treatment is associated with poor prognosis of patients with TICH. Ivascu et al. reported that oral warfarin increased the mortality rate in patients with TICH (48%), which is approximately five times higher than that in patients without anticoagulant therapy.31) The observed poor outcome under warfarin treatment could be attributed to the anticoagulation causing PHI.7,32–34) Oral anticoagulation is associated with PHI even in patients with minor head trauma.31) Therefore, there is a need to improve the prognosis of patients with head trauma under anticoagulant therapy by rapidly neutralizing the anticoagulant effect. Furthermore, risk factors for PHI have been shown to include older age, male gender, and larger initial lesions.35–40) However, these findings were not observed in our study given its small sample size.
For warfarin reversal, the use of PCC, rather than FFP, was associated with a more rapid decrease in the PT-INR17,18,22) and a higher rate of achieving the target PT-INR value without a cardiovascular volume load.9) VK, which induces production of warfarin-inhibiting coagulant factors in the liver, takes about 24 hours to fully exert its effect to modulate prolonged PT-INR by warfarin.41) PCC intravenous administration is to compensate for the shortage of coagulant factor and shows a more rapid decrease in PT-INR levels than VK intravenous administration alone.42) Rapid PT-INR correction by PCC is considered to suppress PHI more effectively than VK alone in patients taking warfarin. To neutralize a warfarin effect by PCC, the short-lasting effect of PCC should be paid attention to. PCC without VK may result in a re-increase in PT-INR and clinical deterioration.43) Therefore, to maintain the rapidly corrected PT-INR by PCC, VK plays an important role. These were consistent with our findings that, in the present study, most of the patients who underwent the combination therapy using PCC and VK had normalized values of PT-INR rapidly (at 1 hour after PCC administration) and remained within or close to the reference values after 12 hours. Immediate and stable effect of the combination of PCC and VK is considered to prevent PHI.
Anticoagulant therapy neutralization is associated with thrombosis risk.44,45) There have been reports on adverse events of PCC, including ischemic stroke, anaphylactic shock, disseminated intravascular coagulation, and deep vein thrombosis.43,46–50) However, none of our patients presented with complications in the present study. Given the association of warfarin with PHI, which could increase the mortality rate,51) we suggest that anticoagulation neutralization should be performed as early as possible in patients with traumatic head injury under anticoagulant therapy.
PCC contains concentrated VK-dependent coagulation factors (factors II, VII, IX, and X) extracted from large donor-pooled plasma and stored as a lyophilized powder. Currently, PCC is available in two forms: 4F-PCC11,14–16,24) and three-factor PCC (3F-PCC),18–21,23) which have both been used in previous studies. Compared with 3F-PCC, 4F-PCC contains higher levels of factor VII, as well as some anticoagulant proteins (Protein C, Protein S, Antithrombin, and heparin),52) and is associated with rapid INR reversal and a reduction in transfusion requirement without the risk of thromboembolic events.53) However, it remains unclear whether 4F-PCC is better than 3F-PCC.
This study has several limitations. First, this was a retrospective study with a small number of patients. Furthermore, there could have been patient selection bias. However, this was minimized by comparing warfarin-reversal using PCC with historical control. Second, although PCC may improve the prognosis of patients with TICH, this was not assessed. There is a need for further studies to confirm our findings and the PCC effect on the prognosis.
Conclusion
Warfarin reversal using combination therapy of PCC with VK after head trauma might be more effective for PIH inhibition than using VK monotherapy. This could be attributed to the rapid and stable neutralization of the warfarin anticoagulant effect. Furthermore, treatment with PCC was not associated with major thrombotic complications. PCC should be administered to patients with TICH taking warfarin to prevent PHI.
Conflicts of Interest Disclosure
All authors declare that they have no conflicts of interest.
Fig. 1 Study profile. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, TICH: traumatic intracranial hemorrhage.
Fig. 2 Time course of PT-INR in patients with combination therapy of PCC with VK. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 1 Patient baseline and clinical characteristics
Total VK monotherapy (n = 13) Combination with PCC (n = 7) P value
Age 79.1 ± 7.08 78.6 ± 7.2 80 ± 6.6 0.72
Female gender 7 (35%) 5 (38.5%) 2 (28.6%) >0.99
Hypertension 14 (70%) 13 (69.2%) 5 (71.4%) >0.99
Diabetes mellitus 9 (45%) 6 (46.2%) 3 (42.9%) >0.99
Antiplatelet therapy 6 (30%) 5 (38.5%) 1 (14.3%) 0.35
mRS before injury 3 (1–3) 5 (4–6) 4 (3.5–5.5) 0.93
GCS on admission 12 (11–14.3) 12 (8.5–14) 12 (11–15) 0.54
PT-INR at admission 2.33 (1.70–3.18) 2.52 (1.78–3.17) 1.83 (1.67–3.39) >0.99
Time from injury to admission (hour) 3.7 ± 2.6 4.5 ± 2.8 2.1 ± 1.3 0.02*
Use of tranexamic acid 60 (%) 7 (53.9%) 5 (71.4%) 0.64
Data are presented as mean (SD), number (%), or median (IQR). *Indicates statistical significance. GCS: Glasgow Coma Scale, IQR: interquartile range, mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 2 Patient characteristics of the hematoma expansion positive and negative groups
Total (n = 20) VK monotherapy (n = 13) Combination with PCC (n = 7) P value
PHI 12 (60) 11 (84.6) 1 (14.3) 0.004*
Reached target-PT-INR after a half day 10 (50) 4 (30.8) 6 (85.7) 0.057
Hospitalization (day) 22.6 ± 30.2 15.1 ± 15.0 36.4 ± 45.7 0.27
mRS at discharge 4.5 (3–6) 5 (4–6) 4 (3.5–5.5) 0.46
Death 8 (40) 6 (46.2) 2 (28.6) 0.48
Craniotomy 3 (15) 2 (15.3) 1 (14.3) >0.99
Data are shown as mean (SD), number (%), or median (IQR). *Shows statistical significance. mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PHI: progressive hemorrhagic injury, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 3 Univariable analysis of predictors of hematoma expansion
Predictor Odds ratio 95% Confidence interval P value
Age >80 0.43 0.07–2.68 0.65
Female sex 0.84 0.092–8.32 >0.99
Hypertension 1.8 0.26–12.5 0.62
Diabetes mellitus 0.3 0.05–1.94 0.36
Antiplatelet therapy 4.9 0.46–54.5 0.32
Tranexamic acid 2.1 0.32–12.5 0.65
GCS score at admission <12 3.1 0.422–21.3 0.37
Delayed admission† 1.19 0.19–7.46 >0.99
Higher PT-INR (>2.0) at admission 0.84 0.134–5.26 >0.99
Reaching target-PT-INR after a half day 0.17 0.0225–1.23 0.17
Reversal using PCC 0.03 0.00–0.41 0.004*
†Time from injury to admission was >4 hours. *Shows a statistical significance. GCS: Glasgow Coma Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33208582 | 18,674,277 | 2021-01-15 |
What was the administration route of drug 'WARFARIN POTASSIUM'? | Combination Therapy Using Prothrombin Complex Concentrate and Vitamin K in Anticoagulated Patients with Traumatic Intracranial Hemorrhage Prevents Progressive Hemorrhagic Injury: A Historically Controlled Study.
Warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk. However, warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) through progressive hemorrhagic injury (PHI). Therefore, a rapid anticoagulation reversal could be required in patients with TICH to prevent PHI. Differences in the warfarin reversal effect between combination therapy of prothrombin complex concentrate (PCC) with vitamin K (VK) and VK monotherapy remain unclear. However, studies have reported that PCC has greater effectiveness and safety for warfarin reversal compared with fresh frozen plasma (FFP). This retrospective study aimed to evaluate the warfarin reversal effects of combination therapy of PCC with VK and VK monotherapy on TICH. We compared the clinical outcomes between the periods before and after the PCC introduction in our hospital. There were 13 and 7 patients who received VK monotherapy and PCC with VK, respectively. PHI predictors were evaluated using univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00-0.41, P = 0.004). None of the patients presented with thrombotic complications. Warfarin reversal through a combination of PCC with VK could be more effective for inhibiting post-trauma PHI compared with VK monotherapy. This could be attributed to a rapid and stable warfarin reversal. PCC should be administered to patients with TICH taking warfarin for PHI prevention.
Introduction
With increasing life expectancy, there has been a concomitant increase in the number of patients requiring long-term anticoagulation to prevent arterial fibrillation-associated cerebral or systemic embolism and deep venous thrombosis.1) These patients receive oral anticoagulants, including warfarin as a vitamin K (VK) antagonist or direct oral anticoagulants (DOAC). A previous large-scale randomized clinical trial reported that DOAC and warfarin had similar efficacy and safety.2–5) Furthermore, DOAC has predictable pharmacokinetics and does not require routine monitoring since their anticoagulating effect does not interact with VK and interacts less frequently with other drugs. Therefore, DOAC has been preferably used for thromboembolic disease prevention recently. However, warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk, including those with an artificial valve, mitral stenosis, etc.2) Furthermore, warfarin is administered to patients with severe renal impairment who cannot be treated with DOAC.
Head trauma could cause an acute subdural hematoma, acute epidural hematoma, cerebral contusion, and traumatic subarachnoid hematoma. Progressive hemorrhagic injury (PHI) could cause a worsening of neurological conditions.3) Warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) since it inhibits hemostasis.6–8) Therefore, a rapid anticoagulation reversal in patients with TICH might be required for PHI prevention.
VK, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) are available for warfarin reversal in emergencies.2) PCC, which is the most recent to become clinically available, could have greater advantages compared with FFP. This is because it does not require blood typing and cross-matching; moreover, it eliminates the risk of FFP-related volume overload. Furthermore, compared with VK, PCC normalizes prothrombin time/international normalized ratio (PT-INR) more rapidly.9,10) Studies have reported that PCC for warfarin reversal could have greater effectiveness and safety than FFP.11) However, prior to PCC becoming clinically available, warfarin reversal was commonly achieved using VK alone rather than FFP infusion followed by VK. This could be because patients on warfarin treatment often present poor cardiac function and FFP could cause volume-overload associated with congestive heart failure.2,12) There is a need to study differences in the warfarin reversal effect in patients with head trauma between combination therapy of PCC with VK and VK monotherapy.
This retrospective study aimed to evaluate the warfarin reversal effects of a combination of PCC with VK and VK monotherapy in patients with TICH. Furthermore, we aimed to compare the clinical outcomes between the periods before and after the PCC introduction in our hospital.
Methods
The protocol for this retrospective study was approved by the ethics committee at our institution, which waived the requirement for patient consent (No. 3758). We retrospectively reviewed the medical records of 498 adult patients (≥18 years old) admitted at our hospital between February 2016 and November 2019 due to TICH within 12 post-injury hours (Fig. 1). Among them, 35 patients underwent warfarin treatment with a PT-INR of ≥1.4. Seven patients were infused with FFP to treat coincidental systemic massive hemorrhage due to aortic, hepatic, or pulmonary injuries. They were excluded from the study population because the clinical status is different from the others. In our hospital, four-factor PCC (4F-PCC) (Kcentra), which is among the clinically available PCC, was introduced for warfarin reversal from December 2017. We considered the periods before and after November 2017 as the VK era and PCC era, respectively. There 18 and 10 patients in the VK and PCC eras, respectively.
We excluded patients with mild head injury or excessively severe trauma on admission who did not receive treatment for warfarin reversal effect. The treatment outcome was evaluated in the remaining 20 patients (13 and 7 patients in the VK and PCC era, respectively). Immediately after TICH identification, all patients in the VK and PCC era were treated using intravenous administration of VK and PCC in combination with VK, respectively. Regarding the patients’ demographic and clinical characteristics, only time from injury to admission showed a significant between-group difference where it was longer in the VK era than in the PCC era (Table 1).
All the patients underwent a computer tomography (CT) scan on admission and repeat scans at least twice within 3 and 4-24 hours after admission. PHI was evaluated on the repeat CT scans and defined as follows: the appearance of a new intracranial hematoma, including intracerebral, intraventricular, subdural, epidural, or subarachnoid hemorrhage not caused by redistributed hemorrhage or expansion of pre-existing hematoma indicated by a qualitative increase in the volume by 1.4 times greater than the volume on the admission CT.13)
For warfarin reversal with and without PCC, the target PT-INR level was <1.40. Regarding reversal using PCC, PCC was intravenously administered immediately followed by intravenous VK administration (10–20 mg). The administered PCC dose was determined according to our institutional protocol, which was approved by the medical safety commission of our hospital, as follows: 25 IU/kg, 35 IU/kg, and 50 IU/kg were given to patients with INR 1.4–4, 4.0–6.0, and >6, respectively. PCC was only administered once. Contrastingly, 10 mg VK was repeatedly administered in case the PT-INR was ≥1.4 in the follow-up test at 8–12 post-admission hours. We performed between-reversal comparisons of the rates of reaching the target PT-INR at half a day after hospitalization.
The PHI incidence was evaluated in all the patients who underwent reversal treatment. Furthermore, we performed between-reversal comparisons of the in-hospital death; modified Rankin Scale (mRS) at discharge; and adverse events, including myocardial infarction, ischemic stroke, pulmonary embolism, and deep vein thrombosis.
Table 1 presents the patients’ baseline and clinical characteristics. Hypertension was defined as a pre-injury or pre-treatment systolic and/or diastolic blood pressure of ≥140 mmHg and ≥90 mmHg, respectively. Patients were considered to have diabetes if their glycosylated hemoglobin A1C level exceeded 6.5% or if they were being treated with insulin and/or oral hypoglycemic medications. The used antiplatelet drugs included aspirin, cilostazol, and clopidogrel with none of the patients taking prasugrel and ticlopidine hydrochloride.
Continuous variables were express as mean ± SD or median (interquartile range [IQR]). Categorical variables were expressed as number (%). All statistical analyses were performed using JMP version 15 software (SAS Institute, Tokyo, Japan). Statistical significance was set at P <0.05. Between-group comparisons were performed using Fisher's exact test or Mann–Whitney U test. Univariable logistic regression analyses were performed to determine PHI predictors.
Results
Figure 2 shows the time course of PT-INR in the seven patients who underwent combination therapy of PCC with VK. There was a rapid decrease in PT-INR, which reached its target (<1.40) at 1 hour after the start of warfarin reversal in all patients. PT-INR at half a day after reversal remained <1.40 in most patients except one who presented a PT-INR of 1.41.
There were no patients who had new bleeding at other sites and all of the PHI was identified as an expansion of pre-existing hematomas. Patients who underwent warfarin therapy had a high PHI incidence. Among the 20 patients, 12 (60%) patients presented with PHI. The PHI incidence was significantly lower in patients who underwent PCC therapy than VK monotherapy (84.6% vs. 14.3%, P = 0.004; Table 2). There were numerically, but not significantly, more patients who underwent PCC therapy with a PT-INR <1.40 at half a day after warfarin reversal induction compared with those who underwent VK monotherapy (85.7% vs 30.8%). There were no significant between-reversal differences in the hospitalization period, mRS at discharge, mortality, and rate of surgical treatment by craniotomy.
As shown in Table 3, PHI predictors were evaluated by univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00–0.41, P = 0.004). Contrastingly, other demographic and patient characteristics were not associated with PHI. Hemostasis-related factors, including antiplatelet therapy and tranexamic acid administration, did not affect PHI. Severely impaired consciousness (Glasgow Coma Scale [GCS] <12) and delayed admission (time from injury to admission >4 hours) did not affect PHI. Higher PT-INR (>2.0) at admission was not associated with PHI. Patients who reached the target-PT-INR (<1.4) at half a day tended to have less PHI but it was not statistically significant.
Discussion
There have been numerous reports that warfarin reversal using PCC is effective in patients with non-TICH or TICH.11,14–28) However, these studies compared warfarin reversal using PCC and FFP11,14–28) with none of the studies comparing the treatment outcome of warfarin reversal using combination therapy of PCC with VK and VK monotherapy. The use of FFP is associated with a greater risk of volume overload and heart failure.9) In some clinical settings, FFP administration for warfarin reversal is difficult since patients on anticoagulant therapy present with a high risk of heart failure, and the complication rate of atrial fibrillation increases in proportion to the severity of heart failure.29) Moreover, heart failure has been reported in 37% of newly developed atrial fibrillation.30) Therefore, there is a need to directly compare the recent warfarin reversal using a combination therapy of PCC and conventional reversal using VK monotherapy. In this novel study, we found that warfarin reversal by PCC significantly suppressed PHI compared with VK monotherapy.
Warfarin treatment is associated with poor prognosis of patients with TICH. Ivascu et al. reported that oral warfarin increased the mortality rate in patients with TICH (48%), which is approximately five times higher than that in patients without anticoagulant therapy.31) The observed poor outcome under warfarin treatment could be attributed to the anticoagulation causing PHI.7,32–34) Oral anticoagulation is associated with PHI even in patients with minor head trauma.31) Therefore, there is a need to improve the prognosis of patients with head trauma under anticoagulant therapy by rapidly neutralizing the anticoagulant effect. Furthermore, risk factors for PHI have been shown to include older age, male gender, and larger initial lesions.35–40) However, these findings were not observed in our study given its small sample size.
For warfarin reversal, the use of PCC, rather than FFP, was associated with a more rapid decrease in the PT-INR17,18,22) and a higher rate of achieving the target PT-INR value without a cardiovascular volume load.9) VK, which induces production of warfarin-inhibiting coagulant factors in the liver, takes about 24 hours to fully exert its effect to modulate prolonged PT-INR by warfarin.41) PCC intravenous administration is to compensate for the shortage of coagulant factor and shows a more rapid decrease in PT-INR levels than VK intravenous administration alone.42) Rapid PT-INR correction by PCC is considered to suppress PHI more effectively than VK alone in patients taking warfarin. To neutralize a warfarin effect by PCC, the short-lasting effect of PCC should be paid attention to. PCC without VK may result in a re-increase in PT-INR and clinical deterioration.43) Therefore, to maintain the rapidly corrected PT-INR by PCC, VK plays an important role. These were consistent with our findings that, in the present study, most of the patients who underwent the combination therapy using PCC and VK had normalized values of PT-INR rapidly (at 1 hour after PCC administration) and remained within or close to the reference values after 12 hours. Immediate and stable effect of the combination of PCC and VK is considered to prevent PHI.
Anticoagulant therapy neutralization is associated with thrombosis risk.44,45) There have been reports on adverse events of PCC, including ischemic stroke, anaphylactic shock, disseminated intravascular coagulation, and deep vein thrombosis.43,46–50) However, none of our patients presented with complications in the present study. Given the association of warfarin with PHI, which could increase the mortality rate,51) we suggest that anticoagulation neutralization should be performed as early as possible in patients with traumatic head injury under anticoagulant therapy.
PCC contains concentrated VK-dependent coagulation factors (factors II, VII, IX, and X) extracted from large donor-pooled plasma and stored as a lyophilized powder. Currently, PCC is available in two forms: 4F-PCC11,14–16,24) and three-factor PCC (3F-PCC),18–21,23) which have both been used in previous studies. Compared with 3F-PCC, 4F-PCC contains higher levels of factor VII, as well as some anticoagulant proteins (Protein C, Protein S, Antithrombin, and heparin),52) and is associated with rapid INR reversal and a reduction in transfusion requirement without the risk of thromboembolic events.53) However, it remains unclear whether 4F-PCC is better than 3F-PCC.
This study has several limitations. First, this was a retrospective study with a small number of patients. Furthermore, there could have been patient selection bias. However, this was minimized by comparing warfarin-reversal using PCC with historical control. Second, although PCC may improve the prognosis of patients with TICH, this was not assessed. There is a need for further studies to confirm our findings and the PCC effect on the prognosis.
Conclusion
Warfarin reversal using combination therapy of PCC with VK after head trauma might be more effective for PIH inhibition than using VK monotherapy. This could be attributed to the rapid and stable neutralization of the warfarin anticoagulant effect. Furthermore, treatment with PCC was not associated with major thrombotic complications. PCC should be administered to patients with TICH taking warfarin to prevent PHI.
Conflicts of Interest Disclosure
All authors declare that they have no conflicts of interest.
Fig. 1 Study profile. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, TICH: traumatic intracranial hemorrhage.
Fig. 2 Time course of PT-INR in patients with combination therapy of PCC with VK. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 1 Patient baseline and clinical characteristics
Total VK monotherapy (n = 13) Combination with PCC (n = 7) P value
Age 79.1 ± 7.08 78.6 ± 7.2 80 ± 6.6 0.72
Female gender 7 (35%) 5 (38.5%) 2 (28.6%) >0.99
Hypertension 14 (70%) 13 (69.2%) 5 (71.4%) >0.99
Diabetes mellitus 9 (45%) 6 (46.2%) 3 (42.9%) >0.99
Antiplatelet therapy 6 (30%) 5 (38.5%) 1 (14.3%) 0.35
mRS before injury 3 (1–3) 5 (4–6) 4 (3.5–5.5) 0.93
GCS on admission 12 (11–14.3) 12 (8.5–14) 12 (11–15) 0.54
PT-INR at admission 2.33 (1.70–3.18) 2.52 (1.78–3.17) 1.83 (1.67–3.39) >0.99
Time from injury to admission (hour) 3.7 ± 2.6 4.5 ± 2.8 2.1 ± 1.3 0.02*
Use of tranexamic acid 60 (%) 7 (53.9%) 5 (71.4%) 0.64
Data are presented as mean (SD), number (%), or median (IQR). *Indicates statistical significance. GCS: Glasgow Coma Scale, IQR: interquartile range, mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 2 Patient characteristics of the hematoma expansion positive and negative groups
Total (n = 20) VK monotherapy (n = 13) Combination with PCC (n = 7) P value
PHI 12 (60) 11 (84.6) 1 (14.3) 0.004*
Reached target-PT-INR after a half day 10 (50) 4 (30.8) 6 (85.7) 0.057
Hospitalization (day) 22.6 ± 30.2 15.1 ± 15.0 36.4 ± 45.7 0.27
mRS at discharge 4.5 (3–6) 5 (4–6) 4 (3.5–5.5) 0.46
Death 8 (40) 6 (46.2) 2 (28.6) 0.48
Craniotomy 3 (15) 2 (15.3) 1 (14.3) >0.99
Data are shown as mean (SD), number (%), or median (IQR). *Shows statistical significance. mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PHI: progressive hemorrhagic injury, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 3 Univariable analysis of predictors of hematoma expansion
Predictor Odds ratio 95% Confidence interval P value
Age >80 0.43 0.07–2.68 0.65
Female sex 0.84 0.092–8.32 >0.99
Hypertension 1.8 0.26–12.5 0.62
Diabetes mellitus 0.3 0.05–1.94 0.36
Antiplatelet therapy 4.9 0.46–54.5 0.32
Tranexamic acid 2.1 0.32–12.5 0.65
GCS score at admission <12 3.1 0.422–21.3 0.37
Delayed admission† 1.19 0.19–7.46 >0.99
Higher PT-INR (>2.0) at admission 0.84 0.134–5.26 >0.99
Reaching target-PT-INR after a half day 0.17 0.0225–1.23 0.17
Reversal using PCC 0.03 0.00–0.41 0.004*
†Time from injury to admission was >4 hours. *Shows a statistical significance. GCS: Glasgow Coma Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33208582 | 18,674,277 | 2021-01-15 |
What was the dosage of drug 'COAGULATION FACTOR IX HUMAN\COAGULATION FACTOR VII HUMAN\COAGULATION FACTOR X HUMAN\PROTEIN C\PROTEIN S HUMAN\PROTHROMBIN'? | Combination Therapy Using Prothrombin Complex Concentrate and Vitamin K in Anticoagulated Patients with Traumatic Intracranial Hemorrhage Prevents Progressive Hemorrhagic Injury: A Historically Controlled Study.
Warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk. However, warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) through progressive hemorrhagic injury (PHI). Therefore, a rapid anticoagulation reversal could be required in patients with TICH to prevent PHI. Differences in the warfarin reversal effect between combination therapy of prothrombin complex concentrate (PCC) with vitamin K (VK) and VK monotherapy remain unclear. However, studies have reported that PCC has greater effectiveness and safety for warfarin reversal compared with fresh frozen plasma (FFP). This retrospective study aimed to evaluate the warfarin reversal effects of combination therapy of PCC with VK and VK monotherapy on TICH. We compared the clinical outcomes between the periods before and after the PCC introduction in our hospital. There were 13 and 7 patients who received VK monotherapy and PCC with VK, respectively. PHI predictors were evaluated using univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00-0.41, P = 0.004). None of the patients presented with thrombotic complications. Warfarin reversal through a combination of PCC with VK could be more effective for inhibiting post-trauma PHI compared with VK monotherapy. This could be attributed to a rapid and stable warfarin reversal. PCC should be administered to patients with TICH taking warfarin for PHI prevention.
Introduction
With increasing life expectancy, there has been a concomitant increase in the number of patients requiring long-term anticoagulation to prevent arterial fibrillation-associated cerebral or systemic embolism and deep venous thrombosis.1) These patients receive oral anticoagulants, including warfarin as a vitamin K (VK) antagonist or direct oral anticoagulants (DOAC). A previous large-scale randomized clinical trial reported that DOAC and warfarin had similar efficacy and safety.2–5) Furthermore, DOAC has predictable pharmacokinetics and does not require routine monitoring since their anticoagulating effect does not interact with VK and interacts less frequently with other drugs. Therefore, DOAC has been preferably used for thromboembolic disease prevention recently. However, warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk, including those with an artificial valve, mitral stenosis, etc.2) Furthermore, warfarin is administered to patients with severe renal impairment who cannot be treated with DOAC.
Head trauma could cause an acute subdural hematoma, acute epidural hematoma, cerebral contusion, and traumatic subarachnoid hematoma. Progressive hemorrhagic injury (PHI) could cause a worsening of neurological conditions.3) Warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) since it inhibits hemostasis.6–8) Therefore, a rapid anticoagulation reversal in patients with TICH might be required for PHI prevention.
VK, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) are available for warfarin reversal in emergencies.2) PCC, which is the most recent to become clinically available, could have greater advantages compared with FFP. This is because it does not require blood typing and cross-matching; moreover, it eliminates the risk of FFP-related volume overload. Furthermore, compared with VK, PCC normalizes prothrombin time/international normalized ratio (PT-INR) more rapidly.9,10) Studies have reported that PCC for warfarin reversal could have greater effectiveness and safety than FFP.11) However, prior to PCC becoming clinically available, warfarin reversal was commonly achieved using VK alone rather than FFP infusion followed by VK. This could be because patients on warfarin treatment often present poor cardiac function and FFP could cause volume-overload associated with congestive heart failure.2,12) There is a need to study differences in the warfarin reversal effect in patients with head trauma between combination therapy of PCC with VK and VK monotherapy.
This retrospective study aimed to evaluate the warfarin reversal effects of a combination of PCC with VK and VK monotherapy in patients with TICH. Furthermore, we aimed to compare the clinical outcomes between the periods before and after the PCC introduction in our hospital.
Methods
The protocol for this retrospective study was approved by the ethics committee at our institution, which waived the requirement for patient consent (No. 3758). We retrospectively reviewed the medical records of 498 adult patients (≥18 years old) admitted at our hospital between February 2016 and November 2019 due to TICH within 12 post-injury hours (Fig. 1). Among them, 35 patients underwent warfarin treatment with a PT-INR of ≥1.4. Seven patients were infused with FFP to treat coincidental systemic massive hemorrhage due to aortic, hepatic, or pulmonary injuries. They were excluded from the study population because the clinical status is different from the others. In our hospital, four-factor PCC (4F-PCC) (Kcentra), which is among the clinically available PCC, was introduced for warfarin reversal from December 2017. We considered the periods before and after November 2017 as the VK era and PCC era, respectively. There 18 and 10 patients in the VK and PCC eras, respectively.
We excluded patients with mild head injury or excessively severe trauma on admission who did not receive treatment for warfarin reversal effect. The treatment outcome was evaluated in the remaining 20 patients (13 and 7 patients in the VK and PCC era, respectively). Immediately after TICH identification, all patients in the VK and PCC era were treated using intravenous administration of VK and PCC in combination with VK, respectively. Regarding the patients’ demographic and clinical characteristics, only time from injury to admission showed a significant between-group difference where it was longer in the VK era than in the PCC era (Table 1).
All the patients underwent a computer tomography (CT) scan on admission and repeat scans at least twice within 3 and 4-24 hours after admission. PHI was evaluated on the repeat CT scans and defined as follows: the appearance of a new intracranial hematoma, including intracerebral, intraventricular, subdural, epidural, or subarachnoid hemorrhage not caused by redistributed hemorrhage or expansion of pre-existing hematoma indicated by a qualitative increase in the volume by 1.4 times greater than the volume on the admission CT.13)
For warfarin reversal with and without PCC, the target PT-INR level was <1.40. Regarding reversal using PCC, PCC was intravenously administered immediately followed by intravenous VK administration (10–20 mg). The administered PCC dose was determined according to our institutional protocol, which was approved by the medical safety commission of our hospital, as follows: 25 IU/kg, 35 IU/kg, and 50 IU/kg were given to patients with INR 1.4–4, 4.0–6.0, and >6, respectively. PCC was only administered once. Contrastingly, 10 mg VK was repeatedly administered in case the PT-INR was ≥1.4 in the follow-up test at 8–12 post-admission hours. We performed between-reversal comparisons of the rates of reaching the target PT-INR at half a day after hospitalization.
The PHI incidence was evaluated in all the patients who underwent reversal treatment. Furthermore, we performed between-reversal comparisons of the in-hospital death; modified Rankin Scale (mRS) at discharge; and adverse events, including myocardial infarction, ischemic stroke, pulmonary embolism, and deep vein thrombosis.
Table 1 presents the patients’ baseline and clinical characteristics. Hypertension was defined as a pre-injury or pre-treatment systolic and/or diastolic blood pressure of ≥140 mmHg and ≥90 mmHg, respectively. Patients were considered to have diabetes if their glycosylated hemoglobin A1C level exceeded 6.5% or if they were being treated with insulin and/or oral hypoglycemic medications. The used antiplatelet drugs included aspirin, cilostazol, and clopidogrel with none of the patients taking prasugrel and ticlopidine hydrochloride.
Continuous variables were express as mean ± SD or median (interquartile range [IQR]). Categorical variables were expressed as number (%). All statistical analyses were performed using JMP version 15 software (SAS Institute, Tokyo, Japan). Statistical significance was set at P <0.05. Between-group comparisons were performed using Fisher's exact test or Mann–Whitney U test. Univariable logistic regression analyses were performed to determine PHI predictors.
Results
Figure 2 shows the time course of PT-INR in the seven patients who underwent combination therapy of PCC with VK. There was a rapid decrease in PT-INR, which reached its target (<1.40) at 1 hour after the start of warfarin reversal in all patients. PT-INR at half a day after reversal remained <1.40 in most patients except one who presented a PT-INR of 1.41.
There were no patients who had new bleeding at other sites and all of the PHI was identified as an expansion of pre-existing hematomas. Patients who underwent warfarin therapy had a high PHI incidence. Among the 20 patients, 12 (60%) patients presented with PHI. The PHI incidence was significantly lower in patients who underwent PCC therapy than VK monotherapy (84.6% vs. 14.3%, P = 0.004; Table 2). There were numerically, but not significantly, more patients who underwent PCC therapy with a PT-INR <1.40 at half a day after warfarin reversal induction compared with those who underwent VK monotherapy (85.7% vs 30.8%). There were no significant between-reversal differences in the hospitalization period, mRS at discharge, mortality, and rate of surgical treatment by craniotomy.
As shown in Table 3, PHI predictors were evaluated by univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00–0.41, P = 0.004). Contrastingly, other demographic and patient characteristics were not associated with PHI. Hemostasis-related factors, including antiplatelet therapy and tranexamic acid administration, did not affect PHI. Severely impaired consciousness (Glasgow Coma Scale [GCS] <12) and delayed admission (time from injury to admission >4 hours) did not affect PHI. Higher PT-INR (>2.0) at admission was not associated with PHI. Patients who reached the target-PT-INR (<1.4) at half a day tended to have less PHI but it was not statistically significant.
Discussion
There have been numerous reports that warfarin reversal using PCC is effective in patients with non-TICH or TICH.11,14–28) However, these studies compared warfarin reversal using PCC and FFP11,14–28) with none of the studies comparing the treatment outcome of warfarin reversal using combination therapy of PCC with VK and VK monotherapy. The use of FFP is associated with a greater risk of volume overload and heart failure.9) In some clinical settings, FFP administration for warfarin reversal is difficult since patients on anticoagulant therapy present with a high risk of heart failure, and the complication rate of atrial fibrillation increases in proportion to the severity of heart failure.29) Moreover, heart failure has been reported in 37% of newly developed atrial fibrillation.30) Therefore, there is a need to directly compare the recent warfarin reversal using a combination therapy of PCC and conventional reversal using VK monotherapy. In this novel study, we found that warfarin reversal by PCC significantly suppressed PHI compared with VK monotherapy.
Warfarin treatment is associated with poor prognosis of patients with TICH. Ivascu et al. reported that oral warfarin increased the mortality rate in patients with TICH (48%), which is approximately five times higher than that in patients without anticoagulant therapy.31) The observed poor outcome under warfarin treatment could be attributed to the anticoagulation causing PHI.7,32–34) Oral anticoagulation is associated with PHI even in patients with minor head trauma.31) Therefore, there is a need to improve the prognosis of patients with head trauma under anticoagulant therapy by rapidly neutralizing the anticoagulant effect. Furthermore, risk factors for PHI have been shown to include older age, male gender, and larger initial lesions.35–40) However, these findings were not observed in our study given its small sample size.
For warfarin reversal, the use of PCC, rather than FFP, was associated with a more rapid decrease in the PT-INR17,18,22) and a higher rate of achieving the target PT-INR value without a cardiovascular volume load.9) VK, which induces production of warfarin-inhibiting coagulant factors in the liver, takes about 24 hours to fully exert its effect to modulate prolonged PT-INR by warfarin.41) PCC intravenous administration is to compensate for the shortage of coagulant factor and shows a more rapid decrease in PT-INR levels than VK intravenous administration alone.42) Rapid PT-INR correction by PCC is considered to suppress PHI more effectively than VK alone in patients taking warfarin. To neutralize a warfarin effect by PCC, the short-lasting effect of PCC should be paid attention to. PCC without VK may result in a re-increase in PT-INR and clinical deterioration.43) Therefore, to maintain the rapidly corrected PT-INR by PCC, VK plays an important role. These were consistent with our findings that, in the present study, most of the patients who underwent the combination therapy using PCC and VK had normalized values of PT-INR rapidly (at 1 hour after PCC administration) and remained within or close to the reference values after 12 hours. Immediate and stable effect of the combination of PCC and VK is considered to prevent PHI.
Anticoagulant therapy neutralization is associated with thrombosis risk.44,45) There have been reports on adverse events of PCC, including ischemic stroke, anaphylactic shock, disseminated intravascular coagulation, and deep vein thrombosis.43,46–50) However, none of our patients presented with complications in the present study. Given the association of warfarin with PHI, which could increase the mortality rate,51) we suggest that anticoagulation neutralization should be performed as early as possible in patients with traumatic head injury under anticoagulant therapy.
PCC contains concentrated VK-dependent coagulation factors (factors II, VII, IX, and X) extracted from large donor-pooled plasma and stored as a lyophilized powder. Currently, PCC is available in two forms: 4F-PCC11,14–16,24) and three-factor PCC (3F-PCC),18–21,23) which have both been used in previous studies. Compared with 3F-PCC, 4F-PCC contains higher levels of factor VII, as well as some anticoagulant proteins (Protein C, Protein S, Antithrombin, and heparin),52) and is associated with rapid INR reversal and a reduction in transfusion requirement without the risk of thromboembolic events.53) However, it remains unclear whether 4F-PCC is better than 3F-PCC.
This study has several limitations. First, this was a retrospective study with a small number of patients. Furthermore, there could have been patient selection bias. However, this was minimized by comparing warfarin-reversal using PCC with historical control. Second, although PCC may improve the prognosis of patients with TICH, this was not assessed. There is a need for further studies to confirm our findings and the PCC effect on the prognosis.
Conclusion
Warfarin reversal using combination therapy of PCC with VK after head trauma might be more effective for PIH inhibition than using VK monotherapy. This could be attributed to the rapid and stable neutralization of the warfarin anticoagulant effect. Furthermore, treatment with PCC was not associated with major thrombotic complications. PCC should be administered to patients with TICH taking warfarin to prevent PHI.
Conflicts of Interest Disclosure
All authors declare that they have no conflicts of interest.
Fig. 1 Study profile. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, TICH: traumatic intracranial hemorrhage.
Fig. 2 Time course of PT-INR in patients with combination therapy of PCC with VK. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 1 Patient baseline and clinical characteristics
Total VK monotherapy (n = 13) Combination with PCC (n = 7) P value
Age 79.1 ± 7.08 78.6 ± 7.2 80 ± 6.6 0.72
Female gender 7 (35%) 5 (38.5%) 2 (28.6%) >0.99
Hypertension 14 (70%) 13 (69.2%) 5 (71.4%) >0.99
Diabetes mellitus 9 (45%) 6 (46.2%) 3 (42.9%) >0.99
Antiplatelet therapy 6 (30%) 5 (38.5%) 1 (14.3%) 0.35
mRS before injury 3 (1–3) 5 (4–6) 4 (3.5–5.5) 0.93
GCS on admission 12 (11–14.3) 12 (8.5–14) 12 (11–15) 0.54
PT-INR at admission 2.33 (1.70–3.18) 2.52 (1.78–3.17) 1.83 (1.67–3.39) >0.99
Time from injury to admission (hour) 3.7 ± 2.6 4.5 ± 2.8 2.1 ± 1.3 0.02*
Use of tranexamic acid 60 (%) 7 (53.9%) 5 (71.4%) 0.64
Data are presented as mean (SD), number (%), or median (IQR). *Indicates statistical significance. GCS: Glasgow Coma Scale, IQR: interquartile range, mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 2 Patient characteristics of the hematoma expansion positive and negative groups
Total (n = 20) VK monotherapy (n = 13) Combination with PCC (n = 7) P value
PHI 12 (60) 11 (84.6) 1 (14.3) 0.004*
Reached target-PT-INR after a half day 10 (50) 4 (30.8) 6 (85.7) 0.057
Hospitalization (day) 22.6 ± 30.2 15.1 ± 15.0 36.4 ± 45.7 0.27
mRS at discharge 4.5 (3–6) 5 (4–6) 4 (3.5–5.5) 0.46
Death 8 (40) 6 (46.2) 2 (28.6) 0.48
Craniotomy 3 (15) 2 (15.3) 1 (14.3) >0.99
Data are shown as mean (SD), number (%), or median (IQR). *Shows statistical significance. mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PHI: progressive hemorrhagic injury, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 3 Univariable analysis of predictors of hematoma expansion
Predictor Odds ratio 95% Confidence interval P value
Age >80 0.43 0.07–2.68 0.65
Female sex 0.84 0.092–8.32 >0.99
Hypertension 1.8 0.26–12.5 0.62
Diabetes mellitus 0.3 0.05–1.94 0.36
Antiplatelet therapy 4.9 0.46–54.5 0.32
Tranexamic acid 2.1 0.32–12.5 0.65
GCS score at admission <12 3.1 0.422–21.3 0.37
Delayed admission† 1.19 0.19–7.46 >0.99
Higher PT-INR (>2.0) at admission 0.84 0.134–5.26 >0.99
Reaching target-PT-INR after a half day 0.17 0.0225–1.23 0.17
Reversal using PCC 0.03 0.00–0.41 0.004*
†Time from injury to admission was >4 hours. *Shows a statistical significance. GCS: Glasgow Coma Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio. | 1675 | DrugDosageText | CC BY-NC-ND | 33208582 | 18,674,277 | 2021-01-15 |
What was the dosage of drug 'PHYTONADIONE'? | Combination Therapy Using Prothrombin Complex Concentrate and Vitamin K in Anticoagulated Patients with Traumatic Intracranial Hemorrhage Prevents Progressive Hemorrhagic Injury: A Historically Controlled Study.
Warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk. However, warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) through progressive hemorrhagic injury (PHI). Therefore, a rapid anticoagulation reversal could be required in patients with TICH to prevent PHI. Differences in the warfarin reversal effect between combination therapy of prothrombin complex concentrate (PCC) with vitamin K (VK) and VK monotherapy remain unclear. However, studies have reported that PCC has greater effectiveness and safety for warfarin reversal compared with fresh frozen plasma (FFP). This retrospective study aimed to evaluate the warfarin reversal effects of combination therapy of PCC with VK and VK monotherapy on TICH. We compared the clinical outcomes between the periods before and after the PCC introduction in our hospital. There were 13 and 7 patients who received VK monotherapy and PCC with VK, respectively. PHI predictors were evaluated using univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00-0.41, P = 0.004). None of the patients presented with thrombotic complications. Warfarin reversal through a combination of PCC with VK could be more effective for inhibiting post-trauma PHI compared with VK monotherapy. This could be attributed to a rapid and stable warfarin reversal. PCC should be administered to patients with TICH taking warfarin for PHI prevention.
Introduction
With increasing life expectancy, there has been a concomitant increase in the number of patients requiring long-term anticoagulation to prevent arterial fibrillation-associated cerebral or systemic embolism and deep venous thrombosis.1) These patients receive oral anticoagulants, including warfarin as a vitamin K (VK) antagonist or direct oral anticoagulants (DOAC). A previous large-scale randomized clinical trial reported that DOAC and warfarin had similar efficacy and safety.2–5) Furthermore, DOAC has predictable pharmacokinetics and does not require routine monitoring since their anticoagulating effect does not interact with VK and interacts less frequently with other drugs. Therefore, DOAC has been preferably used for thromboembolic disease prevention recently. However, warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk, including those with an artificial valve, mitral stenosis, etc.2) Furthermore, warfarin is administered to patients with severe renal impairment who cannot be treated with DOAC.
Head trauma could cause an acute subdural hematoma, acute epidural hematoma, cerebral contusion, and traumatic subarachnoid hematoma. Progressive hemorrhagic injury (PHI) could cause a worsening of neurological conditions.3) Warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) since it inhibits hemostasis.6–8) Therefore, a rapid anticoagulation reversal in patients with TICH might be required for PHI prevention.
VK, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) are available for warfarin reversal in emergencies.2) PCC, which is the most recent to become clinically available, could have greater advantages compared with FFP. This is because it does not require blood typing and cross-matching; moreover, it eliminates the risk of FFP-related volume overload. Furthermore, compared with VK, PCC normalizes prothrombin time/international normalized ratio (PT-INR) more rapidly.9,10) Studies have reported that PCC for warfarin reversal could have greater effectiveness and safety than FFP.11) However, prior to PCC becoming clinically available, warfarin reversal was commonly achieved using VK alone rather than FFP infusion followed by VK. This could be because patients on warfarin treatment often present poor cardiac function and FFP could cause volume-overload associated with congestive heart failure.2,12) There is a need to study differences in the warfarin reversal effect in patients with head trauma between combination therapy of PCC with VK and VK monotherapy.
This retrospective study aimed to evaluate the warfarin reversal effects of a combination of PCC with VK and VK monotherapy in patients with TICH. Furthermore, we aimed to compare the clinical outcomes between the periods before and after the PCC introduction in our hospital.
Methods
The protocol for this retrospective study was approved by the ethics committee at our institution, which waived the requirement for patient consent (No. 3758). We retrospectively reviewed the medical records of 498 adult patients (≥18 years old) admitted at our hospital between February 2016 and November 2019 due to TICH within 12 post-injury hours (Fig. 1). Among them, 35 patients underwent warfarin treatment with a PT-INR of ≥1.4. Seven patients were infused with FFP to treat coincidental systemic massive hemorrhage due to aortic, hepatic, or pulmonary injuries. They were excluded from the study population because the clinical status is different from the others. In our hospital, four-factor PCC (4F-PCC) (Kcentra), which is among the clinically available PCC, was introduced for warfarin reversal from December 2017. We considered the periods before and after November 2017 as the VK era and PCC era, respectively. There 18 and 10 patients in the VK and PCC eras, respectively.
We excluded patients with mild head injury or excessively severe trauma on admission who did not receive treatment for warfarin reversal effect. The treatment outcome was evaluated in the remaining 20 patients (13 and 7 patients in the VK and PCC era, respectively). Immediately after TICH identification, all patients in the VK and PCC era were treated using intravenous administration of VK and PCC in combination with VK, respectively. Regarding the patients’ demographic and clinical characteristics, only time from injury to admission showed a significant between-group difference where it was longer in the VK era than in the PCC era (Table 1).
All the patients underwent a computer tomography (CT) scan on admission and repeat scans at least twice within 3 and 4-24 hours after admission. PHI was evaluated on the repeat CT scans and defined as follows: the appearance of a new intracranial hematoma, including intracerebral, intraventricular, subdural, epidural, or subarachnoid hemorrhage not caused by redistributed hemorrhage or expansion of pre-existing hematoma indicated by a qualitative increase in the volume by 1.4 times greater than the volume on the admission CT.13)
For warfarin reversal with and without PCC, the target PT-INR level was <1.40. Regarding reversal using PCC, PCC was intravenously administered immediately followed by intravenous VK administration (10–20 mg). The administered PCC dose was determined according to our institutional protocol, which was approved by the medical safety commission of our hospital, as follows: 25 IU/kg, 35 IU/kg, and 50 IU/kg were given to patients with INR 1.4–4, 4.0–6.0, and >6, respectively. PCC was only administered once. Contrastingly, 10 mg VK was repeatedly administered in case the PT-INR was ≥1.4 in the follow-up test at 8–12 post-admission hours. We performed between-reversal comparisons of the rates of reaching the target PT-INR at half a day after hospitalization.
The PHI incidence was evaluated in all the patients who underwent reversal treatment. Furthermore, we performed between-reversal comparisons of the in-hospital death; modified Rankin Scale (mRS) at discharge; and adverse events, including myocardial infarction, ischemic stroke, pulmonary embolism, and deep vein thrombosis.
Table 1 presents the patients’ baseline and clinical characteristics. Hypertension was defined as a pre-injury or pre-treatment systolic and/or diastolic blood pressure of ≥140 mmHg and ≥90 mmHg, respectively. Patients were considered to have diabetes if their glycosylated hemoglobin A1C level exceeded 6.5% or if they were being treated with insulin and/or oral hypoglycemic medications. The used antiplatelet drugs included aspirin, cilostazol, and clopidogrel with none of the patients taking prasugrel and ticlopidine hydrochloride.
Continuous variables were express as mean ± SD or median (interquartile range [IQR]). Categorical variables were expressed as number (%). All statistical analyses were performed using JMP version 15 software (SAS Institute, Tokyo, Japan). Statistical significance was set at P <0.05. Between-group comparisons were performed using Fisher's exact test or Mann–Whitney U test. Univariable logistic regression analyses were performed to determine PHI predictors.
Results
Figure 2 shows the time course of PT-INR in the seven patients who underwent combination therapy of PCC with VK. There was a rapid decrease in PT-INR, which reached its target (<1.40) at 1 hour after the start of warfarin reversal in all patients. PT-INR at half a day after reversal remained <1.40 in most patients except one who presented a PT-INR of 1.41.
There were no patients who had new bleeding at other sites and all of the PHI was identified as an expansion of pre-existing hematomas. Patients who underwent warfarin therapy had a high PHI incidence. Among the 20 patients, 12 (60%) patients presented with PHI. The PHI incidence was significantly lower in patients who underwent PCC therapy than VK monotherapy (84.6% vs. 14.3%, P = 0.004; Table 2). There were numerically, but not significantly, more patients who underwent PCC therapy with a PT-INR <1.40 at half a day after warfarin reversal induction compared with those who underwent VK monotherapy (85.7% vs 30.8%). There were no significant between-reversal differences in the hospitalization period, mRS at discharge, mortality, and rate of surgical treatment by craniotomy.
As shown in Table 3, PHI predictors were evaluated by univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00–0.41, P = 0.004). Contrastingly, other demographic and patient characteristics were not associated with PHI. Hemostasis-related factors, including antiplatelet therapy and tranexamic acid administration, did not affect PHI. Severely impaired consciousness (Glasgow Coma Scale [GCS] <12) and delayed admission (time from injury to admission >4 hours) did not affect PHI. Higher PT-INR (>2.0) at admission was not associated with PHI. Patients who reached the target-PT-INR (<1.4) at half a day tended to have less PHI but it was not statistically significant.
Discussion
There have been numerous reports that warfarin reversal using PCC is effective in patients with non-TICH or TICH.11,14–28) However, these studies compared warfarin reversal using PCC and FFP11,14–28) with none of the studies comparing the treatment outcome of warfarin reversal using combination therapy of PCC with VK and VK monotherapy. The use of FFP is associated with a greater risk of volume overload and heart failure.9) In some clinical settings, FFP administration for warfarin reversal is difficult since patients on anticoagulant therapy present with a high risk of heart failure, and the complication rate of atrial fibrillation increases in proportion to the severity of heart failure.29) Moreover, heart failure has been reported in 37% of newly developed atrial fibrillation.30) Therefore, there is a need to directly compare the recent warfarin reversal using a combination therapy of PCC and conventional reversal using VK monotherapy. In this novel study, we found that warfarin reversal by PCC significantly suppressed PHI compared with VK monotherapy.
Warfarin treatment is associated with poor prognosis of patients with TICH. Ivascu et al. reported that oral warfarin increased the mortality rate in patients with TICH (48%), which is approximately five times higher than that in patients without anticoagulant therapy.31) The observed poor outcome under warfarin treatment could be attributed to the anticoagulation causing PHI.7,32–34) Oral anticoagulation is associated with PHI even in patients with minor head trauma.31) Therefore, there is a need to improve the prognosis of patients with head trauma under anticoagulant therapy by rapidly neutralizing the anticoagulant effect. Furthermore, risk factors for PHI have been shown to include older age, male gender, and larger initial lesions.35–40) However, these findings were not observed in our study given its small sample size.
For warfarin reversal, the use of PCC, rather than FFP, was associated with a more rapid decrease in the PT-INR17,18,22) and a higher rate of achieving the target PT-INR value without a cardiovascular volume load.9) VK, which induces production of warfarin-inhibiting coagulant factors in the liver, takes about 24 hours to fully exert its effect to modulate prolonged PT-INR by warfarin.41) PCC intravenous administration is to compensate for the shortage of coagulant factor and shows a more rapid decrease in PT-INR levels than VK intravenous administration alone.42) Rapid PT-INR correction by PCC is considered to suppress PHI more effectively than VK alone in patients taking warfarin. To neutralize a warfarin effect by PCC, the short-lasting effect of PCC should be paid attention to. PCC without VK may result in a re-increase in PT-INR and clinical deterioration.43) Therefore, to maintain the rapidly corrected PT-INR by PCC, VK plays an important role. These were consistent with our findings that, in the present study, most of the patients who underwent the combination therapy using PCC and VK had normalized values of PT-INR rapidly (at 1 hour after PCC administration) and remained within or close to the reference values after 12 hours. Immediate and stable effect of the combination of PCC and VK is considered to prevent PHI.
Anticoagulant therapy neutralization is associated with thrombosis risk.44,45) There have been reports on adverse events of PCC, including ischemic stroke, anaphylactic shock, disseminated intravascular coagulation, and deep vein thrombosis.43,46–50) However, none of our patients presented with complications in the present study. Given the association of warfarin with PHI, which could increase the mortality rate,51) we suggest that anticoagulation neutralization should be performed as early as possible in patients with traumatic head injury under anticoagulant therapy.
PCC contains concentrated VK-dependent coagulation factors (factors II, VII, IX, and X) extracted from large donor-pooled plasma and stored as a lyophilized powder. Currently, PCC is available in two forms: 4F-PCC11,14–16,24) and three-factor PCC (3F-PCC),18–21,23) which have both been used in previous studies. Compared with 3F-PCC, 4F-PCC contains higher levels of factor VII, as well as some anticoagulant proteins (Protein C, Protein S, Antithrombin, and heparin),52) and is associated with rapid INR reversal and a reduction in transfusion requirement without the risk of thromboembolic events.53) However, it remains unclear whether 4F-PCC is better than 3F-PCC.
This study has several limitations. First, this was a retrospective study with a small number of patients. Furthermore, there could have been patient selection bias. However, this was minimized by comparing warfarin-reversal using PCC with historical control. Second, although PCC may improve the prognosis of patients with TICH, this was not assessed. There is a need for further studies to confirm our findings and the PCC effect on the prognosis.
Conclusion
Warfarin reversal using combination therapy of PCC with VK after head trauma might be more effective for PIH inhibition than using VK monotherapy. This could be attributed to the rapid and stable neutralization of the warfarin anticoagulant effect. Furthermore, treatment with PCC was not associated with major thrombotic complications. PCC should be administered to patients with TICH taking warfarin to prevent PHI.
Conflicts of Interest Disclosure
All authors declare that they have no conflicts of interest.
Fig. 1 Study profile. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, TICH: traumatic intracranial hemorrhage.
Fig. 2 Time course of PT-INR in patients with combination therapy of PCC with VK. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 1 Patient baseline and clinical characteristics
Total VK monotherapy (n = 13) Combination with PCC (n = 7) P value
Age 79.1 ± 7.08 78.6 ± 7.2 80 ± 6.6 0.72
Female gender 7 (35%) 5 (38.5%) 2 (28.6%) >0.99
Hypertension 14 (70%) 13 (69.2%) 5 (71.4%) >0.99
Diabetes mellitus 9 (45%) 6 (46.2%) 3 (42.9%) >0.99
Antiplatelet therapy 6 (30%) 5 (38.5%) 1 (14.3%) 0.35
mRS before injury 3 (1–3) 5 (4–6) 4 (3.5–5.5) 0.93
GCS on admission 12 (11–14.3) 12 (8.5–14) 12 (11–15) 0.54
PT-INR at admission 2.33 (1.70–3.18) 2.52 (1.78–3.17) 1.83 (1.67–3.39) >0.99
Time from injury to admission (hour) 3.7 ± 2.6 4.5 ± 2.8 2.1 ± 1.3 0.02*
Use of tranexamic acid 60 (%) 7 (53.9%) 5 (71.4%) 0.64
Data are presented as mean (SD), number (%), or median (IQR). *Indicates statistical significance. GCS: Glasgow Coma Scale, IQR: interquartile range, mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 2 Patient characteristics of the hematoma expansion positive and negative groups
Total (n = 20) VK monotherapy (n = 13) Combination with PCC (n = 7) P value
PHI 12 (60) 11 (84.6) 1 (14.3) 0.004*
Reached target-PT-INR after a half day 10 (50) 4 (30.8) 6 (85.7) 0.057
Hospitalization (day) 22.6 ± 30.2 15.1 ± 15.0 36.4 ± 45.7 0.27
mRS at discharge 4.5 (3–6) 5 (4–6) 4 (3.5–5.5) 0.46
Death 8 (40) 6 (46.2) 2 (28.6) 0.48
Craniotomy 3 (15) 2 (15.3) 1 (14.3) >0.99
Data are shown as mean (SD), number (%), or median (IQR). *Shows statistical significance. mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PHI: progressive hemorrhagic injury, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 3 Univariable analysis of predictors of hematoma expansion
Predictor Odds ratio 95% Confidence interval P value
Age >80 0.43 0.07–2.68 0.65
Female sex 0.84 0.092–8.32 >0.99
Hypertension 1.8 0.26–12.5 0.62
Diabetes mellitus 0.3 0.05–1.94 0.36
Antiplatelet therapy 4.9 0.46–54.5 0.32
Tranexamic acid 2.1 0.32–12.5 0.65
GCS score at admission <12 3.1 0.422–21.3 0.37
Delayed admission† 1.19 0.19–7.46 >0.99
Higher PT-INR (>2.0) at admission 0.84 0.134–5.26 >0.99
Reaching target-PT-INR after a half day 0.17 0.0225–1.23 0.17
Reversal using PCC 0.03 0.00–0.41 0.004*
†Time from injury to admission was >4 hours. *Shows a statistical significance. GCS: Glasgow Coma Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio. | 10?20 MILLIGRAM | DrugDosageText | CC BY-NC-ND | 33208582 | 18,674,277 | 2021-01-15 |
What was the outcome of reaction 'Pneumonia'? | Combination Therapy Using Prothrombin Complex Concentrate and Vitamin K in Anticoagulated Patients with Traumatic Intracranial Hemorrhage Prevents Progressive Hemorrhagic Injury: A Historically Controlled Study.
Warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk. However, warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) through progressive hemorrhagic injury (PHI). Therefore, a rapid anticoagulation reversal could be required in patients with TICH to prevent PHI. Differences in the warfarin reversal effect between combination therapy of prothrombin complex concentrate (PCC) with vitamin K (VK) and VK monotherapy remain unclear. However, studies have reported that PCC has greater effectiveness and safety for warfarin reversal compared with fresh frozen plasma (FFP). This retrospective study aimed to evaluate the warfarin reversal effects of combination therapy of PCC with VK and VK monotherapy on TICH. We compared the clinical outcomes between the periods before and after the PCC introduction in our hospital. There were 13 and 7 patients who received VK monotherapy and PCC with VK, respectively. PHI predictors were evaluated using univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00-0.41, P = 0.004). None of the patients presented with thrombotic complications. Warfarin reversal through a combination of PCC with VK could be more effective for inhibiting post-trauma PHI compared with VK monotherapy. This could be attributed to a rapid and stable warfarin reversal. PCC should be administered to patients with TICH taking warfarin for PHI prevention.
Introduction
With increasing life expectancy, there has been a concomitant increase in the number of patients requiring long-term anticoagulation to prevent arterial fibrillation-associated cerebral or systemic embolism and deep venous thrombosis.1) These patients receive oral anticoagulants, including warfarin as a vitamin K (VK) antagonist or direct oral anticoagulants (DOAC). A previous large-scale randomized clinical trial reported that DOAC and warfarin had similar efficacy and safety.2–5) Furthermore, DOAC has predictable pharmacokinetics and does not require routine monitoring since their anticoagulating effect does not interact with VK and interacts less frequently with other drugs. Therefore, DOAC has been preferably used for thromboembolic disease prevention recently. However, warfarin remains crucially involved in the treatment of patients at thrombotic or thromboembolic risk, including those with an artificial valve, mitral stenosis, etc.2) Furthermore, warfarin is administered to patients with severe renal impairment who cannot be treated with DOAC.
Head trauma could cause an acute subdural hematoma, acute epidural hematoma, cerebral contusion, and traumatic subarachnoid hematoma. Progressive hemorrhagic injury (PHI) could cause a worsening of neurological conditions.3) Warfarin increases the mortality rate among patients with traumatic intracranial hemorrhage (TICH) since it inhibits hemostasis.6–8) Therefore, a rapid anticoagulation reversal in patients with TICH might be required for PHI prevention.
VK, fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC) are available for warfarin reversal in emergencies.2) PCC, which is the most recent to become clinically available, could have greater advantages compared with FFP. This is because it does not require blood typing and cross-matching; moreover, it eliminates the risk of FFP-related volume overload. Furthermore, compared with VK, PCC normalizes prothrombin time/international normalized ratio (PT-INR) more rapidly.9,10) Studies have reported that PCC for warfarin reversal could have greater effectiveness and safety than FFP.11) However, prior to PCC becoming clinically available, warfarin reversal was commonly achieved using VK alone rather than FFP infusion followed by VK. This could be because patients on warfarin treatment often present poor cardiac function and FFP could cause volume-overload associated with congestive heart failure.2,12) There is a need to study differences in the warfarin reversal effect in patients with head trauma between combination therapy of PCC with VK and VK monotherapy.
This retrospective study aimed to evaluate the warfarin reversal effects of a combination of PCC with VK and VK monotherapy in patients with TICH. Furthermore, we aimed to compare the clinical outcomes between the periods before and after the PCC introduction in our hospital.
Methods
The protocol for this retrospective study was approved by the ethics committee at our institution, which waived the requirement for patient consent (No. 3758). We retrospectively reviewed the medical records of 498 adult patients (≥18 years old) admitted at our hospital between February 2016 and November 2019 due to TICH within 12 post-injury hours (Fig. 1). Among them, 35 patients underwent warfarin treatment with a PT-INR of ≥1.4. Seven patients were infused with FFP to treat coincidental systemic massive hemorrhage due to aortic, hepatic, or pulmonary injuries. They were excluded from the study population because the clinical status is different from the others. In our hospital, four-factor PCC (4F-PCC) (Kcentra), which is among the clinically available PCC, was introduced for warfarin reversal from December 2017. We considered the periods before and after November 2017 as the VK era and PCC era, respectively. There 18 and 10 patients in the VK and PCC eras, respectively.
We excluded patients with mild head injury or excessively severe trauma on admission who did not receive treatment for warfarin reversal effect. The treatment outcome was evaluated in the remaining 20 patients (13 and 7 patients in the VK and PCC era, respectively). Immediately after TICH identification, all patients in the VK and PCC era were treated using intravenous administration of VK and PCC in combination with VK, respectively. Regarding the patients’ demographic and clinical characteristics, only time from injury to admission showed a significant between-group difference where it was longer in the VK era than in the PCC era (Table 1).
All the patients underwent a computer tomography (CT) scan on admission and repeat scans at least twice within 3 and 4-24 hours after admission. PHI was evaluated on the repeat CT scans and defined as follows: the appearance of a new intracranial hematoma, including intracerebral, intraventricular, subdural, epidural, or subarachnoid hemorrhage not caused by redistributed hemorrhage or expansion of pre-existing hematoma indicated by a qualitative increase in the volume by 1.4 times greater than the volume on the admission CT.13)
For warfarin reversal with and without PCC, the target PT-INR level was <1.40. Regarding reversal using PCC, PCC was intravenously administered immediately followed by intravenous VK administration (10–20 mg). The administered PCC dose was determined according to our institutional protocol, which was approved by the medical safety commission of our hospital, as follows: 25 IU/kg, 35 IU/kg, and 50 IU/kg were given to patients with INR 1.4–4, 4.0–6.0, and >6, respectively. PCC was only administered once. Contrastingly, 10 mg VK was repeatedly administered in case the PT-INR was ≥1.4 in the follow-up test at 8–12 post-admission hours. We performed between-reversal comparisons of the rates of reaching the target PT-INR at half a day after hospitalization.
The PHI incidence was evaluated in all the patients who underwent reversal treatment. Furthermore, we performed between-reversal comparisons of the in-hospital death; modified Rankin Scale (mRS) at discharge; and adverse events, including myocardial infarction, ischemic stroke, pulmonary embolism, and deep vein thrombosis.
Table 1 presents the patients’ baseline and clinical characteristics. Hypertension was defined as a pre-injury or pre-treatment systolic and/or diastolic blood pressure of ≥140 mmHg and ≥90 mmHg, respectively. Patients were considered to have diabetes if their glycosylated hemoglobin A1C level exceeded 6.5% or if they were being treated with insulin and/or oral hypoglycemic medications. The used antiplatelet drugs included aspirin, cilostazol, and clopidogrel with none of the patients taking prasugrel and ticlopidine hydrochloride.
Continuous variables were express as mean ± SD or median (interquartile range [IQR]). Categorical variables were expressed as number (%). All statistical analyses were performed using JMP version 15 software (SAS Institute, Tokyo, Japan). Statistical significance was set at P <0.05. Between-group comparisons were performed using Fisher's exact test or Mann–Whitney U test. Univariable logistic regression analyses were performed to determine PHI predictors.
Results
Figure 2 shows the time course of PT-INR in the seven patients who underwent combination therapy of PCC with VK. There was a rapid decrease in PT-INR, which reached its target (<1.40) at 1 hour after the start of warfarin reversal in all patients. PT-INR at half a day after reversal remained <1.40 in most patients except one who presented a PT-INR of 1.41.
There were no patients who had new bleeding at other sites and all of the PHI was identified as an expansion of pre-existing hematomas. Patients who underwent warfarin therapy had a high PHI incidence. Among the 20 patients, 12 (60%) patients presented with PHI. The PHI incidence was significantly lower in patients who underwent PCC therapy than VK monotherapy (84.6% vs. 14.3%, P = 0.004; Table 2). There were numerically, but not significantly, more patients who underwent PCC therapy with a PT-INR <1.40 at half a day after warfarin reversal induction compared with those who underwent VK monotherapy (85.7% vs 30.8%). There were no significant between-reversal differences in the hospitalization period, mRS at discharge, mortality, and rate of surgical treatment by craniotomy.
As shown in Table 3, PHI predictors were evaluated by univariate regression analyses. Warfarin reversal using PCC had a significant negative association with PHI (odds ratio: 0.03, 95% confidence interval: 0.00–0.41, P = 0.004). Contrastingly, other demographic and patient characteristics were not associated with PHI. Hemostasis-related factors, including antiplatelet therapy and tranexamic acid administration, did not affect PHI. Severely impaired consciousness (Glasgow Coma Scale [GCS] <12) and delayed admission (time from injury to admission >4 hours) did not affect PHI. Higher PT-INR (>2.0) at admission was not associated with PHI. Patients who reached the target-PT-INR (<1.4) at half a day tended to have less PHI but it was not statistically significant.
Discussion
There have been numerous reports that warfarin reversal using PCC is effective in patients with non-TICH or TICH.11,14–28) However, these studies compared warfarin reversal using PCC and FFP11,14–28) with none of the studies comparing the treatment outcome of warfarin reversal using combination therapy of PCC with VK and VK monotherapy. The use of FFP is associated with a greater risk of volume overload and heart failure.9) In some clinical settings, FFP administration for warfarin reversal is difficult since patients on anticoagulant therapy present with a high risk of heart failure, and the complication rate of atrial fibrillation increases in proportion to the severity of heart failure.29) Moreover, heart failure has been reported in 37% of newly developed atrial fibrillation.30) Therefore, there is a need to directly compare the recent warfarin reversal using a combination therapy of PCC and conventional reversal using VK monotherapy. In this novel study, we found that warfarin reversal by PCC significantly suppressed PHI compared with VK monotherapy.
Warfarin treatment is associated with poor prognosis of patients with TICH. Ivascu et al. reported that oral warfarin increased the mortality rate in patients with TICH (48%), which is approximately five times higher than that in patients without anticoagulant therapy.31) The observed poor outcome under warfarin treatment could be attributed to the anticoagulation causing PHI.7,32–34) Oral anticoagulation is associated with PHI even in patients with minor head trauma.31) Therefore, there is a need to improve the prognosis of patients with head trauma under anticoagulant therapy by rapidly neutralizing the anticoagulant effect. Furthermore, risk factors for PHI have been shown to include older age, male gender, and larger initial lesions.35–40) However, these findings were not observed in our study given its small sample size.
For warfarin reversal, the use of PCC, rather than FFP, was associated with a more rapid decrease in the PT-INR17,18,22) and a higher rate of achieving the target PT-INR value without a cardiovascular volume load.9) VK, which induces production of warfarin-inhibiting coagulant factors in the liver, takes about 24 hours to fully exert its effect to modulate prolonged PT-INR by warfarin.41) PCC intravenous administration is to compensate for the shortage of coagulant factor and shows a more rapid decrease in PT-INR levels than VK intravenous administration alone.42) Rapid PT-INR correction by PCC is considered to suppress PHI more effectively than VK alone in patients taking warfarin. To neutralize a warfarin effect by PCC, the short-lasting effect of PCC should be paid attention to. PCC without VK may result in a re-increase in PT-INR and clinical deterioration.43) Therefore, to maintain the rapidly corrected PT-INR by PCC, VK plays an important role. These were consistent with our findings that, in the present study, most of the patients who underwent the combination therapy using PCC and VK had normalized values of PT-INR rapidly (at 1 hour after PCC administration) and remained within or close to the reference values after 12 hours. Immediate and stable effect of the combination of PCC and VK is considered to prevent PHI.
Anticoagulant therapy neutralization is associated with thrombosis risk.44,45) There have been reports on adverse events of PCC, including ischemic stroke, anaphylactic shock, disseminated intravascular coagulation, and deep vein thrombosis.43,46–50) However, none of our patients presented with complications in the present study. Given the association of warfarin with PHI, which could increase the mortality rate,51) we suggest that anticoagulation neutralization should be performed as early as possible in patients with traumatic head injury under anticoagulant therapy.
PCC contains concentrated VK-dependent coagulation factors (factors II, VII, IX, and X) extracted from large donor-pooled plasma and stored as a lyophilized powder. Currently, PCC is available in two forms: 4F-PCC11,14–16,24) and three-factor PCC (3F-PCC),18–21,23) which have both been used in previous studies. Compared with 3F-PCC, 4F-PCC contains higher levels of factor VII, as well as some anticoagulant proteins (Protein C, Protein S, Antithrombin, and heparin),52) and is associated with rapid INR reversal and a reduction in transfusion requirement without the risk of thromboembolic events.53) However, it remains unclear whether 4F-PCC is better than 3F-PCC.
This study has several limitations. First, this was a retrospective study with a small number of patients. Furthermore, there could have been patient selection bias. However, this was minimized by comparing warfarin-reversal using PCC with historical control. Second, although PCC may improve the prognosis of patients with TICH, this was not assessed. There is a need for further studies to confirm our findings and the PCC effect on the prognosis.
Conclusion
Warfarin reversal using combination therapy of PCC with VK after head trauma might be more effective for PIH inhibition than using VK monotherapy. This could be attributed to the rapid and stable neutralization of the warfarin anticoagulant effect. Furthermore, treatment with PCC was not associated with major thrombotic complications. PCC should be administered to patients with TICH taking warfarin to prevent PHI.
Conflicts of Interest Disclosure
All authors declare that they have no conflicts of interest.
Fig. 1 Study profile. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, TICH: traumatic intracranial hemorrhage.
Fig. 2 Time course of PT-INR in patients with combination therapy of PCC with VK. PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 1 Patient baseline and clinical characteristics
Total VK monotherapy (n = 13) Combination with PCC (n = 7) P value
Age 79.1 ± 7.08 78.6 ± 7.2 80 ± 6.6 0.72
Female gender 7 (35%) 5 (38.5%) 2 (28.6%) >0.99
Hypertension 14 (70%) 13 (69.2%) 5 (71.4%) >0.99
Diabetes mellitus 9 (45%) 6 (46.2%) 3 (42.9%) >0.99
Antiplatelet therapy 6 (30%) 5 (38.5%) 1 (14.3%) 0.35
mRS before injury 3 (1–3) 5 (4–6) 4 (3.5–5.5) 0.93
GCS on admission 12 (11–14.3) 12 (8.5–14) 12 (11–15) 0.54
PT-INR at admission 2.33 (1.70–3.18) 2.52 (1.78–3.17) 1.83 (1.67–3.39) >0.99
Time from injury to admission (hour) 3.7 ± 2.6 4.5 ± 2.8 2.1 ± 1.3 0.02*
Use of tranexamic acid 60 (%) 7 (53.9%) 5 (71.4%) 0.64
Data are presented as mean (SD), number (%), or median (IQR). *Indicates statistical significance. GCS: Glasgow Coma Scale, IQR: interquartile range, mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 2 Patient characteristics of the hematoma expansion positive and negative groups
Total (n = 20) VK monotherapy (n = 13) Combination with PCC (n = 7) P value
PHI 12 (60) 11 (84.6) 1 (14.3) 0.004*
Reached target-PT-INR after a half day 10 (50) 4 (30.8) 6 (85.7) 0.057
Hospitalization (day) 22.6 ± 30.2 15.1 ± 15.0 36.4 ± 45.7 0.27
mRS at discharge 4.5 (3–6) 5 (4–6) 4 (3.5–5.5) 0.46
Death 8 (40) 6 (46.2) 2 (28.6) 0.48
Craniotomy 3 (15) 2 (15.3) 1 (14.3) >0.99
Data are shown as mean (SD), number (%), or median (IQR). *Shows statistical significance. mRS: modified Rankin Scale, PCC: prothrombin complex concentrate, PHI: progressive hemorrhagic injury, PT-INR: prothrombin time-international normalized ratio, VK: vitamin K.
Table 3 Univariable analysis of predictors of hematoma expansion
Predictor Odds ratio 95% Confidence interval P value
Age >80 0.43 0.07–2.68 0.65
Female sex 0.84 0.092–8.32 >0.99
Hypertension 1.8 0.26–12.5 0.62
Diabetes mellitus 0.3 0.05–1.94 0.36
Antiplatelet therapy 4.9 0.46–54.5 0.32
Tranexamic acid 2.1 0.32–12.5 0.65
GCS score at admission <12 3.1 0.422–21.3 0.37
Delayed admission† 1.19 0.19–7.46 >0.99
Higher PT-INR (>2.0) at admission 0.84 0.134–5.26 >0.99
Reaching target-PT-INR after a half day 0.17 0.0225–1.23 0.17
Reversal using PCC 0.03 0.00–0.41 0.004*
†Time from injury to admission was >4 hours. *Shows a statistical significance. GCS: Glasgow Coma Scale, PCC: prothrombin complex concentrate, PT-INR: prothrombin time-international normalized ratio. | Fatal | ReactionOutcome | CC BY-NC-ND | 33208582 | 18,674,277 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'. | A retrospective review of the real-world experience of the Pegfilgrastim biosimilar (Lapelga®) to the reference biologic (Neulasta®).
BACKGROUND
Cancer patients receiving myelosuppressive chemotherapy are vulnerable to febrile neutropenia (FN) which contributes to poor treatment outcomes. The use of granulocyte colony-stimulating factors is administered to prevent chemotherapy-induced neutropenia. The introduction of biosimilars has allowed for greater cost-savings while maintaining safety and efficacy. This retrospective study assessed the incidence of FN and related treatment outcomes and the cost minimization of a pegfilgrastim biosimilar and its reference.
METHODS
A retrospective chart review of breast cancer patients receiving (neo) adjuvant chemotherapy from February 2017 to May 2020 was conducted. The endpoints included the incidence of FN, the occurrence of dose reduction (DR), dose delay (DD) and pain. A cost minimization analysis was performed from a third-party payer perspective.
RESULTS
One hundred Neulasta® and 74 Lapelga® patients were included in the first-cycle analysis. The rate of FN in cycle 1 for Neulasta® and Lapelga® was 2/100 and 4/74, respectively; risk difference (RD) = 3.4%; 95% CI: -2.4 to 9.2%. Eighty-three Neulasta® and 59 Lapelga® patients were included in the all-cycle analyses, where DR was reported in 76 (15%) Neulasta® cycles vs 33 (10%) Lapelga® cycles (RD = -3.6, 95% CI: -10.2 to 2.9). DD was reported in 20 (4%) Neulasta® cycles vs. 11 (3.5%) Lapelga® cycles (RD = -0.3; 95% CI: -2.7 to 2.0). Adverse events were similar between groups. Cost minimization using a cohort of 20,000 patients translated into an incremental savings of $21,606,800 CAD for each cycle.
CONCLUSIONS
The biosimilar pegfilgrastim was non-inferior to the reference biologic based on FN incidence in addition to related outcomes including DR and DD.
pmcIntroduction
Febrile neutropenia (FN) is considered the most serious dose-limiting toxicity of myelosuppressive chemotherapy, as it both increases the immediate risk of infection and limits the delivery of chemotherapy, leading to suboptimal levels of long-term treatment success. 1 It is often defined as an absolute neutrophil count (ANC) less than 0.5 x 109 cells/L (or the expectation that it will fall to <0.5 x 109 cells/L) with a single oral temperature of ≥38.3°C or two consecutive readings of ≥38.0°C for more than one or two hours.2,3 In the acute setting, FN often results in emergency hospitalization requiring antibiotic treatment to avoid fatal consequences, including sepsis. 4 Furthermore, severe or prolonged neutropenia impacts the achievement of target dose intensity and commonly necessitates chemotherapy dose reductions (DR) and delays (DD).5,6 DDs, DRs, and discontinuation of chemotherapy decrease the overall efficacy of this treatment, adversely impacting cancer survival outcomes.5,7 Not only does FN increase morbidity and mortality, but it also results in a substantial economic burden due to hospitalization costs.8–10
FN incidence can be lowered through the use of granulocyte colony-stimulating factors (G-CSFs) to reduce the severity and duration of neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs.11,12 Current practise guidelines recommend the use of G-CSF agents with chemotherapy regimens associated with elevated FN risk of greater than 20% or those of intermediate risk (10–20%) if they present with additional individual risk factors (age, performance status, previous history of FN).3,6,13 Recombinant G-CSFs are available as short- and long-acting forms, which differ in requiring a weight-based, daily-dosing schedule versus a fixed-dose, administered once-per cycle schedule, respectively. A pegylated variant of the short-acting filgrastim, pegfilgrastim, possesses the same mechanism of action but has a longer half-life. Pegfilgrastim levels are self-regulating which allows for clearance only when the neutrophil count increases sufficiently beyond the absolute neutrophil count nadir and growth factor support is no longer required.12,14 Experimental and real-world studies suggest that pegfilgrastim may provide more effective prophylaxis against FN when compared to filgrastim.14–18 Pegfilgrastim is intended to improve treatment adherence due to the need for fewer administrations and has demonstrated better maintenance of relative dose intensity and reduced hospital visits in comparative effectiveness studies.14,17,19
While G-CSF biologics are important for the prophylaxis of FN, they have been identified as significant drivers of global healthcare costs. 20 Biosimilars are lower-cost versions of previously approved reference biologics that must demonstrate high similarity to an authorized reference product in terms of molecular characterisation, purity, stability, pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity.21,22 Biosimilars intend to decrease the costs associated with high-priced biologics and their implementation has conferred significant cost savings. 20 Furthermore, the use of biosimilars has potential to increase patient access to treatment through direct reduction of health systems costs.23,24
The pegfilgrastim biosimilar, (Lapelga®, Apobiologix, Toronto, ON) was the first pegfilgrastim biosimilar approved in a major global market, initially approved by Health Canada in 2018.25,26 The aim of this real-world clinical study was to assess the safety and efficacy of the pegfilgrastim biosimilar, Lapelga® versus the reference pegfilgrastim (Neulasta®, Amgen, Thousand Oaks, CA, USA). in primary prophylaxis of FN in breast cancer patients receiving myelosuppressive, (neo) adjuvant chemotherapy.
Methods
Patient population
This single-center, retrospective, cohort study was approved by the institutional research ethics board [REB #2429]. A manual chart review of all breast cancer patients receiving cytotoxic chemotherapy with G-CSF support from February 2017 to May 2020 was conducted. Included patients were treated with neoadjuvant or adjuvant chemotherapy and were administered G-CSF primary prophylaxis with either pegfilgrastim product. Patient characteristics (age, BMI), pathology (tumour stage, tumour morphology), and treatment characteristics (chemotherapy regimen, treatment intent) were collected. Across all cycles, the incidence of FN, DD, DR, and adverse events associated with the use of G-CSF agent (specifically bone, joint, and muscle pain) were evaluated. Any DD and DR were collected. DDs were defined as a delay in treatment of six or more days and DR were defined as any reduction in dosage of one or more chemotherapy agents when compared to baseline dosage. The incidence of first cycle and all-cycle FN requiring hospitalization plus chemotherapy DD and DR were analyzed independently in both cohorts. The general guidelines for FN diagnosis and standards of care directing G-CSF prophylaxis remained consistent throughout the duration of the study period. The occurrence of bone, joint and/or muscle pain were collected individually, but due to the ambiguity of many pain descriptions, these indicators were grouped into an overall assessment of pain for the analysis.
Patients were excluded if they had a primary cancer other than in the breast, were receiving palliative treatment, had previous chemotherapy, or had begun their chemotherapy with a short-acting G-CSF. Patients were further excluded from the all-cycle analysis if they had prematurely stopped their chemotherapy for a reason other than FN, received secondary G-CSF prophylaxis, switched their chemotherapy or were receiving a weekly treatment regimen. Subjects who switched their G-CSF product or discontinued its usage were still included in the analysis up until their switch. Although the product monograph of both G-CSF products state that it should not be used within 14 days of chemotherapy, it was still administered for patients given treatment every14-days. This simply reflects the real-world practice of medical oncologists at our centre. Patients were instructed to administer G-CSF the next day following the chemotherapy treatment by at least 24 hours.
Endpoints
The primary endpoint was the incidence of FN, which was comparatively assessed as the risk difference between the Neulasta® and Lapelga® cohorts. As FN commonly presents in the first cycle,27–29 the incidence of FN events in the first cycle was the primary endpoint.
Secondary endpoints included FN event throughout the entire course of chemotherapy, length of hospitalization, chemotherapy DR and DD incidence, as well as the magnitude of the DR (compared to baseline) and DD as a deviation ≥ 6 days from the recommended dose scheduling for the prescribed regimen. The incidence of adverse events related to G-CSF usage was restricted to investigating bone pain that was determined by patient-reported cases of pain. Cost minimization was performed to record the incremental cost savings of implementing Lapelga® into a health care setting in Canadian currency.
Statistical analysis
Demographics of patients included in the first and total cycle analysis were summarized using mean, standard deviation (SD), median, inter-quartiles, and range for continuous variables, and proportions for categorical variables. To compare demographics between Lapelga® and Neulasta® patients, Wilcoxon rank-sum nonparametric test or Fisher exact test was applied for continuous or categorical variables as appropriate. The primary objective of non-inferiority of the biosimilar vs reference biologic was evaluated for the rate of FN in cycle 1 and for total cycles, where the risk difference (RD) in the rate of FN with 95% confidence intervals (CI) was reported. The non-inferiority margin was set at 15% for the absolute risk difference in the FN rate between treatments. Non-inferiority was met if the upper limit of 95% CI was <15%.
To compare the incidence of FN, side effect of any pain, DD, and DR between Lapelga® and Neulasta® treatment group in the whole cycles’ analysis, generalized estimating equation (GEE) models were conducted, and a binomial distribution with logit link function were specified in the GEE models. For the duration of FN-associated hospitalization in days, number of days delayed, and percent of reductions, a Poisson distribution with log link function were specified in the GEE model. All models were fit using an exchangeable correlation structure, the independent variables included the binary treatment group (Lapelga® vs. Neulasta®) and chemotherapy cycles (1–8). P-value, RD and 95% confidence intervals (CI) were estimated for each binary endpoint.
Matched analysis was done using one-to-one patient comparators between two treatment groups using age and chemotherapy regimens. For instance, patients were first matched based on chemotherapy regimen and then were matched based on age ± 5 years, then age ± 10 years. Any patient who was not matched would be excluded in the matched analysis. All analyses were conducted using Statistical Analysis Software (SAS version 9.4, Cary, NC). P-value < 0.05 was considered statistically significant.
Cost minimization
A cost minimization analysis was performed from a third-party payer perspective. The base case cost for Lapelga® ($1,424.63 for 6 mg/0.6 mL dose) was obtained from the Ontario Drug Benefit formulary accessed June 22, 2020 and the cost for Neulasta® ($2,504.97 for 6 mg/0.6 mL dose) was obtained from CADTH Submission for Lapelga®. The base case model was computed in Microsoft Excel 2016 (Microsoft, USA) using a hypothetical cohort of 20,000 patients receiving third-generation anthracycline-based chemotherapy in a neoadjuvant or adjuvant setting for early or locally advanced breast cancer. Sensitivity analysis was performed evaluating how costs would vary if the established reference was changed from Neulasta® to Lapelga®. The incremental cost difference was also evaluated if the price of the aforementioned drugs was discounted between 15–35%. Given that the time horizon of the model was under one year, no global discounting was utilized.
Results
Patient demographics
One hundred and twenty-nine patients who had received the reference pegfilgrastim and 93 patients who had received the biosimilar were screened (Figure 1). After applying the inclusion and exclusion criteria, 100 Neulasta® patients and 74 Lapelga® patients were eligible for the cycle-1 chemotherapy analysis. For all-cycle analysis, 83 Neulasta® and 59 Lapelga® patients were included, representing a total of 837 cycles, 515 being the originator and 322 being the biosimilar.
Figure 1. Exclusion criteria used to determine cohorts. *Patients who had Lapelga® or Neulasta® for their first cycle and then were switched to a different GCSF during a portion of their cycle were included in the complete analysis up until the point they switched.
Patient demographics and treatment characteristics were relatively well balanced between the two treatment groups. The demographics are summarized in two separate tables: Table 1 shows the demographics for patients included in the first cycle analysis and Table 2 shows demographics for patients included in the total-cycle analysis. Online Appendix 1 describes the chemotherapy drugs administered during each cycle in common breast chemotherapy treatment regimens. There were no significant differences between the Lapelga® and Neulasta® patients in age, chemotherapy treatment intent, primary diagnosis, body mass index (BMI), baseline hemoglobin levels, baseline white blood cell count, and chemotherapy regimen. However, the weight and BMI were numerically slightly different, as the Neulasta® group had a slightly higher BMI and weight, but this difference was not significant. There was a significant difference in disease stage at baseline with Lapelga® having a greater proportion of patients with a higher stage (p = 0.021) in the all-cycle analysis group, but this difference did not meet the threshold of statistical significance in the first cycle analysis group (p = 0.0562).
Table 1. Demographics of patients included in the first cycle analysis.
Number of patients Total (N = 174) Neulasta® (N = 100) Lapelga® (N = 74) p-valuea
Age (years) 0.3451
N 174 100 74
Mean ± SD 50.77 ± 10.64 49.94 ± 9.92 51.89 ± 11.52
Median (inter-quartiles) 50.0 (44.0, 58.0) 50.0 (43.5, 57.0) 51.0 (44.0, 60.0)
Min, Max 21.0, 78.0 21.0, 71.0 27.0, 78.0
Age categories (years) 0.2536
<40 26 (14.94%) 17 (17.00%) 9 (12.16%)
40–<50 52 (29.89%) 28 (28.00%) 24 (32.43%)
50–<60 59 (33.91%) 38 (38.00%) 21 (28.38%)
≥60 37 (21.26%) 17 (17.00%) 20 (27.03%)
Chemotherapy intent 0.8786
Adjuvant 90 (51.72%) 51 (51.00%) 39 (52.70%)
Neoadjuvant 84 (48.28%) 49 (49.00%) 35 (47.30%)
Primary diagnosis 0.4791
DCIS 1 (0.57%) 1 (1.00%) 0 (0.00%)
IDC 155 (89.08%) 87 (87.00%) 68 (91.89%)
IDC/DCIS 1 (0.57%) 1 (1.00%) 0 (0.00%)
IDC/ILC 1 (0.57%) 0 (0.00%) 1 (1.35%)
ILC 16 (9.20%) 11 (11.00%) 5 (6.76%)
Weight at baseline (kg) 0.0819
N 174 100 74
Mean ± SD 71.30 ± 17.45 73.31 ± 18.34 68.59 ± 15.90
Min, max 40.5, 165.9 42.5, 165.9 40.5, 135.0
BMI at baseline (kg/m2) 0.1411
N 174 100 74
Mean ± SD 27.28 ± 6.14 27.89 ± 6.75 26.45 ± 5.15
Min, max 16.5, 66.5 16.5, 66.5 18.5, 48.4
Hemoglobin at baseline (g/L) 0.6303
N 174 100 74
Mean ± SD 131.93 ± 11.50 131.60 ± 11.68 132.38 ± 11.31
Min, max 90.0, 159.0 90.0, 159.0 94.0, 158.0
WBC at baseline (×109/L) 0.1276
N 173 99 74
Mean ± SD 6.83 ± 2.24 7.07 ± 2.52 6.51 ± 1.75
Min, max 2.7, 23.3 3.0, 23.3 2.7, 10.9
Disease stage at baseline 0.0562
Stage 1 2 (1.15%) 1 (1.00%) 1 (1.35%)
Stage 2 58 (33.33%) 30 (30.00%) 28 (37.84%)
Stage 3 74 (42.53%) 39 (39.00%) 35 (47.30%)
Missing 40 (22.99%) 30 (30.00%) 10 (13.51%)
Chemotherapy regimensb 0.9130
AC-PACLc 84 (48.28%) 49 (49.00%) 35 (47.30%)
FEC-D 61 (35.06%) 33 (33.00%) 28 (37.84%)
DOCETAXCYCLO 26 (14.94%) 16 (16.00%) 10 (13.51%)
TCH 3 (1.72%) 2 (2.00%) 1 (1.35%)
DCIS = ductal carcinoma in situ; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; WBC = white blood cells; BMI = body mass index.
aWilcoxon rank-sum nonparametric test for continuous variables, or Fisher exact test was applied for categorical variables as appropriate. p<0.05 was considered statistically significant. Bold values indicate significance.
bDescriptions of abbreviations found in Online Appendix 1.
cDose dense AC- PACL.
Table 2. Demographics of patients included in the whole cycle analysis.
Number of patients Total (N = 142) Neulasta® (N = 83) Lapelga® (N = 59) p-valuea
Age (years) 0.7893
N 142 83 59
Mean ± SD 50.63 ± 10.66 50.14 ± 10.20 51.31 ± 11.32
Median (inter-quartiles) 50.0 (44.0, 58.0) 51.0 (46.0, 57.0) 50.0 (44.0, 60.0)
Min, max 21.0, 78.0 21.0, 71.0 27.0, 78.0
Age categories (years) 0.1816
<40 22 (15.49%) 15 (18.07%) 7 (11.86%)
40–<50 41 (28.87%) 20 (24.10%) 21 (35.59%)
50–<60 49 (34.51%) 33 (39.76%) 16 (27.12%)
≥60 30 (21.13%) 15 (18.07%) 15 (25.42%)
Chemotherapy intent 0.8649
Adjuvant 75 (52.82%) 43 (51.81%) 32 (54.24%)
Neoadjuvant 67 (47.18%) 40 (48.19%) 27 (45.76%)
Primary diagnosis 0.7853
DCIS 1 (0.70%) 1 (1.20%) 0 (0.00%)
IDC 125 (88.03%) 72 (86.75%) 53 (89.83%)
IDC/DCIS 1 (0.70%) 1 (1.20%) 0 (0.00%)
IDC/ILC 1 (0.70%) 0 (0.00%) 1 (1.69%)
ILC 14 (9.86%) 9 (10.84%) 5 (8.47%)
Weight at baseline (kg) 0.1526
N 142 83 59
Mean ± SD 71.25 ± 16.04 72.69 ± 15.76 69.23 ± 16.34
Median (inter-quartiles) 69.7 (60.4, 79.2) 70.4 (61.3, 81.4) 67.5 (57.0, 76.9)
Min, max 44.1, 135.0 50.0, 130.0 44.1, 135.0
BMI at baseline (kg/m2) 0.1474
N 142 83 59
Mean ± SD 27.27 ± 5.58 27.76 ± 5.65 26.58 ± 5.44
Min, max 16.5, 48.4 16.5, 45.5 18.8, 48.4
Hemoglobin at baseline (g/L) 0.8198
N 142 83 59
Mean ± SD 131.92 ± 11.48 132.01 ± 11.32 131.78 ± 11.80
WBC at baseline (×109/L) 0.3244
N 142 83 59
Mean ± SD 6.80 ± 2.31 6.99 ± 2.63 6.52 ± 1.75
Min, max 2.7, 23.3 3.0, 23.3 2.7, 10.0
Disease stage at baseline 0.0210
Stage 1 1 (0.70%) 0 (0.00%) 1 (1.69%)
Stage 2 53 (37.32%) 27 (32.53%) 26 (44.07%)
Stage 3 55 (38.73%) 30 (36.14%) 25 (42.37%)
Missing 33 (23.24%) 26 (31.33%) 7 (11.86%)
Chemotherapy regimensb 0.7757
AC-PACLc 55 (38.73%) 34 (40.96%) 21 (35.59%)
FEC-D 60 (42.25%) 32 (38.55%) 28 (47.46%)
DOCETAXCYCLO 24 (16.90%) 15 (18.07%) 9 (15.25%)
TCH 3 (2.11%) 2 (2.41%) 1 (1.69%)
DCIS = ductal carcinoma in situ; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; WBC = white blood cells; BMI = body mass index.
aWilcoxon rank-sum nonparametric test for continuous variables, or Fisher exact test was applied for categorical variables as appropriate. p<0.05 was considered statistically significant.
bDescriptions of abbreviations found in Online Appendix 1.
cDose dense AC- PACL.
First cycle analysis FN events
In the first cycle, two (2%, 95% CI: 0.2-7.0%) Neulasta® patients and four (5.4%, 95% CI: 1.5–13.3%) Lapelga® patients experienced an FN event, and the risk difference (RD) was 3.4% (95% CI: –2.4 to 9.2%), demonstrating non-inferiority of the biosimilar compared to the originator. Mean duration of hospitalization was also similar at 7.5± 0.71 days and 8 ± 1.41 days for Neulasta® and Lapelga® patients, respectively (p = 0.74) (Table 3).
Table 3. First cycle outcomes.
Patients included in the first cycle analysis
Number of patients Total (N = 174) Lapelga® (N = 74) Neulasta® (N = 100) p-value RD (%) 95% CI
Febrile neutropenia (FN) 0.2529 3.41 (−2.43, 9.24)
No 168 (96.55%) 70 (94.59%) 98 (98.00%)
Yes 6 (3.45%) 4 (5.41%) 2 (2.00%)
FN associated hospitalization duration (days) 0.7370 N/A N/A
N 6 4 2
Mean ± SD 7.83 ± 1.17 8.00 ± 1.41 7.50 ± 0.71
Min, Max 6.0, 9.0 6.0, 9.0 7.0, 8.0
Side effect: any pain 0.9892 −0.08 (−0.11, 0.12)
No 141 (81.03%) 60 (81.08%) 81 (81.00%)
Yes 33 (18.97%) 14 (18.92%) 19 (19.00%)
Note: The independent variable in all models was the binary treatment group: Lapelga® vs. Neulasta®. P-value, risk difference (RD) and 95% confidence intervals (CI) were estimated between Lapelga® and Neulasta® treatment groups, except for FN associated Hospitalization Duration. P-value < 0.05 was considered statistically significant.
All-cycle analysis FN events
The occurrence of FN was also analyzed on a cycle per cycle basis. The combined cycle and patient values can be found in Table 4 and specific cycle values can be found in Online Appendix 2. In the whole cycle cohort, first cycle FN rates from those in the full cycle analysis were 2/83 (2.4%) and 3/59 (5.1%) for Neulasta® and Lapelga®, respectively (Online Appendix 2). As the exclusion criteria were stricter than the first cycle analysis cohort, the FN rate differs when compared to the above results. FN was compared at each cycle and all FN events occurred in the first half of the cycles, with 2/3 (66%) and 3/4 (75%) of FN events occurring in the first cycle for Neulasta® and Lapelga®, respectively. One Lapelga® patient experienced an FN event in cycle 2 (1.9%) and one Neulasta® patient experienced an FN event in cycle 3 (1.3%). Overall, 3/515 (0.6%, 95% CI: 0.1–1.7%) of the Neulasta® cycles and 4/322 (1.2%, 95% CI: 0.3–3.2%) of Lapelga® cycles were associated with an FN event. Furthermore, as one patient in the Lapelga® cohort experienced two FN events; 3/83 (3.6%, 95% CI: 0.8–10.2%) Neulasta® patients and 3/59 (5.1%, 95% CI: 1.1–14.2%) Lapelga® patients experienced at least one FN event. The difference between Neulasta® and Lapelga® FN incidence was not statistically significant (RD = 0.6%; 95% CI: –1.0 to 2.1) after adjusting for chemotherapy cycles. Mean duration of hospitalization was also similar (7.5± 0.71 days vs. 7.7±1.5 days for Neulasta® and Lapelga® patients, respectively p = 0.99).
Table 4. Whole cycle outcomes.
Number of patients Total Neulasta® Lapelga® p-valuea
Combined ALL cycles N = 837 N = 515 N = 322
Febrile neutropenia (FN) 0.4384
No 830 (99.16%) 512 (99.42%) 318 (98.76%)
Yes 7 (0.84%) 3 (0.58%) 4 (1.24%)
FN associated hospitalization duration (days) 0.5784
N 7 3 4
Mean ± SD 7.6 ± 1.0 7.3 ± 0.6 7.8 ± 1.3
Min, max 6, 9 7, 8 6, 9
Side effect: any pain 0.3471
No 694 (82.92%) 432 (83.88%) 262 (81.37%)
Yes 143 (17.08%) 83 (16.12%) 60 (18.63%)
Dose delayed 0.8514
No 806 (96.30%) 495 (96.12%) 311 (96.58%)
Yes 31 (3.70%) 20 (3.88%) 11 (3.42%)
No. of days of dose delayed 0.6132
N 31 20 11
Mean ± SD 10.9 ± 10.8 10.90 ± 12.13 11.00 ± 8.52
Min, max 6, 60 6.0, 60.0 6.0, 35.0
Dose reduction 0.0724
No 728 (86.98%) 439 (85.24%) 289 (89.75%)
Yes 109 (13.02%) 76 (14.76%) 33 (10.25%)
%. of dose reduction 0.2537
N 109 76 33
Mean ± SD 20.26 ± 10.08 21.24 ± 11.41 18.00 ± 5.49
Min, max 6.0, 74.6 6.3, 74.6 6.0, 28.1
Patients from ALL cycles N = 142 N = 83 N = 59
Febrile neutropenia (FN) 0.6927
No 136 (95.77%) 80 (96.39%) 56 (94.92%)
Yes 6 (4.23%) 3 (3.61%) 3 (5.08%)
FN associated hospitalization duration (days) 0.8222
N 6 3 3
Mean ± SD 8.8 ± 4.1 7.3 ± 0.6 10.3 ± 5.9
Min, max 6, 17 7, 8 6, 17
Side effect: any pain 0.3971
No 64 (45.07%) 40 (48.19%) 24 (40.68%)
Yes 78 (54.93%) 43 (51.81%) 35 (59.32%)
Dose delayed 0.6772
No 112 (78.87%) 64 (77.11%) 48 (81.36%)
Yes 30 (21.13%) 19 (22.89%) 11 (18.64%)
Total no. of days of dose delayed 0.8358
N 30 19 11
Mean ± SD 11.3 ± 11.0 11.47 ± 12.42 11.00 ± 8.52
Min, max 6.0, 60.0 6.0, 60.0 6.0, 35.0
Dose reduction 0.4635
No 98 (69.01%) 55 (66.27%) 43 (72.88%)
Yes 44 (30.99%) 28 (33.73%) 16 (27.12%)
Max %. of dose reduction 0.5258
N 44 28 16
Mean ± SD 21.82 ± 11.61 23.30 ± 13.86 19.24 ± 5.41
Min, Max 10.0, 74.6 10.0, 74.6 10.4, 28.1
aWilcoxon rank-sum nonparametric test for continuous variables, or Fisher exact test was applied for categorical variables as appropriate. p<0.05 was considered statistically significant.
Dose delays and dose reductions
In the Neulasta® cohort, 34% of patients experienced at least one cycle with a dose reduction, compared to 27% of patients in the Lapelga® cohort. Proportions of DD and DR of the combined cycle and patient values are reported in Table 4 and specific cycle values are reported in Online Appendix 2. When analyzed per cycle (Table 4), 76 (15%) cycles with Neulasta® administration were associated with’ a chemotherapy DR vs 33 (10%) in the Lapelga® cohort (p = 0.072). The mean dose reduction was calculated from the baseline dosage and was 21.2% ± 11.4 and 18% ±5.5 for Neulasta® and Lapelga®, respectively (p = 0.254). In the Neulasta® cohort, 19 (23%) patients experienced at least one delayed cycle compared to 11 (19%) patients in the Lapelga® cohort (p = 0.677). When analyzed based on total cycles (Table 4), 20 (4%) Neulasta® cycles were associated with a DD versus 11 (3.5%) in the Lapelga® cohort (p = 0.851). The average duration of a DD in Neulasta® cohort was 10.9 days (range: 6–60) and 11.0 days (range 6–35) in the Lapelga® cohort (p = 0.613). After adjusting for all chemotherapy cycles, RD between two groups (Lapelga® vs. Neulasta®) was –3.6% (95% CI: –10.2% to 2.9%) for chemotherapy DR, and –0.3% (95% CI: –2.7% to 2.0%) for DD (Table 5).
Table 5. Comparing each of endpoints between Lapelga® and Neulasta® in total analysis, after adjusting for chemotherapy cycles.
Patients included in the whole cycle analysis
Endpoints p-valuea RD 95% CI
FN (Yes vs. no) 0.4751 0.56 (−0.98, 2.09)
FN associated hospitalization duration (days) 0.9935 N/A N/A
Any pain (yes vs. no) 0.5291 2.36 (−4.99, 9.72)
Dose delayed (yes vs. no) 0.7901 –0.32 (−2.68, 2.04)
Number of days of dose delayed 0.8818 N/A N/A
Dose reductions (yes vs. no) 0.2756 −3.63 (−10.15, 2.90)
% of dose reductions 0.1376 N/A N/A
FN= Febrile Neutropenia; RD=risk difference between Lapelga® and Neulasta®; CI=confidence interval.
aP-value was obtained by GEE model for this longitudinal data in the whole cycles’ analysis, after adjusting for chemotherapy cycles.
Safety analysis: Reported pain
The occurrence of patient-reported bone, joint and/or muscle pain were reviewed, but due to the ambiguity of many pain descriptions, these indicators were grouped into overall pain. In the first cycle only (Table 3), 14/74 (19%) Lapelga® patients and 19/100 (19%) of Neulasta® patients experienced pain. The RD was not statistically significant (RD -0.08%; 95%CI; –0.11, 0.12). The prevalence of pain was also reported on a per-cycle basis in Online Appendix 2. In the full cycle analysis, in the Neulasta® cohort, 43 (52%) patients experienced at least one pain event compared to 35 (59%) of patients in the Lapelga® cohort. When analyzed with regards to the total cycles received, 83/515 (16%) cycles with Neulasta® administration was associated with pain vs 60/322 (19%) in the Lapelga® cohort (RD = 2.4%, 95% CI: –5.0 to 9.7, p = 0.53) after adjusting for chemotherapy cycles (Tables 4 and 5). Pain was comparable between the two groups as well (19.0% vs 18.9%, for Neulasta® and Lapelga®, respectively; RD = –0.1%, p = 0.99).
Cost minimization
Direct costs of the drugs were compared between Lapelga® and Neulasta®. Direct and indirect costs concerning FN management were not incorporated into the model given the lack of statistically significant difference in this cohort with respect to these rates, DR, DD, and toxicities that could impact quality of life. In the base case, the incremental cost savings of using Lapelga® was $1,080.34 per cycle per patient. In the sensitivity analysis, Neulasta® was favored over Lapelga® if there was a discount in Neulasta® price by at least 56.87% from base case (Figure 2). In a cohort of 20,000 patients using base case price this would translate into an incremental savings of $21,606,800 for each cycle in favour of Lapelga® if there was 100% adoption of biosimilar Lapelga® over Neulasta® (Figure 3).
Figure 2. Incremental cost savings per-patient of Lapelga® versus Neulasta® per cycle of chemotherapy in adjuvant or neoadjuvant setting for early or locally advanced breast cancer.
Figure 3. Cost of GCSF (Lapelga® or Neulasta®) for single chemotherapy cycle in cohort (N=20,000 patients).
Matched analysis
A one-to-one matched sensitivity analysis was completed on all data reported above. The demographics of the matched sensitivity analysis can be found in Online Appendix 3.1 and the results of this matched analysis can be found in Online Appendix 3.2. No statistically significant differences were found, and the matched analysis outcomes did not alter the study results.
Discussion
In this real-world clinical setting study, the non-inferiority of the biosimilar pegfilgrastim to the reference product was demonstrated based on the occurrence of FN in cycle 1. This single-institution, retrospective chart review provided a head-to-head analysis showing clinical comparability of the biosimilar using FN rates, in addition to the duration of hospitalization and chemotherapy DD and DR. These results add to the breadth of research investigating the efficacy and safety of biosimilar growth factors using observational data obtained outside the context of randomized controlled trials. This study’s findings will further strengthen the existing evidence in relation to real-world clinical reports on biosimilar pegfilgrastim and can aid in improving physician confidence in its continued adoption.
The analytical approach of this study was two-part; first-cycle and all-cycle analyses were conducted, where the former was used as the primary endpoint given that the first cycle has been associated with the highest risk for FN.27–29 Jurczak et al. reported FN outcomes in 1,006 lung, breast, ovarian, Hodgkin’s lymphoma and Non-Hodgkin’s lymphoma patients, where 50% of all FN events occurred in the first cycle. 27 In predicting an elevated risk of FN during first cycle treatment, rates are consistently higher during the first 10–20 days after chemotherapy initiation. 28 The overall combined FN rate was 3.5% for first cycle analysis and 0.84% for any cycle; therefore, 85% of all FN events in the combined study analysis occurred in cycle 1.
Primary prophylaxis with G-CSF in patients receiving systemic chemotherapy has been associated with improved dose intensity and risk reductions in all-cause mortality as well as infection-related mortality.30,31 The secondary objectives of this study were, therefore, indicative of the more common consequences of neutropenia that compromise the efficacy of chemotherapy delivered given the association between reductions in relative dose intensity and overall survival outcomes. The percentage of patients that experienced a DR was not statistically significantly different between the two cohorts. In evaluating chemotherapy DD and DR and their impact on cancer cure rates, Denduluri et al. 2018 reported no significant association between DD and overall survival, while DR had a more profound impact in breast cancer patients (HR = 1.24; 95% CI: 1.03–1.48; p = 0.020). 32 Similarly, a 2019 Canadian based study by Veitch et al. consisting of 1,302 breast cancer patients showed those receiving ≥ 85% of the prescribed dose had superior overall survival (OS) at 5 years. 33
For over two decades, G-CSFs have been the mainstay of the treatment and prevention of chemotherapy-induced neutropenia complications, however, the high cost of G-CSF agents may limit access for some patients. 15 With the current evidence that both pegfilgrastim agents were equally efficacious and with a similar safety profile, cost minimization analysis was justified to determine the cost-savings benefit of Lapelga®. The incremental cost savings of using Lapelga® as an alternative to branded pegfilgrastim was $1080.34 per-patient drug costs each cycle. A variety of interrelated factors influence the development, uptake, and cost-savings for biosimilar use, with lower price helping address escalating healthcare costs in oncology. Increasing the rate of adoption would result in large cost savings, as the results of this study report an incremental savings of $21,606,800 for each cycle in favour of Lapelga® if there was 100% adoption of biosimilar Lapelga® over Neulasta® in 20,000 patients. To add to this point, a study by Mansell et al. retrospectively analyzed Canadian drug purchases of three biosimilars and their reference biologics between 2016 and 2018. This study reported varying purchasing ranges of biosimilars between 0.1% and 81.6% and found that in two years, if biosimilars were used 100%, there would be $1.05 billion of savings across the country, with $349 million of savings coming from Ontario. 24 Thus, the pegfilgrastim biosimilar can help reduce health care expenditure.
Moreover, a future consideration regarding biosimilars includes the perception of physicians and patients toward biosimilars. A recent systematic review evaluated 23 studies, which reported clear inconsistencies and existing gaps in physician knowledge plus concerns in comfort level with biosimilars. 34 Studies evaluating patient health literacy have also found low awareness of biosimilars in general. 35 Targeted education on these agents could help increase comfort and knowledge to help improve adoption rates.
Although RCTs are highly regarded for assessments of safety and efficacy, strict eligibility criteria and the overall nature of being on a study versus community-based practise has been observed to decrease the prevalence of FN. 36 Thus, real-world studies are of benefit to areas of literature regarding FN rates and G-CSF prophylaxis. Based on reported differences often arising between the controlled trial setting and actual clinical practice, the analysis of real-world data with respect to G-CSF prophylaxis continues to play a role in understanding the impact of FN as well as different patient, disease, and treatment-related risk factors on its severity.
Some strengths of this study include the nature of observational studies’ ability to account for potential underrepresentation of older patient groups and patients with comorbidities not typical enrolled in clinical trials. Patient characteristics were consistent between groups and a matched sensitivity analysis was applied to further evaluate the potential impact of patient and treatment-related factors on FN outcomes, which did not change the overall conclusion of the study. A retrospective review provides important insights into actual clinical practice use of biosimilar pegfilgrastim. However, due to reliance upon electronic health records, if the outcome was not recorded, it was assumed that it did not occur. One example being DR and DD, as the reasons for their occurrence were not always explicitly recorded and could be due to reasons unrelated to neutropenia. DD and DR being unrelated to neutropenia could potentially pose as confounders. However, since this is true for both cohorts, this outcome remains clinically relevant in investigating the efficacy of supportive care. There were also limitations in the determination of pain as there was no quantitative value to distinguish the degree or duration of pain experienced, as well as the improvement or worsening of pain throughout cycle progression. This study consisted of breast cancer patients undergoing neoadjuvant or adjuvant intent only, thus, the generalizability of results is limited to this patient population. Additionally, the results showed a significant difference in demographics with respect to disease stage. Although this may be explained by the higher number of missing data in Neulasta® vs Lapelga® samples, analyzing a homogenous patient cohort is recommended to enhance the clinical comparability exercise for biosimilars, ideally with all patients of similar disease stage receiving the same chemotherapy regimen.
Conclusion
The findings of this retrospective real-world clinical study in breast cancer patients demonstrated non-inferiority of biosimilar pegfilgrastim and reference product concerning FN incidence in the first cycle. These findings support previously documented literature regarding the safety and efficacy of biosimilars. In cost minimization analysis, the incremental cost savings of Lapelga® over Neulasta® was $1080.34 per cycle and further highlights the benefits to health system budgets associated with increasing the adoption of this biosimilar. With clinically comparable safety and efficacy, biosimilar pegfilgrastim could increase patient access to supportive care while decreasing health-related costs. Further studies comparing the two products in different patient subpopulations would extend future findings. As more biosimilar agents enter the market, continuing research is needed to assess the drug uptake, clinical outcomes, and the extent of realized cost savings.
Supplemental Material
sj-pdf-1-opp-10.1177_1078155220974085 - Supplemental material for A retrospective review of the real-world experience of the Pegfilgrastim biosimilar (Lapelga®) to the reference biologic (Neulasta®)
Click here for additional data file.
Supplemental material, sj-pdf-1-opp-10.1177_1078155220974085 for A retrospective review of the real-world experience of the Pegfilgrastim biosimilar (Lapelga®) to the reference biologic (Neulasta®) by Gina Wong, Liying Zhang, Habeeb Majeed, Yasmeen Razvi, Carlo DeAngelis, Emily Lam, Erin McKenzie, Katie Wang and Mark Pasetka in Journal of Oncology Pharmacy Practice
Acknowledgement
Dr Mark Pasetka is the Principal Investigator and Senior Author of this project.
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.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Gina Wong https://orcid.org/0000-0002-5093-4181
Supplemental material: Supplemental material for this article is available online. | PEGFILGRASTIM | DrugsGivenReaction | CC BY-NC | 33215563 | 18,558,932 | 2022-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pain'. | A retrospective review of the real-world experience of the Pegfilgrastim biosimilar (Lapelga®) to the reference biologic (Neulasta®).
BACKGROUND
Cancer patients receiving myelosuppressive chemotherapy are vulnerable to febrile neutropenia (FN) which contributes to poor treatment outcomes. The use of granulocyte colony-stimulating factors is administered to prevent chemotherapy-induced neutropenia. The introduction of biosimilars has allowed for greater cost-savings while maintaining safety and efficacy. This retrospective study assessed the incidence of FN and related treatment outcomes and the cost minimization of a pegfilgrastim biosimilar and its reference.
METHODS
A retrospective chart review of breast cancer patients receiving (neo) adjuvant chemotherapy from February 2017 to May 2020 was conducted. The endpoints included the incidence of FN, the occurrence of dose reduction (DR), dose delay (DD) and pain. A cost minimization analysis was performed from a third-party payer perspective.
RESULTS
One hundred Neulasta® and 74 Lapelga® patients were included in the first-cycle analysis. The rate of FN in cycle 1 for Neulasta® and Lapelga® was 2/100 and 4/74, respectively; risk difference (RD) = 3.4%; 95% CI: -2.4 to 9.2%. Eighty-three Neulasta® and 59 Lapelga® patients were included in the all-cycle analyses, where DR was reported in 76 (15%) Neulasta® cycles vs 33 (10%) Lapelga® cycles (RD = -3.6, 95% CI: -10.2 to 2.9). DD was reported in 20 (4%) Neulasta® cycles vs. 11 (3.5%) Lapelga® cycles (RD = -0.3; 95% CI: -2.7 to 2.0). Adverse events were similar between groups. Cost minimization using a cohort of 20,000 patients translated into an incremental savings of $21,606,800 CAD for each cycle.
CONCLUSIONS
The biosimilar pegfilgrastim was non-inferior to the reference biologic based on FN incidence in addition to related outcomes including DR and DD.
pmcIntroduction
Febrile neutropenia (FN) is considered the most serious dose-limiting toxicity of myelosuppressive chemotherapy, as it both increases the immediate risk of infection and limits the delivery of chemotherapy, leading to suboptimal levels of long-term treatment success. 1 It is often defined as an absolute neutrophil count (ANC) less than 0.5 x 109 cells/L (or the expectation that it will fall to <0.5 x 109 cells/L) with a single oral temperature of ≥38.3°C or two consecutive readings of ≥38.0°C for more than one or two hours.2,3 In the acute setting, FN often results in emergency hospitalization requiring antibiotic treatment to avoid fatal consequences, including sepsis. 4 Furthermore, severe or prolonged neutropenia impacts the achievement of target dose intensity and commonly necessitates chemotherapy dose reductions (DR) and delays (DD).5,6 DDs, DRs, and discontinuation of chemotherapy decrease the overall efficacy of this treatment, adversely impacting cancer survival outcomes.5,7 Not only does FN increase morbidity and mortality, but it also results in a substantial economic burden due to hospitalization costs.8–10
FN incidence can be lowered through the use of granulocyte colony-stimulating factors (G-CSFs) to reduce the severity and duration of neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs.11,12 Current practise guidelines recommend the use of G-CSF agents with chemotherapy regimens associated with elevated FN risk of greater than 20% or those of intermediate risk (10–20%) if they present with additional individual risk factors (age, performance status, previous history of FN).3,6,13 Recombinant G-CSFs are available as short- and long-acting forms, which differ in requiring a weight-based, daily-dosing schedule versus a fixed-dose, administered once-per cycle schedule, respectively. A pegylated variant of the short-acting filgrastim, pegfilgrastim, possesses the same mechanism of action but has a longer half-life. Pegfilgrastim levels are self-regulating which allows for clearance only when the neutrophil count increases sufficiently beyond the absolute neutrophil count nadir and growth factor support is no longer required.12,14 Experimental and real-world studies suggest that pegfilgrastim may provide more effective prophylaxis against FN when compared to filgrastim.14–18 Pegfilgrastim is intended to improve treatment adherence due to the need for fewer administrations and has demonstrated better maintenance of relative dose intensity and reduced hospital visits in comparative effectiveness studies.14,17,19
While G-CSF biologics are important for the prophylaxis of FN, they have been identified as significant drivers of global healthcare costs. 20 Biosimilars are lower-cost versions of previously approved reference biologics that must demonstrate high similarity to an authorized reference product in terms of molecular characterisation, purity, stability, pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity.21,22 Biosimilars intend to decrease the costs associated with high-priced biologics and their implementation has conferred significant cost savings. 20 Furthermore, the use of biosimilars has potential to increase patient access to treatment through direct reduction of health systems costs.23,24
The pegfilgrastim biosimilar, (Lapelga®, Apobiologix, Toronto, ON) was the first pegfilgrastim biosimilar approved in a major global market, initially approved by Health Canada in 2018.25,26 The aim of this real-world clinical study was to assess the safety and efficacy of the pegfilgrastim biosimilar, Lapelga® versus the reference pegfilgrastim (Neulasta®, Amgen, Thousand Oaks, CA, USA). in primary prophylaxis of FN in breast cancer patients receiving myelosuppressive, (neo) adjuvant chemotherapy.
Methods
Patient population
This single-center, retrospective, cohort study was approved by the institutional research ethics board [REB #2429]. A manual chart review of all breast cancer patients receiving cytotoxic chemotherapy with G-CSF support from February 2017 to May 2020 was conducted. Included patients were treated with neoadjuvant or adjuvant chemotherapy and were administered G-CSF primary prophylaxis with either pegfilgrastim product. Patient characteristics (age, BMI), pathology (tumour stage, tumour morphology), and treatment characteristics (chemotherapy regimen, treatment intent) were collected. Across all cycles, the incidence of FN, DD, DR, and adverse events associated with the use of G-CSF agent (specifically bone, joint, and muscle pain) were evaluated. Any DD and DR were collected. DDs were defined as a delay in treatment of six or more days and DR were defined as any reduction in dosage of one or more chemotherapy agents when compared to baseline dosage. The incidence of first cycle and all-cycle FN requiring hospitalization plus chemotherapy DD and DR were analyzed independently in both cohorts. The general guidelines for FN diagnosis and standards of care directing G-CSF prophylaxis remained consistent throughout the duration of the study period. The occurrence of bone, joint and/or muscle pain were collected individually, but due to the ambiguity of many pain descriptions, these indicators were grouped into an overall assessment of pain for the analysis.
Patients were excluded if they had a primary cancer other than in the breast, were receiving palliative treatment, had previous chemotherapy, or had begun their chemotherapy with a short-acting G-CSF. Patients were further excluded from the all-cycle analysis if they had prematurely stopped their chemotherapy for a reason other than FN, received secondary G-CSF prophylaxis, switched their chemotherapy or were receiving a weekly treatment regimen. Subjects who switched their G-CSF product or discontinued its usage were still included in the analysis up until their switch. Although the product monograph of both G-CSF products state that it should not be used within 14 days of chemotherapy, it was still administered for patients given treatment every14-days. This simply reflects the real-world practice of medical oncologists at our centre. Patients were instructed to administer G-CSF the next day following the chemotherapy treatment by at least 24 hours.
Endpoints
The primary endpoint was the incidence of FN, which was comparatively assessed as the risk difference between the Neulasta® and Lapelga® cohorts. As FN commonly presents in the first cycle,27–29 the incidence of FN events in the first cycle was the primary endpoint.
Secondary endpoints included FN event throughout the entire course of chemotherapy, length of hospitalization, chemotherapy DR and DD incidence, as well as the magnitude of the DR (compared to baseline) and DD as a deviation ≥ 6 days from the recommended dose scheduling for the prescribed regimen. The incidence of adverse events related to G-CSF usage was restricted to investigating bone pain that was determined by patient-reported cases of pain. Cost minimization was performed to record the incremental cost savings of implementing Lapelga® into a health care setting in Canadian currency.
Statistical analysis
Demographics of patients included in the first and total cycle analysis were summarized using mean, standard deviation (SD), median, inter-quartiles, and range for continuous variables, and proportions for categorical variables. To compare demographics between Lapelga® and Neulasta® patients, Wilcoxon rank-sum nonparametric test or Fisher exact test was applied for continuous or categorical variables as appropriate. The primary objective of non-inferiority of the biosimilar vs reference biologic was evaluated for the rate of FN in cycle 1 and for total cycles, where the risk difference (RD) in the rate of FN with 95% confidence intervals (CI) was reported. The non-inferiority margin was set at 15% for the absolute risk difference in the FN rate between treatments. Non-inferiority was met if the upper limit of 95% CI was <15%.
To compare the incidence of FN, side effect of any pain, DD, and DR between Lapelga® and Neulasta® treatment group in the whole cycles’ analysis, generalized estimating equation (GEE) models were conducted, and a binomial distribution with logit link function were specified in the GEE models. For the duration of FN-associated hospitalization in days, number of days delayed, and percent of reductions, a Poisson distribution with log link function were specified in the GEE model. All models were fit using an exchangeable correlation structure, the independent variables included the binary treatment group (Lapelga® vs. Neulasta®) and chemotherapy cycles (1–8). P-value, RD and 95% confidence intervals (CI) were estimated for each binary endpoint.
Matched analysis was done using one-to-one patient comparators between two treatment groups using age and chemotherapy regimens. For instance, patients were first matched based on chemotherapy regimen and then were matched based on age ± 5 years, then age ± 10 years. Any patient who was not matched would be excluded in the matched analysis. All analyses were conducted using Statistical Analysis Software (SAS version 9.4, Cary, NC). P-value < 0.05 was considered statistically significant.
Cost minimization
A cost minimization analysis was performed from a third-party payer perspective. The base case cost for Lapelga® ($1,424.63 for 6 mg/0.6 mL dose) was obtained from the Ontario Drug Benefit formulary accessed June 22, 2020 and the cost for Neulasta® ($2,504.97 for 6 mg/0.6 mL dose) was obtained from CADTH Submission for Lapelga®. The base case model was computed in Microsoft Excel 2016 (Microsoft, USA) using a hypothetical cohort of 20,000 patients receiving third-generation anthracycline-based chemotherapy in a neoadjuvant or adjuvant setting for early or locally advanced breast cancer. Sensitivity analysis was performed evaluating how costs would vary if the established reference was changed from Neulasta® to Lapelga®. The incremental cost difference was also evaluated if the price of the aforementioned drugs was discounted between 15–35%. Given that the time horizon of the model was under one year, no global discounting was utilized.
Results
Patient demographics
One hundred and twenty-nine patients who had received the reference pegfilgrastim and 93 patients who had received the biosimilar were screened (Figure 1). After applying the inclusion and exclusion criteria, 100 Neulasta® patients and 74 Lapelga® patients were eligible for the cycle-1 chemotherapy analysis. For all-cycle analysis, 83 Neulasta® and 59 Lapelga® patients were included, representing a total of 837 cycles, 515 being the originator and 322 being the biosimilar.
Figure 1. Exclusion criteria used to determine cohorts. *Patients who had Lapelga® or Neulasta® for their first cycle and then were switched to a different GCSF during a portion of their cycle were included in the complete analysis up until the point they switched.
Patient demographics and treatment characteristics were relatively well balanced between the two treatment groups. The demographics are summarized in two separate tables: Table 1 shows the demographics for patients included in the first cycle analysis and Table 2 shows demographics for patients included in the total-cycle analysis. Online Appendix 1 describes the chemotherapy drugs administered during each cycle in common breast chemotherapy treatment regimens. There were no significant differences between the Lapelga® and Neulasta® patients in age, chemotherapy treatment intent, primary diagnosis, body mass index (BMI), baseline hemoglobin levels, baseline white blood cell count, and chemotherapy regimen. However, the weight and BMI were numerically slightly different, as the Neulasta® group had a slightly higher BMI and weight, but this difference was not significant. There was a significant difference in disease stage at baseline with Lapelga® having a greater proportion of patients with a higher stage (p = 0.021) in the all-cycle analysis group, but this difference did not meet the threshold of statistical significance in the first cycle analysis group (p = 0.0562).
Table 1. Demographics of patients included in the first cycle analysis.
Number of patients Total (N = 174) Neulasta® (N = 100) Lapelga® (N = 74) p-valuea
Age (years) 0.3451
N 174 100 74
Mean ± SD 50.77 ± 10.64 49.94 ± 9.92 51.89 ± 11.52
Median (inter-quartiles) 50.0 (44.0, 58.0) 50.0 (43.5, 57.0) 51.0 (44.0, 60.0)
Min, Max 21.0, 78.0 21.0, 71.0 27.0, 78.0
Age categories (years) 0.2536
<40 26 (14.94%) 17 (17.00%) 9 (12.16%)
40–<50 52 (29.89%) 28 (28.00%) 24 (32.43%)
50–<60 59 (33.91%) 38 (38.00%) 21 (28.38%)
≥60 37 (21.26%) 17 (17.00%) 20 (27.03%)
Chemotherapy intent 0.8786
Adjuvant 90 (51.72%) 51 (51.00%) 39 (52.70%)
Neoadjuvant 84 (48.28%) 49 (49.00%) 35 (47.30%)
Primary diagnosis 0.4791
DCIS 1 (0.57%) 1 (1.00%) 0 (0.00%)
IDC 155 (89.08%) 87 (87.00%) 68 (91.89%)
IDC/DCIS 1 (0.57%) 1 (1.00%) 0 (0.00%)
IDC/ILC 1 (0.57%) 0 (0.00%) 1 (1.35%)
ILC 16 (9.20%) 11 (11.00%) 5 (6.76%)
Weight at baseline (kg) 0.0819
N 174 100 74
Mean ± SD 71.30 ± 17.45 73.31 ± 18.34 68.59 ± 15.90
Min, max 40.5, 165.9 42.5, 165.9 40.5, 135.0
BMI at baseline (kg/m2) 0.1411
N 174 100 74
Mean ± SD 27.28 ± 6.14 27.89 ± 6.75 26.45 ± 5.15
Min, max 16.5, 66.5 16.5, 66.5 18.5, 48.4
Hemoglobin at baseline (g/L) 0.6303
N 174 100 74
Mean ± SD 131.93 ± 11.50 131.60 ± 11.68 132.38 ± 11.31
Min, max 90.0, 159.0 90.0, 159.0 94.0, 158.0
WBC at baseline (×109/L) 0.1276
N 173 99 74
Mean ± SD 6.83 ± 2.24 7.07 ± 2.52 6.51 ± 1.75
Min, max 2.7, 23.3 3.0, 23.3 2.7, 10.9
Disease stage at baseline 0.0562
Stage 1 2 (1.15%) 1 (1.00%) 1 (1.35%)
Stage 2 58 (33.33%) 30 (30.00%) 28 (37.84%)
Stage 3 74 (42.53%) 39 (39.00%) 35 (47.30%)
Missing 40 (22.99%) 30 (30.00%) 10 (13.51%)
Chemotherapy regimensb 0.9130
AC-PACLc 84 (48.28%) 49 (49.00%) 35 (47.30%)
FEC-D 61 (35.06%) 33 (33.00%) 28 (37.84%)
DOCETAXCYCLO 26 (14.94%) 16 (16.00%) 10 (13.51%)
TCH 3 (1.72%) 2 (2.00%) 1 (1.35%)
DCIS = ductal carcinoma in situ; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; WBC = white blood cells; BMI = body mass index.
aWilcoxon rank-sum nonparametric test for continuous variables, or Fisher exact test was applied for categorical variables as appropriate. p<0.05 was considered statistically significant. Bold values indicate significance.
bDescriptions of abbreviations found in Online Appendix 1.
cDose dense AC- PACL.
Table 2. Demographics of patients included in the whole cycle analysis.
Number of patients Total (N = 142) Neulasta® (N = 83) Lapelga® (N = 59) p-valuea
Age (years) 0.7893
N 142 83 59
Mean ± SD 50.63 ± 10.66 50.14 ± 10.20 51.31 ± 11.32
Median (inter-quartiles) 50.0 (44.0, 58.0) 51.0 (46.0, 57.0) 50.0 (44.0, 60.0)
Min, max 21.0, 78.0 21.0, 71.0 27.0, 78.0
Age categories (years) 0.1816
<40 22 (15.49%) 15 (18.07%) 7 (11.86%)
40–<50 41 (28.87%) 20 (24.10%) 21 (35.59%)
50–<60 49 (34.51%) 33 (39.76%) 16 (27.12%)
≥60 30 (21.13%) 15 (18.07%) 15 (25.42%)
Chemotherapy intent 0.8649
Adjuvant 75 (52.82%) 43 (51.81%) 32 (54.24%)
Neoadjuvant 67 (47.18%) 40 (48.19%) 27 (45.76%)
Primary diagnosis 0.7853
DCIS 1 (0.70%) 1 (1.20%) 0 (0.00%)
IDC 125 (88.03%) 72 (86.75%) 53 (89.83%)
IDC/DCIS 1 (0.70%) 1 (1.20%) 0 (0.00%)
IDC/ILC 1 (0.70%) 0 (0.00%) 1 (1.69%)
ILC 14 (9.86%) 9 (10.84%) 5 (8.47%)
Weight at baseline (kg) 0.1526
N 142 83 59
Mean ± SD 71.25 ± 16.04 72.69 ± 15.76 69.23 ± 16.34
Median (inter-quartiles) 69.7 (60.4, 79.2) 70.4 (61.3, 81.4) 67.5 (57.0, 76.9)
Min, max 44.1, 135.0 50.0, 130.0 44.1, 135.0
BMI at baseline (kg/m2) 0.1474
N 142 83 59
Mean ± SD 27.27 ± 5.58 27.76 ± 5.65 26.58 ± 5.44
Min, max 16.5, 48.4 16.5, 45.5 18.8, 48.4
Hemoglobin at baseline (g/L) 0.8198
N 142 83 59
Mean ± SD 131.92 ± 11.48 132.01 ± 11.32 131.78 ± 11.80
WBC at baseline (×109/L) 0.3244
N 142 83 59
Mean ± SD 6.80 ± 2.31 6.99 ± 2.63 6.52 ± 1.75
Min, max 2.7, 23.3 3.0, 23.3 2.7, 10.0
Disease stage at baseline 0.0210
Stage 1 1 (0.70%) 0 (0.00%) 1 (1.69%)
Stage 2 53 (37.32%) 27 (32.53%) 26 (44.07%)
Stage 3 55 (38.73%) 30 (36.14%) 25 (42.37%)
Missing 33 (23.24%) 26 (31.33%) 7 (11.86%)
Chemotherapy regimensb 0.7757
AC-PACLc 55 (38.73%) 34 (40.96%) 21 (35.59%)
FEC-D 60 (42.25%) 32 (38.55%) 28 (47.46%)
DOCETAXCYCLO 24 (16.90%) 15 (18.07%) 9 (15.25%)
TCH 3 (2.11%) 2 (2.41%) 1 (1.69%)
DCIS = ductal carcinoma in situ; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; WBC = white blood cells; BMI = body mass index.
aWilcoxon rank-sum nonparametric test for continuous variables, or Fisher exact test was applied for categorical variables as appropriate. p<0.05 was considered statistically significant.
bDescriptions of abbreviations found in Online Appendix 1.
cDose dense AC- PACL.
First cycle analysis FN events
In the first cycle, two (2%, 95% CI: 0.2-7.0%) Neulasta® patients and four (5.4%, 95% CI: 1.5–13.3%) Lapelga® patients experienced an FN event, and the risk difference (RD) was 3.4% (95% CI: –2.4 to 9.2%), demonstrating non-inferiority of the biosimilar compared to the originator. Mean duration of hospitalization was also similar at 7.5± 0.71 days and 8 ± 1.41 days for Neulasta® and Lapelga® patients, respectively (p = 0.74) (Table 3).
Table 3. First cycle outcomes.
Patients included in the first cycle analysis
Number of patients Total (N = 174) Lapelga® (N = 74) Neulasta® (N = 100) p-value RD (%) 95% CI
Febrile neutropenia (FN) 0.2529 3.41 (−2.43, 9.24)
No 168 (96.55%) 70 (94.59%) 98 (98.00%)
Yes 6 (3.45%) 4 (5.41%) 2 (2.00%)
FN associated hospitalization duration (days) 0.7370 N/A N/A
N 6 4 2
Mean ± SD 7.83 ± 1.17 8.00 ± 1.41 7.50 ± 0.71
Min, Max 6.0, 9.0 6.0, 9.0 7.0, 8.0
Side effect: any pain 0.9892 −0.08 (−0.11, 0.12)
No 141 (81.03%) 60 (81.08%) 81 (81.00%)
Yes 33 (18.97%) 14 (18.92%) 19 (19.00%)
Note: The independent variable in all models was the binary treatment group: Lapelga® vs. Neulasta®. P-value, risk difference (RD) and 95% confidence intervals (CI) were estimated between Lapelga® and Neulasta® treatment groups, except for FN associated Hospitalization Duration. P-value < 0.05 was considered statistically significant.
All-cycle analysis FN events
The occurrence of FN was also analyzed on a cycle per cycle basis. The combined cycle and patient values can be found in Table 4 and specific cycle values can be found in Online Appendix 2. In the whole cycle cohort, first cycle FN rates from those in the full cycle analysis were 2/83 (2.4%) and 3/59 (5.1%) for Neulasta® and Lapelga®, respectively (Online Appendix 2). As the exclusion criteria were stricter than the first cycle analysis cohort, the FN rate differs when compared to the above results. FN was compared at each cycle and all FN events occurred in the first half of the cycles, with 2/3 (66%) and 3/4 (75%) of FN events occurring in the first cycle for Neulasta® and Lapelga®, respectively. One Lapelga® patient experienced an FN event in cycle 2 (1.9%) and one Neulasta® patient experienced an FN event in cycle 3 (1.3%). Overall, 3/515 (0.6%, 95% CI: 0.1–1.7%) of the Neulasta® cycles and 4/322 (1.2%, 95% CI: 0.3–3.2%) of Lapelga® cycles were associated with an FN event. Furthermore, as one patient in the Lapelga® cohort experienced two FN events; 3/83 (3.6%, 95% CI: 0.8–10.2%) Neulasta® patients and 3/59 (5.1%, 95% CI: 1.1–14.2%) Lapelga® patients experienced at least one FN event. The difference between Neulasta® and Lapelga® FN incidence was not statistically significant (RD = 0.6%; 95% CI: –1.0 to 2.1) after adjusting for chemotherapy cycles. Mean duration of hospitalization was also similar (7.5± 0.71 days vs. 7.7±1.5 days for Neulasta® and Lapelga® patients, respectively p = 0.99).
Table 4. Whole cycle outcomes.
Number of patients Total Neulasta® Lapelga® p-valuea
Combined ALL cycles N = 837 N = 515 N = 322
Febrile neutropenia (FN) 0.4384
No 830 (99.16%) 512 (99.42%) 318 (98.76%)
Yes 7 (0.84%) 3 (0.58%) 4 (1.24%)
FN associated hospitalization duration (days) 0.5784
N 7 3 4
Mean ± SD 7.6 ± 1.0 7.3 ± 0.6 7.8 ± 1.3
Min, max 6, 9 7, 8 6, 9
Side effect: any pain 0.3471
No 694 (82.92%) 432 (83.88%) 262 (81.37%)
Yes 143 (17.08%) 83 (16.12%) 60 (18.63%)
Dose delayed 0.8514
No 806 (96.30%) 495 (96.12%) 311 (96.58%)
Yes 31 (3.70%) 20 (3.88%) 11 (3.42%)
No. of days of dose delayed 0.6132
N 31 20 11
Mean ± SD 10.9 ± 10.8 10.90 ± 12.13 11.00 ± 8.52
Min, max 6, 60 6.0, 60.0 6.0, 35.0
Dose reduction 0.0724
No 728 (86.98%) 439 (85.24%) 289 (89.75%)
Yes 109 (13.02%) 76 (14.76%) 33 (10.25%)
%. of dose reduction 0.2537
N 109 76 33
Mean ± SD 20.26 ± 10.08 21.24 ± 11.41 18.00 ± 5.49
Min, max 6.0, 74.6 6.3, 74.6 6.0, 28.1
Patients from ALL cycles N = 142 N = 83 N = 59
Febrile neutropenia (FN) 0.6927
No 136 (95.77%) 80 (96.39%) 56 (94.92%)
Yes 6 (4.23%) 3 (3.61%) 3 (5.08%)
FN associated hospitalization duration (days) 0.8222
N 6 3 3
Mean ± SD 8.8 ± 4.1 7.3 ± 0.6 10.3 ± 5.9
Min, max 6, 17 7, 8 6, 17
Side effect: any pain 0.3971
No 64 (45.07%) 40 (48.19%) 24 (40.68%)
Yes 78 (54.93%) 43 (51.81%) 35 (59.32%)
Dose delayed 0.6772
No 112 (78.87%) 64 (77.11%) 48 (81.36%)
Yes 30 (21.13%) 19 (22.89%) 11 (18.64%)
Total no. of days of dose delayed 0.8358
N 30 19 11
Mean ± SD 11.3 ± 11.0 11.47 ± 12.42 11.00 ± 8.52
Min, max 6.0, 60.0 6.0, 60.0 6.0, 35.0
Dose reduction 0.4635
No 98 (69.01%) 55 (66.27%) 43 (72.88%)
Yes 44 (30.99%) 28 (33.73%) 16 (27.12%)
Max %. of dose reduction 0.5258
N 44 28 16
Mean ± SD 21.82 ± 11.61 23.30 ± 13.86 19.24 ± 5.41
Min, Max 10.0, 74.6 10.0, 74.6 10.4, 28.1
aWilcoxon rank-sum nonparametric test for continuous variables, or Fisher exact test was applied for categorical variables as appropriate. p<0.05 was considered statistically significant.
Dose delays and dose reductions
In the Neulasta® cohort, 34% of patients experienced at least one cycle with a dose reduction, compared to 27% of patients in the Lapelga® cohort. Proportions of DD and DR of the combined cycle and patient values are reported in Table 4 and specific cycle values are reported in Online Appendix 2. When analyzed per cycle (Table 4), 76 (15%) cycles with Neulasta® administration were associated with’ a chemotherapy DR vs 33 (10%) in the Lapelga® cohort (p = 0.072). The mean dose reduction was calculated from the baseline dosage and was 21.2% ± 11.4 and 18% ±5.5 for Neulasta® and Lapelga®, respectively (p = 0.254). In the Neulasta® cohort, 19 (23%) patients experienced at least one delayed cycle compared to 11 (19%) patients in the Lapelga® cohort (p = 0.677). When analyzed based on total cycles (Table 4), 20 (4%) Neulasta® cycles were associated with a DD versus 11 (3.5%) in the Lapelga® cohort (p = 0.851). The average duration of a DD in Neulasta® cohort was 10.9 days (range: 6–60) and 11.0 days (range 6–35) in the Lapelga® cohort (p = 0.613). After adjusting for all chemotherapy cycles, RD between two groups (Lapelga® vs. Neulasta®) was –3.6% (95% CI: –10.2% to 2.9%) for chemotherapy DR, and –0.3% (95% CI: –2.7% to 2.0%) for DD (Table 5).
Table 5. Comparing each of endpoints between Lapelga® and Neulasta® in total analysis, after adjusting for chemotherapy cycles.
Patients included in the whole cycle analysis
Endpoints p-valuea RD 95% CI
FN (Yes vs. no) 0.4751 0.56 (−0.98, 2.09)
FN associated hospitalization duration (days) 0.9935 N/A N/A
Any pain (yes vs. no) 0.5291 2.36 (−4.99, 9.72)
Dose delayed (yes vs. no) 0.7901 –0.32 (−2.68, 2.04)
Number of days of dose delayed 0.8818 N/A N/A
Dose reductions (yes vs. no) 0.2756 −3.63 (−10.15, 2.90)
% of dose reductions 0.1376 N/A N/A
FN= Febrile Neutropenia; RD=risk difference between Lapelga® and Neulasta®; CI=confidence interval.
aP-value was obtained by GEE model for this longitudinal data in the whole cycles’ analysis, after adjusting for chemotherapy cycles.
Safety analysis: Reported pain
The occurrence of patient-reported bone, joint and/or muscle pain were reviewed, but due to the ambiguity of many pain descriptions, these indicators were grouped into overall pain. In the first cycle only (Table 3), 14/74 (19%) Lapelga® patients and 19/100 (19%) of Neulasta® patients experienced pain. The RD was not statistically significant (RD -0.08%; 95%CI; –0.11, 0.12). The prevalence of pain was also reported on a per-cycle basis in Online Appendix 2. In the full cycle analysis, in the Neulasta® cohort, 43 (52%) patients experienced at least one pain event compared to 35 (59%) of patients in the Lapelga® cohort. When analyzed with regards to the total cycles received, 83/515 (16%) cycles with Neulasta® administration was associated with pain vs 60/322 (19%) in the Lapelga® cohort (RD = 2.4%, 95% CI: –5.0 to 9.7, p = 0.53) after adjusting for chemotherapy cycles (Tables 4 and 5). Pain was comparable between the two groups as well (19.0% vs 18.9%, for Neulasta® and Lapelga®, respectively; RD = –0.1%, p = 0.99).
Cost minimization
Direct costs of the drugs were compared between Lapelga® and Neulasta®. Direct and indirect costs concerning FN management were not incorporated into the model given the lack of statistically significant difference in this cohort with respect to these rates, DR, DD, and toxicities that could impact quality of life. In the base case, the incremental cost savings of using Lapelga® was $1,080.34 per cycle per patient. In the sensitivity analysis, Neulasta® was favored over Lapelga® if there was a discount in Neulasta® price by at least 56.87% from base case (Figure 2). In a cohort of 20,000 patients using base case price this would translate into an incremental savings of $21,606,800 for each cycle in favour of Lapelga® if there was 100% adoption of biosimilar Lapelga® over Neulasta® (Figure 3).
Figure 2. Incremental cost savings per-patient of Lapelga® versus Neulasta® per cycle of chemotherapy in adjuvant or neoadjuvant setting for early or locally advanced breast cancer.
Figure 3. Cost of GCSF (Lapelga® or Neulasta®) for single chemotherapy cycle in cohort (N=20,000 patients).
Matched analysis
A one-to-one matched sensitivity analysis was completed on all data reported above. The demographics of the matched sensitivity analysis can be found in Online Appendix 3.1 and the results of this matched analysis can be found in Online Appendix 3.2. No statistically significant differences were found, and the matched analysis outcomes did not alter the study results.
Discussion
In this real-world clinical setting study, the non-inferiority of the biosimilar pegfilgrastim to the reference product was demonstrated based on the occurrence of FN in cycle 1. This single-institution, retrospective chart review provided a head-to-head analysis showing clinical comparability of the biosimilar using FN rates, in addition to the duration of hospitalization and chemotherapy DD and DR. These results add to the breadth of research investigating the efficacy and safety of biosimilar growth factors using observational data obtained outside the context of randomized controlled trials. This study’s findings will further strengthen the existing evidence in relation to real-world clinical reports on biosimilar pegfilgrastim and can aid in improving physician confidence in its continued adoption.
The analytical approach of this study was two-part; first-cycle and all-cycle analyses were conducted, where the former was used as the primary endpoint given that the first cycle has been associated with the highest risk for FN.27–29 Jurczak et al. reported FN outcomes in 1,006 lung, breast, ovarian, Hodgkin’s lymphoma and Non-Hodgkin’s lymphoma patients, where 50% of all FN events occurred in the first cycle. 27 In predicting an elevated risk of FN during first cycle treatment, rates are consistently higher during the first 10–20 days after chemotherapy initiation. 28 The overall combined FN rate was 3.5% for first cycle analysis and 0.84% for any cycle; therefore, 85% of all FN events in the combined study analysis occurred in cycle 1.
Primary prophylaxis with G-CSF in patients receiving systemic chemotherapy has been associated with improved dose intensity and risk reductions in all-cause mortality as well as infection-related mortality.30,31 The secondary objectives of this study were, therefore, indicative of the more common consequences of neutropenia that compromise the efficacy of chemotherapy delivered given the association between reductions in relative dose intensity and overall survival outcomes. The percentage of patients that experienced a DR was not statistically significantly different between the two cohorts. In evaluating chemotherapy DD and DR and their impact on cancer cure rates, Denduluri et al. 2018 reported no significant association between DD and overall survival, while DR had a more profound impact in breast cancer patients (HR = 1.24; 95% CI: 1.03–1.48; p = 0.020). 32 Similarly, a 2019 Canadian based study by Veitch et al. consisting of 1,302 breast cancer patients showed those receiving ≥ 85% of the prescribed dose had superior overall survival (OS) at 5 years. 33
For over two decades, G-CSFs have been the mainstay of the treatment and prevention of chemotherapy-induced neutropenia complications, however, the high cost of G-CSF agents may limit access for some patients. 15 With the current evidence that both pegfilgrastim agents were equally efficacious and with a similar safety profile, cost minimization analysis was justified to determine the cost-savings benefit of Lapelga®. The incremental cost savings of using Lapelga® as an alternative to branded pegfilgrastim was $1080.34 per-patient drug costs each cycle. A variety of interrelated factors influence the development, uptake, and cost-savings for biosimilar use, with lower price helping address escalating healthcare costs in oncology. Increasing the rate of adoption would result in large cost savings, as the results of this study report an incremental savings of $21,606,800 for each cycle in favour of Lapelga® if there was 100% adoption of biosimilar Lapelga® over Neulasta® in 20,000 patients. To add to this point, a study by Mansell et al. retrospectively analyzed Canadian drug purchases of three biosimilars and their reference biologics between 2016 and 2018. This study reported varying purchasing ranges of biosimilars between 0.1% and 81.6% and found that in two years, if biosimilars were used 100%, there would be $1.05 billion of savings across the country, with $349 million of savings coming from Ontario. 24 Thus, the pegfilgrastim biosimilar can help reduce health care expenditure.
Moreover, a future consideration regarding biosimilars includes the perception of physicians and patients toward biosimilars. A recent systematic review evaluated 23 studies, which reported clear inconsistencies and existing gaps in physician knowledge plus concerns in comfort level with biosimilars. 34 Studies evaluating patient health literacy have also found low awareness of biosimilars in general. 35 Targeted education on these agents could help increase comfort and knowledge to help improve adoption rates.
Although RCTs are highly regarded for assessments of safety and efficacy, strict eligibility criteria and the overall nature of being on a study versus community-based practise has been observed to decrease the prevalence of FN. 36 Thus, real-world studies are of benefit to areas of literature regarding FN rates and G-CSF prophylaxis. Based on reported differences often arising between the controlled trial setting and actual clinical practice, the analysis of real-world data with respect to G-CSF prophylaxis continues to play a role in understanding the impact of FN as well as different patient, disease, and treatment-related risk factors on its severity.
Some strengths of this study include the nature of observational studies’ ability to account for potential underrepresentation of older patient groups and patients with comorbidities not typical enrolled in clinical trials. Patient characteristics were consistent between groups and a matched sensitivity analysis was applied to further evaluate the potential impact of patient and treatment-related factors on FN outcomes, which did not change the overall conclusion of the study. A retrospective review provides important insights into actual clinical practice use of biosimilar pegfilgrastim. However, due to reliance upon electronic health records, if the outcome was not recorded, it was assumed that it did not occur. One example being DR and DD, as the reasons for their occurrence were not always explicitly recorded and could be due to reasons unrelated to neutropenia. DD and DR being unrelated to neutropenia could potentially pose as confounders. However, since this is true for both cohorts, this outcome remains clinically relevant in investigating the efficacy of supportive care. There were also limitations in the determination of pain as there was no quantitative value to distinguish the degree or duration of pain experienced, as well as the improvement or worsening of pain throughout cycle progression. This study consisted of breast cancer patients undergoing neoadjuvant or adjuvant intent only, thus, the generalizability of results is limited to this patient population. Additionally, the results showed a significant difference in demographics with respect to disease stage. Although this may be explained by the higher number of missing data in Neulasta® vs Lapelga® samples, analyzing a homogenous patient cohort is recommended to enhance the clinical comparability exercise for biosimilars, ideally with all patients of similar disease stage receiving the same chemotherapy regimen.
Conclusion
The findings of this retrospective real-world clinical study in breast cancer patients demonstrated non-inferiority of biosimilar pegfilgrastim and reference product concerning FN incidence in the first cycle. These findings support previously documented literature regarding the safety and efficacy of biosimilars. In cost minimization analysis, the incremental cost savings of Lapelga® over Neulasta® was $1080.34 per cycle and further highlights the benefits to health system budgets associated with increasing the adoption of this biosimilar. With clinically comparable safety and efficacy, biosimilar pegfilgrastim could increase patient access to supportive care while decreasing health-related costs. Further studies comparing the two products in different patient subpopulations would extend future findings. As more biosimilar agents enter the market, continuing research is needed to assess the drug uptake, clinical outcomes, and the extent of realized cost savings.
Supplemental Material
sj-pdf-1-opp-10.1177_1078155220974085 - Supplemental material for A retrospective review of the real-world experience of the Pegfilgrastim biosimilar (Lapelga®) to the reference biologic (Neulasta®)
Click here for additional data file.
Supplemental material, sj-pdf-1-opp-10.1177_1078155220974085 for A retrospective review of the real-world experience of the Pegfilgrastim biosimilar (Lapelga®) to the reference biologic (Neulasta®) by Gina Wong, Liying Zhang, Habeeb Majeed, Yasmeen Razvi, Carlo DeAngelis, Emily Lam, Erin McKenzie, Katie Wang and Mark Pasetka in Journal of Oncology Pharmacy Practice
Acknowledgement
Dr Mark Pasetka is the Principal Investigator and Senior Author of this project.
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.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Gina Wong https://orcid.org/0000-0002-5093-4181
Supplemental material: Supplemental material for this article is available online. | PEGFILGRASTIM | DrugsGivenReaction | CC BY-NC | 33215563 | 18,558,932 | 2022-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment.
High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy.
The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP).
In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group.
The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events.
High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX.
Introduction
High‐dose (HD) methotrexate (MTX; defined as MTX dose >500 mg/m2) has been used for several decades as an important backbone in treatment protocols for acute lymphoblastic leukemia, osteosarcoma, and lymphoma [1, 2, 3]. MTX acts as folate antimetabolite and inhibits DNA synthesis by blocking the enzyme dihydrofolate reductase. High doses of MTX are feasible by using folinic acid (syn, leucovorin, the reduced form of folic acid) to reduce the toxic effects upon nonmalignant cells as a “leucovorin rescue.”
Notable toxicities of HD‐MTX are mucositis, myelosuppression, renal failure, liver injury, and neurotoxicity [4]. The risk of HD‐MTX toxicity is especially increased in the case of therapy‐induced renal failure because impaired renal function leads to reduced MTX renal clearance, which is the major route (90%) of MTX elimination [5]. Prolonged exposure to toxic MTX levels can induce severe myelosuppression and mucositis and is a life‐threatening condition. Avoidance of renal injury and the consecutive risk of impaired MTX clearance is therefore paramount to prevent MTX toxicity.
HD‐MTX administration demands specialized supportive care to prevent adverse events. This includes strict urine alkalinization and hyperhydration to increase MTX elimination and to prevent kidney damage as well as administration of leucovorin to reduce mucositis and myelosuppression [4, 6].
Urine alkalinization has been identified as a crucial aspect of MTX clearance and prevention of renal toxicity. At a urine pH of 5, the solubility of MTX is very low, and it can precipitate within renal tubuli, which induces severe kidney damage with the consequence of acute renal failure. In some cases, this condition will require hemodialysis. By raising the urine pH from 5 to 7.5, solubility of MTX increases about 20‐fold [4, 5, 6, 7]. Therefore, permanent and effective urine alkalinization and hyperhydration are absolutely mandatory for safe HD‐MTX treatment.
As MTX can accumulate in third‐space fluids like ascites and pleural effusions, thereby leading to prolonged MTX clearance due to distribution processes, the presence of such third‐space fluids prior to HD‐MTX needs to be ruled out. This is usually performed by sonography.
Furthermore, pharmacokinetic interactions between several drugs (i.e., proton‐pump inhibitors, β‐lactam antibiotics, nonsteroidal anti‐inflammatory drugs like indomethacin and naproxen) and MTX have been previously identified as reason for delayed MTX elimination and subsequent toxicity [4, 8, 9, 10, 11]. Avoidance of such interactions is another important part of supportive care during HD‐MTX therapy.
Even slight deviations from optimal supportive therapy may lead to profound toxicities of HD‐MTX. Therefore, strict adherence to supportive measures during HD‐MTX is vital for patient safety. As HD‐MTX is often used in curative treatment settings (i.e., acute lymphoblastic leukemia, lymphoma), toxicity of HD‐MTX needs to be minimized to prevent treatment delays as this may impair the overall prognosis.
We hypothesized that supportive care for HD‐MTX can be significantly improved by implementing standardized protocols for all relevant elements of supportive treatment.
Materials and Methods
Additional tools for supportive care during HD‐MTX therapy including a checklist for supportive care and a urine alkalinization protocol were implemented in our clinic, a tertiary comprehensive cancer center.
The checklist contains several elements of supportive care and treatment preparation during HD‐MTX (Fig. 1). Important items of the checklist are sonographic detection of third‐space fluids, correct intravenous fluid administration, proper urine alkalinization before the start of MTX infusion, preparation of a leucovorin rescue protocol, and evaluation of possible pharmacokinetic interactions.
Figure 1 Checklist for high‐dose MTX therapy. Abbreviation: ASS, acetylsalicyclic acid; MTX, methotrexate; NSAID, nonsteroidal anti‐inflammatory drug.
A protocol for measurement and recording of urine pH values as well as documentation of alkalinization therapy was designed to ensure proper urinary alkalinization (Fig. 2).
Figure 2 Protocol for urine pH measurement and urine alkalinization during HD‐MTX. Abbreviations: HD‐MTX, high‐dose methotrexate.
The use of both the checklist and the alkalinization protocol was implemented in all patients receiving HD‐MTX starting in April 2017. These two documents were individually used for every single HD‐MTX treatment course in every patient. Both physicians and the nursing staff were responsible for using this documentation system. To assess the efficacy of this intervention, treatment data of 118 patients receiving HD‐MTX from April 2017 to April 2019 were analyzed (intervention group).
Prior to implementation of this standardized documentation, supportive care for HD‐MTX in our clinic was performed as recommended by international guidelines [4, 6], with modifications according to local practice following a dedicated standard operating procedure (SOP). This included urine alkalinization and hyperhydration, leucovorin rescue, detection of third‐space fluids, and avoidance of pharmacokinetic interactions. Urine alkalinization was achieved by intravenous application of sodium bicarbonate, and a urine pH of 8 was defined as target value. Fluid administration and leucovorin rescue were performed according to standardized chemotherapy treatment protocols. Documentation of supportive care was done in electronic patient records but was not standardized.
Predefined adverse events (acute kidney injury, prolongation of MTX clearance) were retrospectively assessed in a cohort of 108 patients treated from January 2015 to March 2017. In this control group, supportive care was delivered following the SOP but without standardized documentation tools.
Delayed MTX clearance was defined as failure to reach prespecified thresholds (<0.2 μmol/L at 72 hours after therapy) and if prolonged leucovorin rescue was necessary.
Acute kidney injury was defined according to the AKIN classification [12]. The threshold for definition of acute kidney injury was AKIN stage 1. By definition, this finding is made in patients with an absolute serum creatinine increase of 0.3 mg/dL or greater, an increase of 1.5‐fold or greater above the baseline serum creatinine, or onset of oliguria (urine output <0.5 mL/kg per hour lasting 6–12 hours).
For statistical comparison of adverse events between the treatment groups, the Fisher‐Yates test was used. A p value < .05 was defined as statistically significant.
This study was conducted after review by the local ethics committee of the Hamburg chamber of physicians, Germany (Ref. no. WF106‐20).
Results
In the intervention group, 118 patients were treated with 414 cycles of HD‐MTX. The SOP group consisted of 108 patients who received 332 cycles of HD‐MTX (Table 1). The most common indications for HD‐MTX in both groups were central nervous system lymphoma (43 patients in both groups), acute lymphoblastic leukemia (36 patients in the intervention and 23 in the SOP group), and non‐Hodgkin lymphoma (16 patients in the intervention and 18 in the SOP group).
Table 1 Characteristics of SOP and intervention groups and frequency of adverse events
Characteristic SOP group Intervention group
p value
No. of patients 108 118
No. of treatment cycles 332 414
Mean age (range), yr 53 (18–85) 52 (18–83)
Burkitt lymphoma, n
16 19
CNS lymphoma, n
43 43
Osteosarcoma, n
8 2
Choriocarcinoma, n
0 2
Acute lymphoblastic leukemia, n
23 36
Non‐Hodgkin Lymphoma, n
18 16
MTX dose, mean (range), g/m2
2.7 (0.5–12) 2.1 (0.5–12)
No. of cycles with delayed MTX clearance (%) 51 (15.2) 11 (2.6) <.001
Acute kidney injury, n (%) 21 (6.2.) 3 (0.7) <.001
No. of cycles with use of carboxypeptidase (%)
5 (1.47) 2 (0.48) .25
Abbreviations: CNS, central nervous system; MTX, methotrexate; SOP, standard operating procedure.
The average MTX dose per treatment cycle was 2.7 g/m2 in the SOP group and 2.1 g/m2 in the intervention group. All patients with acute lymphoblastic leukemia received HD‐MTX as a continuous infusion over 24 hours, whereas in all other indications, MTX was administered as an infusion over 3–4 hours.
In 51 of 332 HD‐MTX cycles (15.2%) within the SOP group, MTX clearance was delayed. In contrast, delayed MTX clearance was only observed in 11 of 414 treatment cycles of the intervention group (2.6%, p < .001)
Acute kidney injury occurred in 6.3% of cycles (n = 21) within the SOP group and in only 0.7% of cycles (n = 3) in the intervention group (p < .001).
One patient with acute renal failure in the SOP group underwent hemodialysis. In all patients experiencing acute kidney injury, kidney damage was reversible and did not induce chronic renal impairment.
HD‐MTX therapy was permanently discontinued because of toxicity in five patients of the SOP group and in one patient of the intervention group. Five patients of the SOP group and two patients within the intervention group received carboxypeptidase because of acute renal failure and insufficient MTX clearance. The indication for carboxypeptidase was evaluated according to international recommendations [6, 13]. There were no treatment‐related deaths.
A review of potential reasons for complications in the SOP group by analysis of all treatment cycles with acute kidney injury and/or delayed MTX clearance revealed potential pharmacokinetic drug–drug interactions in 17 treatment cycles and inadequate control of urine alkalinization in 5 treatment cycles.
In the 21 treatment cycles of the SOP group that resulted in acute kidney injury, a potential drug–drug interaction was present in eight cases and inadequate urine alkalinization was present in five cycles. Other causes for nephrotoxicity were one case of tumor lysis syndrome and two patients with pretherapeutic renal impairment.
In the intervention cohort, administration of potentially interacting drugs could be successfully avoided. Specifically, in the three cases of acute kidney injury in the intervention group, no interfering medication was given. Table 2 summarizes the analysis of underlying causes for acute kidney injury in both treatment groups.
Table 2 Analysis of patients with acute kidney injury after high‐dose MTX
Potential reason for MTX toxicity Intervention group (n = 3) SOP group (n = 21)
Concomitant medication 0 8
Tumor lysis syndrome 0 1
Urinary retention due to bladder obstruction 1 0
Insufficient urine alkalinization 0 5
Preexisting renal impairment 0 2
Unknown 2 12
Abbreviations: MTX, methotrexate; SOP, standard operating procedure.
Discussion
Herein, we demonstrate that standardized documentation protocols for supportive care significantly reduce the rate of adverse events during HD‐MTX therapy by using a simplified and structured guidance consisting of only two single‐page documents (checklist and urine alkalinization protocol). Implementation of these measures was performed with high acceptance by physicians and nurses, as both the checklist and the alkalinization protocol were successfully applied in all patients within the intervention group for every treatment course.
Even slight deviations in supportive care may lead to acute kidney failure and subsequent toxicities of HD‐MTX. In clinical practice, strict adherence to these requirements can be challenging, and errors may occur. Optimal supportive care has been previously demonstrated to reduce the risk of HD‐MTX toxicity [4, 6, 13, 14].
Pharmacokinetic interactions between concomitant medications and MTX with significantly delayed MTX elimination have been previously described [8, 9, 10, 11, 15]. Therefore, avoidance of such pharmacokinetic interactions is imperative to administer HD‐MTX safely. The use of a checklist containing information on potential pharmacokinetic interactions can assist in preventing these adverse events.
For instance, we observed a case of acute renal failure necessitating hemodialysis in our SOP group after intravenous administration of a single dose of 40 mg pantoprazole only a few hours after infusion of HD‐MTX. As this example demonstrates, supportive care prior, during, and after HD‐MTX administration has to follow strict rules to avoid serious toxicity.
The important role of pharmacokinetic interactions for HD‐MTX toxicity is also supported by the finding of potentially interacting medication in about one third of the 21 cycles leading to acute kidney injury within the SOP group. In contrast, no patient within the intervention group had received interacting medications.
Previously, the rate of renal failure after HD‐MTX despite adequate, nonstandardized supportive care was reported to be 1.8% [6]. In another retrospective analysis in patients with lymphoma receiving HD‐MTX, the rate of renal injury was about 9% [16]. The reason for these different findings are presumably patient‐related factors like age and comorbidities.
In our intervention group, the overall rate of any degree of acute kidney injury (according to the AKIN classification) could be reduced from 6.3% (SOP group) to 0.7%. This finding demonstrates the high efficacy of standardized supportive care documentation to prevent acute renal failure during HD‐MTX treatment. The low rate of nephrotoxicity in our intervention group also shows the importance of effective and continuous urine alkalinization to prevent kidney damage during HD‐MTX treatment. The crucial role of urine alkalinization for adequate HD‐MTX clearance was also reported by other studies [7, 14].
The use of a standardized urine alkalinization protocol is an effective approach to optimize urine alkalinization during HD‐MTX therapy.
We decided to use a checklist for control of supportive care because previously, the usage of checklist‐based interventions was proven to be highly effective for improving the quality of routine clinical care and to ensure adherence to guidelines in clinical practice [17]. The low rate of adverse events in our intervention group demonstrates that the checklist‐based control of supportive care can improve the safety of HD‐MTX therapy. As outlined before, the most important element of this checklist is presumably the prevention of pharmacokinetic drug–drug interactions.
Another advantage of the checklist‐based documentation for supportive care during HD‐MTX therapy is that this approach enables a comprehensive, transparent overview of all important supportive care measures. Thus, the risk of insufficient supportive care is minimized while clinicians and nurses require less time and effort to control whether all necessary preparations for HD‐MTX are present.
Regarding the risk profile for adverse events in the SOP and intervention groups, the average age in both groups was about 53 years. The average MTX dose was slightly higher in the SOP cohort (2.7 vs. 2.1 g/m2). There was also a higher proportion of patients receiving 24‐hour infusional MTX within the intervention cohort. However, although both lower MTX dose and longer infusion times may reduce the overall risk of MTX toxicity, insufficient supportive care is still a major risk factor for adverse events in such circumstances. In comparison with the findings in our intervention group, other studies have reported comparable or even significantly higher rates of acute kidney injury for HD‐MTX in patients with childhood acute lymphoblastic leukemia [18, 19].
Limitations of our study are its retrospective, nonrandomized design and the evaluation within a single treatment center. However, our intervention of standardized supportive care documentation for HD‐MTX was effective in a broad, nonselected real‐world patient population, which warrants confirmation in further prospective clinical trials.
Our drug–drug interaction list did not include tyrosine kinase inhibitors like imatinib and dasatinib. However, it has been recently reported that such drugs may reduce MTX clearance and should therefore also be avoided during HD‐MTX treatment [20, 21].
Conclusion
The use of a standardized, checklist‐based documentation for supportive care significantly improves the safety of HD‐MTX treatment. These tools are able to minimize the risk of pharmacokinetic drug–drug interactions and insufficient urine alkalinization, leading to a low rate of adverse events. We therefore highly recommend implementation of such adjunctive measures for all patients receiving HD‐MTX. In our experience, the use of a checklist and urine alkalinization protocol is very efficient and can be easily implemented into clinical practice.
Author Contributions
Conception/design: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Provision of study material or patients: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Collection and/or assembly of data: Claudia Langebrake, Winfried Alsdorf, Christian Frenzel
Data analysis and interpretation: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Manuscript writing: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Final approval of manuscript: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Disclosures
Panagiotis Karagiannis: Abbvie Inc. (OI); Carsten Bokemeyer: Sanofi Aventis, Novartis, Merck Sharpe & Dohme, Bristol‐Myers Squibb, Eli Lilly & Co/Imclone, GSO Hamburg, AOK Health Insurance, Merck Darmstadt, Roche, Bayer Healthcare (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board | LEUCOVORIN, METHOTREXATE, PANTOPRAZOLE, SODIUM BICARBONATE | DrugsGivenReaction | CC BY-NC-ND | 33215763 | 19,172,964 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment.
High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy.
The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP).
In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group.
The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events.
High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX.
Introduction
High‐dose (HD) methotrexate (MTX; defined as MTX dose >500 mg/m2) has been used for several decades as an important backbone in treatment protocols for acute lymphoblastic leukemia, osteosarcoma, and lymphoma [1, 2, 3]. MTX acts as folate antimetabolite and inhibits DNA synthesis by blocking the enzyme dihydrofolate reductase. High doses of MTX are feasible by using folinic acid (syn, leucovorin, the reduced form of folic acid) to reduce the toxic effects upon nonmalignant cells as a “leucovorin rescue.”
Notable toxicities of HD‐MTX are mucositis, myelosuppression, renal failure, liver injury, and neurotoxicity [4]. The risk of HD‐MTX toxicity is especially increased in the case of therapy‐induced renal failure because impaired renal function leads to reduced MTX renal clearance, which is the major route (90%) of MTX elimination [5]. Prolonged exposure to toxic MTX levels can induce severe myelosuppression and mucositis and is a life‐threatening condition. Avoidance of renal injury and the consecutive risk of impaired MTX clearance is therefore paramount to prevent MTX toxicity.
HD‐MTX administration demands specialized supportive care to prevent adverse events. This includes strict urine alkalinization and hyperhydration to increase MTX elimination and to prevent kidney damage as well as administration of leucovorin to reduce mucositis and myelosuppression [4, 6].
Urine alkalinization has been identified as a crucial aspect of MTX clearance and prevention of renal toxicity. At a urine pH of 5, the solubility of MTX is very low, and it can precipitate within renal tubuli, which induces severe kidney damage with the consequence of acute renal failure. In some cases, this condition will require hemodialysis. By raising the urine pH from 5 to 7.5, solubility of MTX increases about 20‐fold [4, 5, 6, 7]. Therefore, permanent and effective urine alkalinization and hyperhydration are absolutely mandatory for safe HD‐MTX treatment.
As MTX can accumulate in third‐space fluids like ascites and pleural effusions, thereby leading to prolonged MTX clearance due to distribution processes, the presence of such third‐space fluids prior to HD‐MTX needs to be ruled out. This is usually performed by sonography.
Furthermore, pharmacokinetic interactions between several drugs (i.e., proton‐pump inhibitors, β‐lactam antibiotics, nonsteroidal anti‐inflammatory drugs like indomethacin and naproxen) and MTX have been previously identified as reason for delayed MTX elimination and subsequent toxicity [4, 8, 9, 10, 11]. Avoidance of such interactions is another important part of supportive care during HD‐MTX therapy.
Even slight deviations from optimal supportive therapy may lead to profound toxicities of HD‐MTX. Therefore, strict adherence to supportive measures during HD‐MTX is vital for patient safety. As HD‐MTX is often used in curative treatment settings (i.e., acute lymphoblastic leukemia, lymphoma), toxicity of HD‐MTX needs to be minimized to prevent treatment delays as this may impair the overall prognosis.
We hypothesized that supportive care for HD‐MTX can be significantly improved by implementing standardized protocols for all relevant elements of supportive treatment.
Materials and Methods
Additional tools for supportive care during HD‐MTX therapy including a checklist for supportive care and a urine alkalinization protocol were implemented in our clinic, a tertiary comprehensive cancer center.
The checklist contains several elements of supportive care and treatment preparation during HD‐MTX (Fig. 1). Important items of the checklist are sonographic detection of third‐space fluids, correct intravenous fluid administration, proper urine alkalinization before the start of MTX infusion, preparation of a leucovorin rescue protocol, and evaluation of possible pharmacokinetic interactions.
Figure 1 Checklist for high‐dose MTX therapy. Abbreviation: ASS, acetylsalicyclic acid; MTX, methotrexate; NSAID, nonsteroidal anti‐inflammatory drug.
A protocol for measurement and recording of urine pH values as well as documentation of alkalinization therapy was designed to ensure proper urinary alkalinization (Fig. 2).
Figure 2 Protocol for urine pH measurement and urine alkalinization during HD‐MTX. Abbreviations: HD‐MTX, high‐dose methotrexate.
The use of both the checklist and the alkalinization protocol was implemented in all patients receiving HD‐MTX starting in April 2017. These two documents were individually used for every single HD‐MTX treatment course in every patient. Both physicians and the nursing staff were responsible for using this documentation system. To assess the efficacy of this intervention, treatment data of 118 patients receiving HD‐MTX from April 2017 to April 2019 were analyzed (intervention group).
Prior to implementation of this standardized documentation, supportive care for HD‐MTX in our clinic was performed as recommended by international guidelines [4, 6], with modifications according to local practice following a dedicated standard operating procedure (SOP). This included urine alkalinization and hyperhydration, leucovorin rescue, detection of third‐space fluids, and avoidance of pharmacokinetic interactions. Urine alkalinization was achieved by intravenous application of sodium bicarbonate, and a urine pH of 8 was defined as target value. Fluid administration and leucovorin rescue were performed according to standardized chemotherapy treatment protocols. Documentation of supportive care was done in electronic patient records but was not standardized.
Predefined adverse events (acute kidney injury, prolongation of MTX clearance) were retrospectively assessed in a cohort of 108 patients treated from January 2015 to March 2017. In this control group, supportive care was delivered following the SOP but without standardized documentation tools.
Delayed MTX clearance was defined as failure to reach prespecified thresholds (<0.2 μmol/L at 72 hours after therapy) and if prolonged leucovorin rescue was necessary.
Acute kidney injury was defined according to the AKIN classification [12]. The threshold for definition of acute kidney injury was AKIN stage 1. By definition, this finding is made in patients with an absolute serum creatinine increase of 0.3 mg/dL or greater, an increase of 1.5‐fold or greater above the baseline serum creatinine, or onset of oliguria (urine output <0.5 mL/kg per hour lasting 6–12 hours).
For statistical comparison of adverse events between the treatment groups, the Fisher‐Yates test was used. A p value < .05 was defined as statistically significant.
This study was conducted after review by the local ethics committee of the Hamburg chamber of physicians, Germany (Ref. no. WF106‐20).
Results
In the intervention group, 118 patients were treated with 414 cycles of HD‐MTX. The SOP group consisted of 108 patients who received 332 cycles of HD‐MTX (Table 1). The most common indications for HD‐MTX in both groups were central nervous system lymphoma (43 patients in both groups), acute lymphoblastic leukemia (36 patients in the intervention and 23 in the SOP group), and non‐Hodgkin lymphoma (16 patients in the intervention and 18 in the SOP group).
Table 1 Characteristics of SOP and intervention groups and frequency of adverse events
Characteristic SOP group Intervention group
p value
No. of patients 108 118
No. of treatment cycles 332 414
Mean age (range), yr 53 (18–85) 52 (18–83)
Burkitt lymphoma, n
16 19
CNS lymphoma, n
43 43
Osteosarcoma, n
8 2
Choriocarcinoma, n
0 2
Acute lymphoblastic leukemia, n
23 36
Non‐Hodgkin Lymphoma, n
18 16
MTX dose, mean (range), g/m2
2.7 (0.5–12) 2.1 (0.5–12)
No. of cycles with delayed MTX clearance (%) 51 (15.2) 11 (2.6) <.001
Acute kidney injury, n (%) 21 (6.2.) 3 (0.7) <.001
No. of cycles with use of carboxypeptidase (%)
5 (1.47) 2 (0.48) .25
Abbreviations: CNS, central nervous system; MTX, methotrexate; SOP, standard operating procedure.
The average MTX dose per treatment cycle was 2.7 g/m2 in the SOP group and 2.1 g/m2 in the intervention group. All patients with acute lymphoblastic leukemia received HD‐MTX as a continuous infusion over 24 hours, whereas in all other indications, MTX was administered as an infusion over 3–4 hours.
In 51 of 332 HD‐MTX cycles (15.2%) within the SOP group, MTX clearance was delayed. In contrast, delayed MTX clearance was only observed in 11 of 414 treatment cycles of the intervention group (2.6%, p < .001)
Acute kidney injury occurred in 6.3% of cycles (n = 21) within the SOP group and in only 0.7% of cycles (n = 3) in the intervention group (p < .001).
One patient with acute renal failure in the SOP group underwent hemodialysis. In all patients experiencing acute kidney injury, kidney damage was reversible and did not induce chronic renal impairment.
HD‐MTX therapy was permanently discontinued because of toxicity in five patients of the SOP group and in one patient of the intervention group. Five patients of the SOP group and two patients within the intervention group received carboxypeptidase because of acute renal failure and insufficient MTX clearance. The indication for carboxypeptidase was evaluated according to international recommendations [6, 13]. There were no treatment‐related deaths.
A review of potential reasons for complications in the SOP group by analysis of all treatment cycles with acute kidney injury and/or delayed MTX clearance revealed potential pharmacokinetic drug–drug interactions in 17 treatment cycles and inadequate control of urine alkalinization in 5 treatment cycles.
In the 21 treatment cycles of the SOP group that resulted in acute kidney injury, a potential drug–drug interaction was present in eight cases and inadequate urine alkalinization was present in five cycles. Other causes for nephrotoxicity were one case of tumor lysis syndrome and two patients with pretherapeutic renal impairment.
In the intervention cohort, administration of potentially interacting drugs could be successfully avoided. Specifically, in the three cases of acute kidney injury in the intervention group, no interfering medication was given. Table 2 summarizes the analysis of underlying causes for acute kidney injury in both treatment groups.
Table 2 Analysis of patients with acute kidney injury after high‐dose MTX
Potential reason for MTX toxicity Intervention group (n = 3) SOP group (n = 21)
Concomitant medication 0 8
Tumor lysis syndrome 0 1
Urinary retention due to bladder obstruction 1 0
Insufficient urine alkalinization 0 5
Preexisting renal impairment 0 2
Unknown 2 12
Abbreviations: MTX, methotrexate; SOP, standard operating procedure.
Discussion
Herein, we demonstrate that standardized documentation protocols for supportive care significantly reduce the rate of adverse events during HD‐MTX therapy by using a simplified and structured guidance consisting of only two single‐page documents (checklist and urine alkalinization protocol). Implementation of these measures was performed with high acceptance by physicians and nurses, as both the checklist and the alkalinization protocol were successfully applied in all patients within the intervention group for every treatment course.
Even slight deviations in supportive care may lead to acute kidney failure and subsequent toxicities of HD‐MTX. In clinical practice, strict adherence to these requirements can be challenging, and errors may occur. Optimal supportive care has been previously demonstrated to reduce the risk of HD‐MTX toxicity [4, 6, 13, 14].
Pharmacokinetic interactions between concomitant medications and MTX with significantly delayed MTX elimination have been previously described [8, 9, 10, 11, 15]. Therefore, avoidance of such pharmacokinetic interactions is imperative to administer HD‐MTX safely. The use of a checklist containing information on potential pharmacokinetic interactions can assist in preventing these adverse events.
For instance, we observed a case of acute renal failure necessitating hemodialysis in our SOP group after intravenous administration of a single dose of 40 mg pantoprazole only a few hours after infusion of HD‐MTX. As this example demonstrates, supportive care prior, during, and after HD‐MTX administration has to follow strict rules to avoid serious toxicity.
The important role of pharmacokinetic interactions for HD‐MTX toxicity is also supported by the finding of potentially interacting medication in about one third of the 21 cycles leading to acute kidney injury within the SOP group. In contrast, no patient within the intervention group had received interacting medications.
Previously, the rate of renal failure after HD‐MTX despite adequate, nonstandardized supportive care was reported to be 1.8% [6]. In another retrospective analysis in patients with lymphoma receiving HD‐MTX, the rate of renal injury was about 9% [16]. The reason for these different findings are presumably patient‐related factors like age and comorbidities.
In our intervention group, the overall rate of any degree of acute kidney injury (according to the AKIN classification) could be reduced from 6.3% (SOP group) to 0.7%. This finding demonstrates the high efficacy of standardized supportive care documentation to prevent acute renal failure during HD‐MTX treatment. The low rate of nephrotoxicity in our intervention group also shows the importance of effective and continuous urine alkalinization to prevent kidney damage during HD‐MTX treatment. The crucial role of urine alkalinization for adequate HD‐MTX clearance was also reported by other studies [7, 14].
The use of a standardized urine alkalinization protocol is an effective approach to optimize urine alkalinization during HD‐MTX therapy.
We decided to use a checklist for control of supportive care because previously, the usage of checklist‐based interventions was proven to be highly effective for improving the quality of routine clinical care and to ensure adherence to guidelines in clinical practice [17]. The low rate of adverse events in our intervention group demonstrates that the checklist‐based control of supportive care can improve the safety of HD‐MTX therapy. As outlined before, the most important element of this checklist is presumably the prevention of pharmacokinetic drug–drug interactions.
Another advantage of the checklist‐based documentation for supportive care during HD‐MTX therapy is that this approach enables a comprehensive, transparent overview of all important supportive care measures. Thus, the risk of insufficient supportive care is minimized while clinicians and nurses require less time and effort to control whether all necessary preparations for HD‐MTX are present.
Regarding the risk profile for adverse events in the SOP and intervention groups, the average age in both groups was about 53 years. The average MTX dose was slightly higher in the SOP cohort (2.7 vs. 2.1 g/m2). There was also a higher proportion of patients receiving 24‐hour infusional MTX within the intervention cohort. However, although both lower MTX dose and longer infusion times may reduce the overall risk of MTX toxicity, insufficient supportive care is still a major risk factor for adverse events in such circumstances. In comparison with the findings in our intervention group, other studies have reported comparable or even significantly higher rates of acute kidney injury for HD‐MTX in patients with childhood acute lymphoblastic leukemia [18, 19].
Limitations of our study are its retrospective, nonrandomized design and the evaluation within a single treatment center. However, our intervention of standardized supportive care documentation for HD‐MTX was effective in a broad, nonselected real‐world patient population, which warrants confirmation in further prospective clinical trials.
Our drug–drug interaction list did not include tyrosine kinase inhibitors like imatinib and dasatinib. However, it has been recently reported that such drugs may reduce MTX clearance and should therefore also be avoided during HD‐MTX treatment [20, 21].
Conclusion
The use of a standardized, checklist‐based documentation for supportive care significantly improves the safety of HD‐MTX treatment. These tools are able to minimize the risk of pharmacokinetic drug–drug interactions and insufficient urine alkalinization, leading to a low rate of adverse events. We therefore highly recommend implementation of such adjunctive measures for all patients receiving HD‐MTX. In our experience, the use of a checklist and urine alkalinization protocol is very efficient and can be easily implemented into clinical practice.
Author Contributions
Conception/design: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Provision of study material or patients: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Collection and/or assembly of data: Claudia Langebrake, Winfried Alsdorf, Christian Frenzel
Data analysis and interpretation: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Manuscript writing: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Final approval of manuscript: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Disclosures
Panagiotis Karagiannis: Abbvie Inc. (OI); Carsten Bokemeyer: Sanofi Aventis, Novartis, Merck Sharpe & Dohme, Bristol‐Myers Squibb, Eli Lilly & Co/Imclone, GSO Hamburg, AOK Health Insurance, Merck Darmstadt, Roche, Bayer Healthcare (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board | LEUCOVORIN, METHOTREXATE, PANTOPRAZOLE, SODIUM BICARBONATE | DrugsGivenReaction | CC BY-NC-ND | 33215763 | 19,196,320 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Labelled drug-drug interaction medication error'. | Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment.
High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy.
The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP).
In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group.
The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events.
High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX.
Introduction
High‐dose (HD) methotrexate (MTX; defined as MTX dose >500 mg/m2) has been used for several decades as an important backbone in treatment protocols for acute lymphoblastic leukemia, osteosarcoma, and lymphoma [1, 2, 3]. MTX acts as folate antimetabolite and inhibits DNA synthesis by blocking the enzyme dihydrofolate reductase. High doses of MTX are feasible by using folinic acid (syn, leucovorin, the reduced form of folic acid) to reduce the toxic effects upon nonmalignant cells as a “leucovorin rescue.”
Notable toxicities of HD‐MTX are mucositis, myelosuppression, renal failure, liver injury, and neurotoxicity [4]. The risk of HD‐MTX toxicity is especially increased in the case of therapy‐induced renal failure because impaired renal function leads to reduced MTX renal clearance, which is the major route (90%) of MTX elimination [5]. Prolonged exposure to toxic MTX levels can induce severe myelosuppression and mucositis and is a life‐threatening condition. Avoidance of renal injury and the consecutive risk of impaired MTX clearance is therefore paramount to prevent MTX toxicity.
HD‐MTX administration demands specialized supportive care to prevent adverse events. This includes strict urine alkalinization and hyperhydration to increase MTX elimination and to prevent kidney damage as well as administration of leucovorin to reduce mucositis and myelosuppression [4, 6].
Urine alkalinization has been identified as a crucial aspect of MTX clearance and prevention of renal toxicity. At a urine pH of 5, the solubility of MTX is very low, and it can precipitate within renal tubuli, which induces severe kidney damage with the consequence of acute renal failure. In some cases, this condition will require hemodialysis. By raising the urine pH from 5 to 7.5, solubility of MTX increases about 20‐fold [4, 5, 6, 7]. Therefore, permanent and effective urine alkalinization and hyperhydration are absolutely mandatory for safe HD‐MTX treatment.
As MTX can accumulate in third‐space fluids like ascites and pleural effusions, thereby leading to prolonged MTX clearance due to distribution processes, the presence of such third‐space fluids prior to HD‐MTX needs to be ruled out. This is usually performed by sonography.
Furthermore, pharmacokinetic interactions between several drugs (i.e., proton‐pump inhibitors, β‐lactam antibiotics, nonsteroidal anti‐inflammatory drugs like indomethacin and naproxen) and MTX have been previously identified as reason for delayed MTX elimination and subsequent toxicity [4, 8, 9, 10, 11]. Avoidance of such interactions is another important part of supportive care during HD‐MTX therapy.
Even slight deviations from optimal supportive therapy may lead to profound toxicities of HD‐MTX. Therefore, strict adherence to supportive measures during HD‐MTX is vital for patient safety. As HD‐MTX is often used in curative treatment settings (i.e., acute lymphoblastic leukemia, lymphoma), toxicity of HD‐MTX needs to be minimized to prevent treatment delays as this may impair the overall prognosis.
We hypothesized that supportive care for HD‐MTX can be significantly improved by implementing standardized protocols for all relevant elements of supportive treatment.
Materials and Methods
Additional tools for supportive care during HD‐MTX therapy including a checklist for supportive care and a urine alkalinization protocol were implemented in our clinic, a tertiary comprehensive cancer center.
The checklist contains several elements of supportive care and treatment preparation during HD‐MTX (Fig. 1). Important items of the checklist are sonographic detection of third‐space fluids, correct intravenous fluid administration, proper urine alkalinization before the start of MTX infusion, preparation of a leucovorin rescue protocol, and evaluation of possible pharmacokinetic interactions.
Figure 1 Checklist for high‐dose MTX therapy. Abbreviation: ASS, acetylsalicyclic acid; MTX, methotrexate; NSAID, nonsteroidal anti‐inflammatory drug.
A protocol for measurement and recording of urine pH values as well as documentation of alkalinization therapy was designed to ensure proper urinary alkalinization (Fig. 2).
Figure 2 Protocol for urine pH measurement and urine alkalinization during HD‐MTX. Abbreviations: HD‐MTX, high‐dose methotrexate.
The use of both the checklist and the alkalinization protocol was implemented in all patients receiving HD‐MTX starting in April 2017. These two documents were individually used for every single HD‐MTX treatment course in every patient. Both physicians and the nursing staff were responsible for using this documentation system. To assess the efficacy of this intervention, treatment data of 118 patients receiving HD‐MTX from April 2017 to April 2019 were analyzed (intervention group).
Prior to implementation of this standardized documentation, supportive care for HD‐MTX in our clinic was performed as recommended by international guidelines [4, 6], with modifications according to local practice following a dedicated standard operating procedure (SOP). This included urine alkalinization and hyperhydration, leucovorin rescue, detection of third‐space fluids, and avoidance of pharmacokinetic interactions. Urine alkalinization was achieved by intravenous application of sodium bicarbonate, and a urine pH of 8 was defined as target value. Fluid administration and leucovorin rescue were performed according to standardized chemotherapy treatment protocols. Documentation of supportive care was done in electronic patient records but was not standardized.
Predefined adverse events (acute kidney injury, prolongation of MTX clearance) were retrospectively assessed in a cohort of 108 patients treated from January 2015 to March 2017. In this control group, supportive care was delivered following the SOP but without standardized documentation tools.
Delayed MTX clearance was defined as failure to reach prespecified thresholds (<0.2 μmol/L at 72 hours after therapy) and if prolonged leucovorin rescue was necessary.
Acute kidney injury was defined according to the AKIN classification [12]. The threshold for definition of acute kidney injury was AKIN stage 1. By definition, this finding is made in patients with an absolute serum creatinine increase of 0.3 mg/dL or greater, an increase of 1.5‐fold or greater above the baseline serum creatinine, or onset of oliguria (urine output <0.5 mL/kg per hour lasting 6–12 hours).
For statistical comparison of adverse events between the treatment groups, the Fisher‐Yates test was used. A p value < .05 was defined as statistically significant.
This study was conducted after review by the local ethics committee of the Hamburg chamber of physicians, Germany (Ref. no. WF106‐20).
Results
In the intervention group, 118 patients were treated with 414 cycles of HD‐MTX. The SOP group consisted of 108 patients who received 332 cycles of HD‐MTX (Table 1). The most common indications for HD‐MTX in both groups were central nervous system lymphoma (43 patients in both groups), acute lymphoblastic leukemia (36 patients in the intervention and 23 in the SOP group), and non‐Hodgkin lymphoma (16 patients in the intervention and 18 in the SOP group).
Table 1 Characteristics of SOP and intervention groups and frequency of adverse events
Characteristic SOP group Intervention group
p value
No. of patients 108 118
No. of treatment cycles 332 414
Mean age (range), yr 53 (18–85) 52 (18–83)
Burkitt lymphoma, n
16 19
CNS lymphoma, n
43 43
Osteosarcoma, n
8 2
Choriocarcinoma, n
0 2
Acute lymphoblastic leukemia, n
23 36
Non‐Hodgkin Lymphoma, n
18 16
MTX dose, mean (range), g/m2
2.7 (0.5–12) 2.1 (0.5–12)
No. of cycles with delayed MTX clearance (%) 51 (15.2) 11 (2.6) <.001
Acute kidney injury, n (%) 21 (6.2.) 3 (0.7) <.001
No. of cycles with use of carboxypeptidase (%)
5 (1.47) 2 (0.48) .25
Abbreviations: CNS, central nervous system; MTX, methotrexate; SOP, standard operating procedure.
The average MTX dose per treatment cycle was 2.7 g/m2 in the SOP group and 2.1 g/m2 in the intervention group. All patients with acute lymphoblastic leukemia received HD‐MTX as a continuous infusion over 24 hours, whereas in all other indications, MTX was administered as an infusion over 3–4 hours.
In 51 of 332 HD‐MTX cycles (15.2%) within the SOP group, MTX clearance was delayed. In contrast, delayed MTX clearance was only observed in 11 of 414 treatment cycles of the intervention group (2.6%, p < .001)
Acute kidney injury occurred in 6.3% of cycles (n = 21) within the SOP group and in only 0.7% of cycles (n = 3) in the intervention group (p < .001).
One patient with acute renal failure in the SOP group underwent hemodialysis. In all patients experiencing acute kidney injury, kidney damage was reversible and did not induce chronic renal impairment.
HD‐MTX therapy was permanently discontinued because of toxicity in five patients of the SOP group and in one patient of the intervention group. Five patients of the SOP group and two patients within the intervention group received carboxypeptidase because of acute renal failure and insufficient MTX clearance. The indication for carboxypeptidase was evaluated according to international recommendations [6, 13]. There were no treatment‐related deaths.
A review of potential reasons for complications in the SOP group by analysis of all treatment cycles with acute kidney injury and/or delayed MTX clearance revealed potential pharmacokinetic drug–drug interactions in 17 treatment cycles and inadequate control of urine alkalinization in 5 treatment cycles.
In the 21 treatment cycles of the SOP group that resulted in acute kidney injury, a potential drug–drug interaction was present in eight cases and inadequate urine alkalinization was present in five cycles. Other causes for nephrotoxicity were one case of tumor lysis syndrome and two patients with pretherapeutic renal impairment.
In the intervention cohort, administration of potentially interacting drugs could be successfully avoided. Specifically, in the three cases of acute kidney injury in the intervention group, no interfering medication was given. Table 2 summarizes the analysis of underlying causes for acute kidney injury in both treatment groups.
Table 2 Analysis of patients with acute kidney injury after high‐dose MTX
Potential reason for MTX toxicity Intervention group (n = 3) SOP group (n = 21)
Concomitant medication 0 8
Tumor lysis syndrome 0 1
Urinary retention due to bladder obstruction 1 0
Insufficient urine alkalinization 0 5
Preexisting renal impairment 0 2
Unknown 2 12
Abbreviations: MTX, methotrexate; SOP, standard operating procedure.
Discussion
Herein, we demonstrate that standardized documentation protocols for supportive care significantly reduce the rate of adverse events during HD‐MTX therapy by using a simplified and structured guidance consisting of only two single‐page documents (checklist and urine alkalinization protocol). Implementation of these measures was performed with high acceptance by physicians and nurses, as both the checklist and the alkalinization protocol were successfully applied in all patients within the intervention group for every treatment course.
Even slight deviations in supportive care may lead to acute kidney failure and subsequent toxicities of HD‐MTX. In clinical practice, strict adherence to these requirements can be challenging, and errors may occur. Optimal supportive care has been previously demonstrated to reduce the risk of HD‐MTX toxicity [4, 6, 13, 14].
Pharmacokinetic interactions between concomitant medications and MTX with significantly delayed MTX elimination have been previously described [8, 9, 10, 11, 15]. Therefore, avoidance of such pharmacokinetic interactions is imperative to administer HD‐MTX safely. The use of a checklist containing information on potential pharmacokinetic interactions can assist in preventing these adverse events.
For instance, we observed a case of acute renal failure necessitating hemodialysis in our SOP group after intravenous administration of a single dose of 40 mg pantoprazole only a few hours after infusion of HD‐MTX. As this example demonstrates, supportive care prior, during, and after HD‐MTX administration has to follow strict rules to avoid serious toxicity.
The important role of pharmacokinetic interactions for HD‐MTX toxicity is also supported by the finding of potentially interacting medication in about one third of the 21 cycles leading to acute kidney injury within the SOP group. In contrast, no patient within the intervention group had received interacting medications.
Previously, the rate of renal failure after HD‐MTX despite adequate, nonstandardized supportive care was reported to be 1.8% [6]. In another retrospective analysis in patients with lymphoma receiving HD‐MTX, the rate of renal injury was about 9% [16]. The reason for these different findings are presumably patient‐related factors like age and comorbidities.
In our intervention group, the overall rate of any degree of acute kidney injury (according to the AKIN classification) could be reduced from 6.3% (SOP group) to 0.7%. This finding demonstrates the high efficacy of standardized supportive care documentation to prevent acute renal failure during HD‐MTX treatment. The low rate of nephrotoxicity in our intervention group also shows the importance of effective and continuous urine alkalinization to prevent kidney damage during HD‐MTX treatment. The crucial role of urine alkalinization for adequate HD‐MTX clearance was also reported by other studies [7, 14].
The use of a standardized urine alkalinization protocol is an effective approach to optimize urine alkalinization during HD‐MTX therapy.
We decided to use a checklist for control of supportive care because previously, the usage of checklist‐based interventions was proven to be highly effective for improving the quality of routine clinical care and to ensure adherence to guidelines in clinical practice [17]. The low rate of adverse events in our intervention group demonstrates that the checklist‐based control of supportive care can improve the safety of HD‐MTX therapy. As outlined before, the most important element of this checklist is presumably the prevention of pharmacokinetic drug–drug interactions.
Another advantage of the checklist‐based documentation for supportive care during HD‐MTX therapy is that this approach enables a comprehensive, transparent overview of all important supportive care measures. Thus, the risk of insufficient supportive care is minimized while clinicians and nurses require less time and effort to control whether all necessary preparations for HD‐MTX are present.
Regarding the risk profile for adverse events in the SOP and intervention groups, the average age in both groups was about 53 years. The average MTX dose was slightly higher in the SOP cohort (2.7 vs. 2.1 g/m2). There was also a higher proportion of patients receiving 24‐hour infusional MTX within the intervention cohort. However, although both lower MTX dose and longer infusion times may reduce the overall risk of MTX toxicity, insufficient supportive care is still a major risk factor for adverse events in such circumstances. In comparison with the findings in our intervention group, other studies have reported comparable or even significantly higher rates of acute kidney injury for HD‐MTX in patients with childhood acute lymphoblastic leukemia [18, 19].
Limitations of our study are its retrospective, nonrandomized design and the evaluation within a single treatment center. However, our intervention of standardized supportive care documentation for HD‐MTX was effective in a broad, nonselected real‐world patient population, which warrants confirmation in further prospective clinical trials.
Our drug–drug interaction list did not include tyrosine kinase inhibitors like imatinib and dasatinib. However, it has been recently reported that such drugs may reduce MTX clearance and should therefore also be avoided during HD‐MTX treatment [20, 21].
Conclusion
The use of a standardized, checklist‐based documentation for supportive care significantly improves the safety of HD‐MTX treatment. These tools are able to minimize the risk of pharmacokinetic drug–drug interactions and insufficient urine alkalinization, leading to a low rate of adverse events. We therefore highly recommend implementation of such adjunctive measures for all patients receiving HD‐MTX. In our experience, the use of a checklist and urine alkalinization protocol is very efficient and can be easily implemented into clinical practice.
Author Contributions
Conception/design: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Provision of study material or patients: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Collection and/or assembly of data: Claudia Langebrake, Winfried Alsdorf, Christian Frenzel
Data analysis and interpretation: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Manuscript writing: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Final approval of manuscript: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Disclosures
Panagiotis Karagiannis: Abbvie Inc. (OI); Carsten Bokemeyer: Sanofi Aventis, Novartis, Merck Sharpe & Dohme, Bristol‐Myers Squibb, Eli Lilly & Co/Imclone, GSO Hamburg, AOK Health Insurance, Merck Darmstadt, Roche, Bayer Healthcare (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board | LEUCOVORIN, METHOTREXATE, PANTOPRAZOLE, SODIUM BICARBONATE | DrugsGivenReaction | CC BY-NC-ND | 33215763 | 19,172,964 | 2021-02 |
What was the administration route of drug 'METHOTREXATE'? | Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment.
High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy.
The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP).
In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group.
The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events.
High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX.
Introduction
High‐dose (HD) methotrexate (MTX; defined as MTX dose >500 mg/m2) has been used for several decades as an important backbone in treatment protocols for acute lymphoblastic leukemia, osteosarcoma, and lymphoma [1, 2, 3]. MTX acts as folate antimetabolite and inhibits DNA synthesis by blocking the enzyme dihydrofolate reductase. High doses of MTX are feasible by using folinic acid (syn, leucovorin, the reduced form of folic acid) to reduce the toxic effects upon nonmalignant cells as a “leucovorin rescue.”
Notable toxicities of HD‐MTX are mucositis, myelosuppression, renal failure, liver injury, and neurotoxicity [4]. The risk of HD‐MTX toxicity is especially increased in the case of therapy‐induced renal failure because impaired renal function leads to reduced MTX renal clearance, which is the major route (90%) of MTX elimination [5]. Prolonged exposure to toxic MTX levels can induce severe myelosuppression and mucositis and is a life‐threatening condition. Avoidance of renal injury and the consecutive risk of impaired MTX clearance is therefore paramount to prevent MTX toxicity.
HD‐MTX administration demands specialized supportive care to prevent adverse events. This includes strict urine alkalinization and hyperhydration to increase MTX elimination and to prevent kidney damage as well as administration of leucovorin to reduce mucositis and myelosuppression [4, 6].
Urine alkalinization has been identified as a crucial aspect of MTX clearance and prevention of renal toxicity. At a urine pH of 5, the solubility of MTX is very low, and it can precipitate within renal tubuli, which induces severe kidney damage with the consequence of acute renal failure. In some cases, this condition will require hemodialysis. By raising the urine pH from 5 to 7.5, solubility of MTX increases about 20‐fold [4, 5, 6, 7]. Therefore, permanent and effective urine alkalinization and hyperhydration are absolutely mandatory for safe HD‐MTX treatment.
As MTX can accumulate in third‐space fluids like ascites and pleural effusions, thereby leading to prolonged MTX clearance due to distribution processes, the presence of such third‐space fluids prior to HD‐MTX needs to be ruled out. This is usually performed by sonography.
Furthermore, pharmacokinetic interactions between several drugs (i.e., proton‐pump inhibitors, β‐lactam antibiotics, nonsteroidal anti‐inflammatory drugs like indomethacin and naproxen) and MTX have been previously identified as reason for delayed MTX elimination and subsequent toxicity [4, 8, 9, 10, 11]. Avoidance of such interactions is another important part of supportive care during HD‐MTX therapy.
Even slight deviations from optimal supportive therapy may lead to profound toxicities of HD‐MTX. Therefore, strict adherence to supportive measures during HD‐MTX is vital for patient safety. As HD‐MTX is often used in curative treatment settings (i.e., acute lymphoblastic leukemia, lymphoma), toxicity of HD‐MTX needs to be minimized to prevent treatment delays as this may impair the overall prognosis.
We hypothesized that supportive care for HD‐MTX can be significantly improved by implementing standardized protocols for all relevant elements of supportive treatment.
Materials and Methods
Additional tools for supportive care during HD‐MTX therapy including a checklist for supportive care and a urine alkalinization protocol were implemented in our clinic, a tertiary comprehensive cancer center.
The checklist contains several elements of supportive care and treatment preparation during HD‐MTX (Fig. 1). Important items of the checklist are sonographic detection of third‐space fluids, correct intravenous fluid administration, proper urine alkalinization before the start of MTX infusion, preparation of a leucovorin rescue protocol, and evaluation of possible pharmacokinetic interactions.
Figure 1 Checklist for high‐dose MTX therapy. Abbreviation: ASS, acetylsalicyclic acid; MTX, methotrexate; NSAID, nonsteroidal anti‐inflammatory drug.
A protocol for measurement and recording of urine pH values as well as documentation of alkalinization therapy was designed to ensure proper urinary alkalinization (Fig. 2).
Figure 2 Protocol for urine pH measurement and urine alkalinization during HD‐MTX. Abbreviations: HD‐MTX, high‐dose methotrexate.
The use of both the checklist and the alkalinization protocol was implemented in all patients receiving HD‐MTX starting in April 2017. These two documents were individually used for every single HD‐MTX treatment course in every patient. Both physicians and the nursing staff were responsible for using this documentation system. To assess the efficacy of this intervention, treatment data of 118 patients receiving HD‐MTX from April 2017 to April 2019 were analyzed (intervention group).
Prior to implementation of this standardized documentation, supportive care for HD‐MTX in our clinic was performed as recommended by international guidelines [4, 6], with modifications according to local practice following a dedicated standard operating procedure (SOP). This included urine alkalinization and hyperhydration, leucovorin rescue, detection of third‐space fluids, and avoidance of pharmacokinetic interactions. Urine alkalinization was achieved by intravenous application of sodium bicarbonate, and a urine pH of 8 was defined as target value. Fluid administration and leucovorin rescue were performed according to standardized chemotherapy treatment protocols. Documentation of supportive care was done in electronic patient records but was not standardized.
Predefined adverse events (acute kidney injury, prolongation of MTX clearance) were retrospectively assessed in a cohort of 108 patients treated from January 2015 to March 2017. In this control group, supportive care was delivered following the SOP but without standardized documentation tools.
Delayed MTX clearance was defined as failure to reach prespecified thresholds (<0.2 μmol/L at 72 hours after therapy) and if prolonged leucovorin rescue was necessary.
Acute kidney injury was defined according to the AKIN classification [12]. The threshold for definition of acute kidney injury was AKIN stage 1. By definition, this finding is made in patients with an absolute serum creatinine increase of 0.3 mg/dL or greater, an increase of 1.5‐fold or greater above the baseline serum creatinine, or onset of oliguria (urine output <0.5 mL/kg per hour lasting 6–12 hours).
For statistical comparison of adverse events between the treatment groups, the Fisher‐Yates test was used. A p value < .05 was defined as statistically significant.
This study was conducted after review by the local ethics committee of the Hamburg chamber of physicians, Germany (Ref. no. WF106‐20).
Results
In the intervention group, 118 patients were treated with 414 cycles of HD‐MTX. The SOP group consisted of 108 patients who received 332 cycles of HD‐MTX (Table 1). The most common indications for HD‐MTX in both groups were central nervous system lymphoma (43 patients in both groups), acute lymphoblastic leukemia (36 patients in the intervention and 23 in the SOP group), and non‐Hodgkin lymphoma (16 patients in the intervention and 18 in the SOP group).
Table 1 Characteristics of SOP and intervention groups and frequency of adverse events
Characteristic SOP group Intervention group
p value
No. of patients 108 118
No. of treatment cycles 332 414
Mean age (range), yr 53 (18–85) 52 (18–83)
Burkitt lymphoma, n
16 19
CNS lymphoma, n
43 43
Osteosarcoma, n
8 2
Choriocarcinoma, n
0 2
Acute lymphoblastic leukemia, n
23 36
Non‐Hodgkin Lymphoma, n
18 16
MTX dose, mean (range), g/m2
2.7 (0.5–12) 2.1 (0.5–12)
No. of cycles with delayed MTX clearance (%) 51 (15.2) 11 (2.6) <.001
Acute kidney injury, n (%) 21 (6.2.) 3 (0.7) <.001
No. of cycles with use of carboxypeptidase (%)
5 (1.47) 2 (0.48) .25
Abbreviations: CNS, central nervous system; MTX, methotrexate; SOP, standard operating procedure.
The average MTX dose per treatment cycle was 2.7 g/m2 in the SOP group and 2.1 g/m2 in the intervention group. All patients with acute lymphoblastic leukemia received HD‐MTX as a continuous infusion over 24 hours, whereas in all other indications, MTX was administered as an infusion over 3–4 hours.
In 51 of 332 HD‐MTX cycles (15.2%) within the SOP group, MTX clearance was delayed. In contrast, delayed MTX clearance was only observed in 11 of 414 treatment cycles of the intervention group (2.6%, p < .001)
Acute kidney injury occurred in 6.3% of cycles (n = 21) within the SOP group and in only 0.7% of cycles (n = 3) in the intervention group (p < .001).
One patient with acute renal failure in the SOP group underwent hemodialysis. In all patients experiencing acute kidney injury, kidney damage was reversible and did not induce chronic renal impairment.
HD‐MTX therapy was permanently discontinued because of toxicity in five patients of the SOP group and in one patient of the intervention group. Five patients of the SOP group and two patients within the intervention group received carboxypeptidase because of acute renal failure and insufficient MTX clearance. The indication for carboxypeptidase was evaluated according to international recommendations [6, 13]. There were no treatment‐related deaths.
A review of potential reasons for complications in the SOP group by analysis of all treatment cycles with acute kidney injury and/or delayed MTX clearance revealed potential pharmacokinetic drug–drug interactions in 17 treatment cycles and inadequate control of urine alkalinization in 5 treatment cycles.
In the 21 treatment cycles of the SOP group that resulted in acute kidney injury, a potential drug–drug interaction was present in eight cases and inadequate urine alkalinization was present in five cycles. Other causes for nephrotoxicity were one case of tumor lysis syndrome and two patients with pretherapeutic renal impairment.
In the intervention cohort, administration of potentially interacting drugs could be successfully avoided. Specifically, in the three cases of acute kidney injury in the intervention group, no interfering medication was given. Table 2 summarizes the analysis of underlying causes for acute kidney injury in both treatment groups.
Table 2 Analysis of patients with acute kidney injury after high‐dose MTX
Potential reason for MTX toxicity Intervention group (n = 3) SOP group (n = 21)
Concomitant medication 0 8
Tumor lysis syndrome 0 1
Urinary retention due to bladder obstruction 1 0
Insufficient urine alkalinization 0 5
Preexisting renal impairment 0 2
Unknown 2 12
Abbreviations: MTX, methotrexate; SOP, standard operating procedure.
Discussion
Herein, we demonstrate that standardized documentation protocols for supportive care significantly reduce the rate of adverse events during HD‐MTX therapy by using a simplified and structured guidance consisting of only two single‐page documents (checklist and urine alkalinization protocol). Implementation of these measures was performed with high acceptance by physicians and nurses, as both the checklist and the alkalinization protocol were successfully applied in all patients within the intervention group for every treatment course.
Even slight deviations in supportive care may lead to acute kidney failure and subsequent toxicities of HD‐MTX. In clinical practice, strict adherence to these requirements can be challenging, and errors may occur. Optimal supportive care has been previously demonstrated to reduce the risk of HD‐MTX toxicity [4, 6, 13, 14].
Pharmacokinetic interactions between concomitant medications and MTX with significantly delayed MTX elimination have been previously described [8, 9, 10, 11, 15]. Therefore, avoidance of such pharmacokinetic interactions is imperative to administer HD‐MTX safely. The use of a checklist containing information on potential pharmacokinetic interactions can assist in preventing these adverse events.
For instance, we observed a case of acute renal failure necessitating hemodialysis in our SOP group after intravenous administration of a single dose of 40 mg pantoprazole only a few hours after infusion of HD‐MTX. As this example demonstrates, supportive care prior, during, and after HD‐MTX administration has to follow strict rules to avoid serious toxicity.
The important role of pharmacokinetic interactions for HD‐MTX toxicity is also supported by the finding of potentially interacting medication in about one third of the 21 cycles leading to acute kidney injury within the SOP group. In contrast, no patient within the intervention group had received interacting medications.
Previously, the rate of renal failure after HD‐MTX despite adequate, nonstandardized supportive care was reported to be 1.8% [6]. In another retrospective analysis in patients with lymphoma receiving HD‐MTX, the rate of renal injury was about 9% [16]. The reason for these different findings are presumably patient‐related factors like age and comorbidities.
In our intervention group, the overall rate of any degree of acute kidney injury (according to the AKIN classification) could be reduced from 6.3% (SOP group) to 0.7%. This finding demonstrates the high efficacy of standardized supportive care documentation to prevent acute renal failure during HD‐MTX treatment. The low rate of nephrotoxicity in our intervention group also shows the importance of effective and continuous urine alkalinization to prevent kidney damage during HD‐MTX treatment. The crucial role of urine alkalinization for adequate HD‐MTX clearance was also reported by other studies [7, 14].
The use of a standardized urine alkalinization protocol is an effective approach to optimize urine alkalinization during HD‐MTX therapy.
We decided to use a checklist for control of supportive care because previously, the usage of checklist‐based interventions was proven to be highly effective for improving the quality of routine clinical care and to ensure adherence to guidelines in clinical practice [17]. The low rate of adverse events in our intervention group demonstrates that the checklist‐based control of supportive care can improve the safety of HD‐MTX therapy. As outlined before, the most important element of this checklist is presumably the prevention of pharmacokinetic drug–drug interactions.
Another advantage of the checklist‐based documentation for supportive care during HD‐MTX therapy is that this approach enables a comprehensive, transparent overview of all important supportive care measures. Thus, the risk of insufficient supportive care is minimized while clinicians and nurses require less time and effort to control whether all necessary preparations for HD‐MTX are present.
Regarding the risk profile for adverse events in the SOP and intervention groups, the average age in both groups was about 53 years. The average MTX dose was slightly higher in the SOP cohort (2.7 vs. 2.1 g/m2). There was also a higher proportion of patients receiving 24‐hour infusional MTX within the intervention cohort. However, although both lower MTX dose and longer infusion times may reduce the overall risk of MTX toxicity, insufficient supportive care is still a major risk factor for adverse events in such circumstances. In comparison with the findings in our intervention group, other studies have reported comparable or even significantly higher rates of acute kidney injury for HD‐MTX in patients with childhood acute lymphoblastic leukemia [18, 19].
Limitations of our study are its retrospective, nonrandomized design and the evaluation within a single treatment center. However, our intervention of standardized supportive care documentation for HD‐MTX was effective in a broad, nonselected real‐world patient population, which warrants confirmation in further prospective clinical trials.
Our drug–drug interaction list did not include tyrosine kinase inhibitors like imatinib and dasatinib. However, it has been recently reported that such drugs may reduce MTX clearance and should therefore also be avoided during HD‐MTX treatment [20, 21].
Conclusion
The use of a standardized, checklist‐based documentation for supportive care significantly improves the safety of HD‐MTX treatment. These tools are able to minimize the risk of pharmacokinetic drug–drug interactions and insufficient urine alkalinization, leading to a low rate of adverse events. We therefore highly recommend implementation of such adjunctive measures for all patients receiving HD‐MTX. In our experience, the use of a checklist and urine alkalinization protocol is very efficient and can be easily implemented into clinical practice.
Author Contributions
Conception/design: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Provision of study material or patients: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Collection and/or assembly of data: Claudia Langebrake, Winfried Alsdorf, Christian Frenzel
Data analysis and interpretation: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Manuscript writing: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Final approval of manuscript: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Disclosures
Panagiotis Karagiannis: Abbvie Inc. (OI); Carsten Bokemeyer: Sanofi Aventis, Novartis, Merck Sharpe & Dohme, Bristol‐Myers Squibb, Eli Lilly & Co/Imclone, GSO Hamburg, AOK Health Insurance, Merck Darmstadt, Roche, Bayer Healthcare (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board | Other | DrugAdministrationRoute | CC BY-NC-ND | 33215763 | 19,196,320 | 2021-02 |
What was the administration route of drug 'PANTOPRAZOLE'? | Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment.
High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy.
The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP).
In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group.
The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events.
High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX.
Introduction
High‐dose (HD) methotrexate (MTX; defined as MTX dose >500 mg/m2) has been used for several decades as an important backbone in treatment protocols for acute lymphoblastic leukemia, osteosarcoma, and lymphoma [1, 2, 3]. MTX acts as folate antimetabolite and inhibits DNA synthesis by blocking the enzyme dihydrofolate reductase. High doses of MTX are feasible by using folinic acid (syn, leucovorin, the reduced form of folic acid) to reduce the toxic effects upon nonmalignant cells as a “leucovorin rescue.”
Notable toxicities of HD‐MTX are mucositis, myelosuppression, renal failure, liver injury, and neurotoxicity [4]. The risk of HD‐MTX toxicity is especially increased in the case of therapy‐induced renal failure because impaired renal function leads to reduced MTX renal clearance, which is the major route (90%) of MTX elimination [5]. Prolonged exposure to toxic MTX levels can induce severe myelosuppression and mucositis and is a life‐threatening condition. Avoidance of renal injury and the consecutive risk of impaired MTX clearance is therefore paramount to prevent MTX toxicity.
HD‐MTX administration demands specialized supportive care to prevent adverse events. This includes strict urine alkalinization and hyperhydration to increase MTX elimination and to prevent kidney damage as well as administration of leucovorin to reduce mucositis and myelosuppression [4, 6].
Urine alkalinization has been identified as a crucial aspect of MTX clearance and prevention of renal toxicity. At a urine pH of 5, the solubility of MTX is very low, and it can precipitate within renal tubuli, which induces severe kidney damage with the consequence of acute renal failure. In some cases, this condition will require hemodialysis. By raising the urine pH from 5 to 7.5, solubility of MTX increases about 20‐fold [4, 5, 6, 7]. Therefore, permanent and effective urine alkalinization and hyperhydration are absolutely mandatory for safe HD‐MTX treatment.
As MTX can accumulate in third‐space fluids like ascites and pleural effusions, thereby leading to prolonged MTX clearance due to distribution processes, the presence of such third‐space fluids prior to HD‐MTX needs to be ruled out. This is usually performed by sonography.
Furthermore, pharmacokinetic interactions between several drugs (i.e., proton‐pump inhibitors, β‐lactam antibiotics, nonsteroidal anti‐inflammatory drugs like indomethacin and naproxen) and MTX have been previously identified as reason for delayed MTX elimination and subsequent toxicity [4, 8, 9, 10, 11]. Avoidance of such interactions is another important part of supportive care during HD‐MTX therapy.
Even slight deviations from optimal supportive therapy may lead to profound toxicities of HD‐MTX. Therefore, strict adherence to supportive measures during HD‐MTX is vital for patient safety. As HD‐MTX is often used in curative treatment settings (i.e., acute lymphoblastic leukemia, lymphoma), toxicity of HD‐MTX needs to be minimized to prevent treatment delays as this may impair the overall prognosis.
We hypothesized that supportive care for HD‐MTX can be significantly improved by implementing standardized protocols for all relevant elements of supportive treatment.
Materials and Methods
Additional tools for supportive care during HD‐MTX therapy including a checklist for supportive care and a urine alkalinization protocol were implemented in our clinic, a tertiary comprehensive cancer center.
The checklist contains several elements of supportive care and treatment preparation during HD‐MTX (Fig. 1). Important items of the checklist are sonographic detection of third‐space fluids, correct intravenous fluid administration, proper urine alkalinization before the start of MTX infusion, preparation of a leucovorin rescue protocol, and evaluation of possible pharmacokinetic interactions.
Figure 1 Checklist for high‐dose MTX therapy. Abbreviation: ASS, acetylsalicyclic acid; MTX, methotrexate; NSAID, nonsteroidal anti‐inflammatory drug.
A protocol for measurement and recording of urine pH values as well as documentation of alkalinization therapy was designed to ensure proper urinary alkalinization (Fig. 2).
Figure 2 Protocol for urine pH measurement and urine alkalinization during HD‐MTX. Abbreviations: HD‐MTX, high‐dose methotrexate.
The use of both the checklist and the alkalinization protocol was implemented in all patients receiving HD‐MTX starting in April 2017. These two documents were individually used for every single HD‐MTX treatment course in every patient. Both physicians and the nursing staff were responsible for using this documentation system. To assess the efficacy of this intervention, treatment data of 118 patients receiving HD‐MTX from April 2017 to April 2019 were analyzed (intervention group).
Prior to implementation of this standardized documentation, supportive care for HD‐MTX in our clinic was performed as recommended by international guidelines [4, 6], with modifications according to local practice following a dedicated standard operating procedure (SOP). This included urine alkalinization and hyperhydration, leucovorin rescue, detection of third‐space fluids, and avoidance of pharmacokinetic interactions. Urine alkalinization was achieved by intravenous application of sodium bicarbonate, and a urine pH of 8 was defined as target value. Fluid administration and leucovorin rescue were performed according to standardized chemotherapy treatment protocols. Documentation of supportive care was done in electronic patient records but was not standardized.
Predefined adverse events (acute kidney injury, prolongation of MTX clearance) were retrospectively assessed in a cohort of 108 patients treated from January 2015 to March 2017. In this control group, supportive care was delivered following the SOP but without standardized documentation tools.
Delayed MTX clearance was defined as failure to reach prespecified thresholds (<0.2 μmol/L at 72 hours after therapy) and if prolonged leucovorin rescue was necessary.
Acute kidney injury was defined according to the AKIN classification [12]. The threshold for definition of acute kidney injury was AKIN stage 1. By definition, this finding is made in patients with an absolute serum creatinine increase of 0.3 mg/dL or greater, an increase of 1.5‐fold or greater above the baseline serum creatinine, or onset of oliguria (urine output <0.5 mL/kg per hour lasting 6–12 hours).
For statistical comparison of adverse events between the treatment groups, the Fisher‐Yates test was used. A p value < .05 was defined as statistically significant.
This study was conducted after review by the local ethics committee of the Hamburg chamber of physicians, Germany (Ref. no. WF106‐20).
Results
In the intervention group, 118 patients were treated with 414 cycles of HD‐MTX. The SOP group consisted of 108 patients who received 332 cycles of HD‐MTX (Table 1). The most common indications for HD‐MTX in both groups were central nervous system lymphoma (43 patients in both groups), acute lymphoblastic leukemia (36 patients in the intervention and 23 in the SOP group), and non‐Hodgkin lymphoma (16 patients in the intervention and 18 in the SOP group).
Table 1 Characteristics of SOP and intervention groups and frequency of adverse events
Characteristic SOP group Intervention group
p value
No. of patients 108 118
No. of treatment cycles 332 414
Mean age (range), yr 53 (18–85) 52 (18–83)
Burkitt lymphoma, n
16 19
CNS lymphoma, n
43 43
Osteosarcoma, n
8 2
Choriocarcinoma, n
0 2
Acute lymphoblastic leukemia, n
23 36
Non‐Hodgkin Lymphoma, n
18 16
MTX dose, mean (range), g/m2
2.7 (0.5–12) 2.1 (0.5–12)
No. of cycles with delayed MTX clearance (%) 51 (15.2) 11 (2.6) <.001
Acute kidney injury, n (%) 21 (6.2.) 3 (0.7) <.001
No. of cycles with use of carboxypeptidase (%)
5 (1.47) 2 (0.48) .25
Abbreviations: CNS, central nervous system; MTX, methotrexate; SOP, standard operating procedure.
The average MTX dose per treatment cycle was 2.7 g/m2 in the SOP group and 2.1 g/m2 in the intervention group. All patients with acute lymphoblastic leukemia received HD‐MTX as a continuous infusion over 24 hours, whereas in all other indications, MTX was administered as an infusion over 3–4 hours.
In 51 of 332 HD‐MTX cycles (15.2%) within the SOP group, MTX clearance was delayed. In contrast, delayed MTX clearance was only observed in 11 of 414 treatment cycles of the intervention group (2.6%, p < .001)
Acute kidney injury occurred in 6.3% of cycles (n = 21) within the SOP group and in only 0.7% of cycles (n = 3) in the intervention group (p < .001).
One patient with acute renal failure in the SOP group underwent hemodialysis. In all patients experiencing acute kidney injury, kidney damage was reversible and did not induce chronic renal impairment.
HD‐MTX therapy was permanently discontinued because of toxicity in five patients of the SOP group and in one patient of the intervention group. Five patients of the SOP group and two patients within the intervention group received carboxypeptidase because of acute renal failure and insufficient MTX clearance. The indication for carboxypeptidase was evaluated according to international recommendations [6, 13]. There were no treatment‐related deaths.
A review of potential reasons for complications in the SOP group by analysis of all treatment cycles with acute kidney injury and/or delayed MTX clearance revealed potential pharmacokinetic drug–drug interactions in 17 treatment cycles and inadequate control of urine alkalinization in 5 treatment cycles.
In the 21 treatment cycles of the SOP group that resulted in acute kidney injury, a potential drug–drug interaction was present in eight cases and inadequate urine alkalinization was present in five cycles. Other causes for nephrotoxicity were one case of tumor lysis syndrome and two patients with pretherapeutic renal impairment.
In the intervention cohort, administration of potentially interacting drugs could be successfully avoided. Specifically, in the three cases of acute kidney injury in the intervention group, no interfering medication was given. Table 2 summarizes the analysis of underlying causes for acute kidney injury in both treatment groups.
Table 2 Analysis of patients with acute kidney injury after high‐dose MTX
Potential reason for MTX toxicity Intervention group (n = 3) SOP group (n = 21)
Concomitant medication 0 8
Tumor lysis syndrome 0 1
Urinary retention due to bladder obstruction 1 0
Insufficient urine alkalinization 0 5
Preexisting renal impairment 0 2
Unknown 2 12
Abbreviations: MTX, methotrexate; SOP, standard operating procedure.
Discussion
Herein, we demonstrate that standardized documentation protocols for supportive care significantly reduce the rate of adverse events during HD‐MTX therapy by using a simplified and structured guidance consisting of only two single‐page documents (checklist and urine alkalinization protocol). Implementation of these measures was performed with high acceptance by physicians and nurses, as both the checklist and the alkalinization protocol were successfully applied in all patients within the intervention group for every treatment course.
Even slight deviations in supportive care may lead to acute kidney failure and subsequent toxicities of HD‐MTX. In clinical practice, strict adherence to these requirements can be challenging, and errors may occur. Optimal supportive care has been previously demonstrated to reduce the risk of HD‐MTX toxicity [4, 6, 13, 14].
Pharmacokinetic interactions between concomitant medications and MTX with significantly delayed MTX elimination have been previously described [8, 9, 10, 11, 15]. Therefore, avoidance of such pharmacokinetic interactions is imperative to administer HD‐MTX safely. The use of a checklist containing information on potential pharmacokinetic interactions can assist in preventing these adverse events.
For instance, we observed a case of acute renal failure necessitating hemodialysis in our SOP group after intravenous administration of a single dose of 40 mg pantoprazole only a few hours after infusion of HD‐MTX. As this example demonstrates, supportive care prior, during, and after HD‐MTX administration has to follow strict rules to avoid serious toxicity.
The important role of pharmacokinetic interactions for HD‐MTX toxicity is also supported by the finding of potentially interacting medication in about one third of the 21 cycles leading to acute kidney injury within the SOP group. In contrast, no patient within the intervention group had received interacting medications.
Previously, the rate of renal failure after HD‐MTX despite adequate, nonstandardized supportive care was reported to be 1.8% [6]. In another retrospective analysis in patients with lymphoma receiving HD‐MTX, the rate of renal injury was about 9% [16]. The reason for these different findings are presumably patient‐related factors like age and comorbidities.
In our intervention group, the overall rate of any degree of acute kidney injury (according to the AKIN classification) could be reduced from 6.3% (SOP group) to 0.7%. This finding demonstrates the high efficacy of standardized supportive care documentation to prevent acute renal failure during HD‐MTX treatment. The low rate of nephrotoxicity in our intervention group also shows the importance of effective and continuous urine alkalinization to prevent kidney damage during HD‐MTX treatment. The crucial role of urine alkalinization for adequate HD‐MTX clearance was also reported by other studies [7, 14].
The use of a standardized urine alkalinization protocol is an effective approach to optimize urine alkalinization during HD‐MTX therapy.
We decided to use a checklist for control of supportive care because previously, the usage of checklist‐based interventions was proven to be highly effective for improving the quality of routine clinical care and to ensure adherence to guidelines in clinical practice [17]. The low rate of adverse events in our intervention group demonstrates that the checklist‐based control of supportive care can improve the safety of HD‐MTX therapy. As outlined before, the most important element of this checklist is presumably the prevention of pharmacokinetic drug–drug interactions.
Another advantage of the checklist‐based documentation for supportive care during HD‐MTX therapy is that this approach enables a comprehensive, transparent overview of all important supportive care measures. Thus, the risk of insufficient supportive care is minimized while clinicians and nurses require less time and effort to control whether all necessary preparations for HD‐MTX are present.
Regarding the risk profile for adverse events in the SOP and intervention groups, the average age in both groups was about 53 years. The average MTX dose was slightly higher in the SOP cohort (2.7 vs. 2.1 g/m2). There was also a higher proportion of patients receiving 24‐hour infusional MTX within the intervention cohort. However, although both lower MTX dose and longer infusion times may reduce the overall risk of MTX toxicity, insufficient supportive care is still a major risk factor for adverse events in such circumstances. In comparison with the findings in our intervention group, other studies have reported comparable or even significantly higher rates of acute kidney injury for HD‐MTX in patients with childhood acute lymphoblastic leukemia [18, 19].
Limitations of our study are its retrospective, nonrandomized design and the evaluation within a single treatment center. However, our intervention of standardized supportive care documentation for HD‐MTX was effective in a broad, nonselected real‐world patient population, which warrants confirmation in further prospective clinical trials.
Our drug–drug interaction list did not include tyrosine kinase inhibitors like imatinib and dasatinib. However, it has been recently reported that such drugs may reduce MTX clearance and should therefore also be avoided during HD‐MTX treatment [20, 21].
Conclusion
The use of a standardized, checklist‐based documentation for supportive care significantly improves the safety of HD‐MTX treatment. These tools are able to minimize the risk of pharmacokinetic drug–drug interactions and insufficient urine alkalinization, leading to a low rate of adverse events. We therefore highly recommend implementation of such adjunctive measures for all patients receiving HD‐MTX. In our experience, the use of a checklist and urine alkalinization protocol is very efficient and can be easily implemented into clinical practice.
Author Contributions
Conception/design: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Provision of study material or patients: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Collection and/or assembly of data: Claudia Langebrake, Winfried Alsdorf, Christian Frenzel
Data analysis and interpretation: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Manuscript writing: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Final approval of manuscript: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Disclosures
Panagiotis Karagiannis: Abbvie Inc. (OI); Carsten Bokemeyer: Sanofi Aventis, Novartis, Merck Sharpe & Dohme, Bristol‐Myers Squibb, Eli Lilly & Co/Imclone, GSO Hamburg, AOK Health Insurance, Merck Darmstadt, Roche, Bayer Healthcare (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33215763 | 19,172,964 | 2021-02 |
What was the administration route of drug 'SODIUM BICARBONATE'? | Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment.
High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy.
The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP).
In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group.
The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events.
High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX.
Introduction
High‐dose (HD) methotrexate (MTX; defined as MTX dose >500 mg/m2) has been used for several decades as an important backbone in treatment protocols for acute lymphoblastic leukemia, osteosarcoma, and lymphoma [1, 2, 3]. MTX acts as folate antimetabolite and inhibits DNA synthesis by blocking the enzyme dihydrofolate reductase. High doses of MTX are feasible by using folinic acid (syn, leucovorin, the reduced form of folic acid) to reduce the toxic effects upon nonmalignant cells as a “leucovorin rescue.”
Notable toxicities of HD‐MTX are mucositis, myelosuppression, renal failure, liver injury, and neurotoxicity [4]. The risk of HD‐MTX toxicity is especially increased in the case of therapy‐induced renal failure because impaired renal function leads to reduced MTX renal clearance, which is the major route (90%) of MTX elimination [5]. Prolonged exposure to toxic MTX levels can induce severe myelosuppression and mucositis and is a life‐threatening condition. Avoidance of renal injury and the consecutive risk of impaired MTX clearance is therefore paramount to prevent MTX toxicity.
HD‐MTX administration demands specialized supportive care to prevent adverse events. This includes strict urine alkalinization and hyperhydration to increase MTX elimination and to prevent kidney damage as well as administration of leucovorin to reduce mucositis and myelosuppression [4, 6].
Urine alkalinization has been identified as a crucial aspect of MTX clearance and prevention of renal toxicity. At a urine pH of 5, the solubility of MTX is very low, and it can precipitate within renal tubuli, which induces severe kidney damage with the consequence of acute renal failure. In some cases, this condition will require hemodialysis. By raising the urine pH from 5 to 7.5, solubility of MTX increases about 20‐fold [4, 5, 6, 7]. Therefore, permanent and effective urine alkalinization and hyperhydration are absolutely mandatory for safe HD‐MTX treatment.
As MTX can accumulate in third‐space fluids like ascites and pleural effusions, thereby leading to prolonged MTX clearance due to distribution processes, the presence of such third‐space fluids prior to HD‐MTX needs to be ruled out. This is usually performed by sonography.
Furthermore, pharmacokinetic interactions between several drugs (i.e., proton‐pump inhibitors, β‐lactam antibiotics, nonsteroidal anti‐inflammatory drugs like indomethacin and naproxen) and MTX have been previously identified as reason for delayed MTX elimination and subsequent toxicity [4, 8, 9, 10, 11]. Avoidance of such interactions is another important part of supportive care during HD‐MTX therapy.
Even slight deviations from optimal supportive therapy may lead to profound toxicities of HD‐MTX. Therefore, strict adherence to supportive measures during HD‐MTX is vital for patient safety. As HD‐MTX is often used in curative treatment settings (i.e., acute lymphoblastic leukemia, lymphoma), toxicity of HD‐MTX needs to be minimized to prevent treatment delays as this may impair the overall prognosis.
We hypothesized that supportive care for HD‐MTX can be significantly improved by implementing standardized protocols for all relevant elements of supportive treatment.
Materials and Methods
Additional tools for supportive care during HD‐MTX therapy including a checklist for supportive care and a urine alkalinization protocol were implemented in our clinic, a tertiary comprehensive cancer center.
The checklist contains several elements of supportive care and treatment preparation during HD‐MTX (Fig. 1). Important items of the checklist are sonographic detection of third‐space fluids, correct intravenous fluid administration, proper urine alkalinization before the start of MTX infusion, preparation of a leucovorin rescue protocol, and evaluation of possible pharmacokinetic interactions.
Figure 1 Checklist for high‐dose MTX therapy. Abbreviation: ASS, acetylsalicyclic acid; MTX, methotrexate; NSAID, nonsteroidal anti‐inflammatory drug.
A protocol for measurement and recording of urine pH values as well as documentation of alkalinization therapy was designed to ensure proper urinary alkalinization (Fig. 2).
Figure 2 Protocol for urine pH measurement and urine alkalinization during HD‐MTX. Abbreviations: HD‐MTX, high‐dose methotrexate.
The use of both the checklist and the alkalinization protocol was implemented in all patients receiving HD‐MTX starting in April 2017. These two documents were individually used for every single HD‐MTX treatment course in every patient. Both physicians and the nursing staff were responsible for using this documentation system. To assess the efficacy of this intervention, treatment data of 118 patients receiving HD‐MTX from April 2017 to April 2019 were analyzed (intervention group).
Prior to implementation of this standardized documentation, supportive care for HD‐MTX in our clinic was performed as recommended by international guidelines [4, 6], with modifications according to local practice following a dedicated standard operating procedure (SOP). This included urine alkalinization and hyperhydration, leucovorin rescue, detection of third‐space fluids, and avoidance of pharmacokinetic interactions. Urine alkalinization was achieved by intravenous application of sodium bicarbonate, and a urine pH of 8 was defined as target value. Fluid administration and leucovorin rescue were performed according to standardized chemotherapy treatment protocols. Documentation of supportive care was done in electronic patient records but was not standardized.
Predefined adverse events (acute kidney injury, prolongation of MTX clearance) were retrospectively assessed in a cohort of 108 patients treated from January 2015 to March 2017. In this control group, supportive care was delivered following the SOP but without standardized documentation tools.
Delayed MTX clearance was defined as failure to reach prespecified thresholds (<0.2 μmol/L at 72 hours after therapy) and if prolonged leucovorin rescue was necessary.
Acute kidney injury was defined according to the AKIN classification [12]. The threshold for definition of acute kidney injury was AKIN stage 1. By definition, this finding is made in patients with an absolute serum creatinine increase of 0.3 mg/dL or greater, an increase of 1.5‐fold or greater above the baseline serum creatinine, or onset of oliguria (urine output <0.5 mL/kg per hour lasting 6–12 hours).
For statistical comparison of adverse events between the treatment groups, the Fisher‐Yates test was used. A p value < .05 was defined as statistically significant.
This study was conducted after review by the local ethics committee of the Hamburg chamber of physicians, Germany (Ref. no. WF106‐20).
Results
In the intervention group, 118 patients were treated with 414 cycles of HD‐MTX. The SOP group consisted of 108 patients who received 332 cycles of HD‐MTX (Table 1). The most common indications for HD‐MTX in both groups were central nervous system lymphoma (43 patients in both groups), acute lymphoblastic leukemia (36 patients in the intervention and 23 in the SOP group), and non‐Hodgkin lymphoma (16 patients in the intervention and 18 in the SOP group).
Table 1 Characteristics of SOP and intervention groups and frequency of adverse events
Characteristic SOP group Intervention group
p value
No. of patients 108 118
No. of treatment cycles 332 414
Mean age (range), yr 53 (18–85) 52 (18–83)
Burkitt lymphoma, n
16 19
CNS lymphoma, n
43 43
Osteosarcoma, n
8 2
Choriocarcinoma, n
0 2
Acute lymphoblastic leukemia, n
23 36
Non‐Hodgkin Lymphoma, n
18 16
MTX dose, mean (range), g/m2
2.7 (0.5–12) 2.1 (0.5–12)
No. of cycles with delayed MTX clearance (%) 51 (15.2) 11 (2.6) <.001
Acute kidney injury, n (%) 21 (6.2.) 3 (0.7) <.001
No. of cycles with use of carboxypeptidase (%)
5 (1.47) 2 (0.48) .25
Abbreviations: CNS, central nervous system; MTX, methotrexate; SOP, standard operating procedure.
The average MTX dose per treatment cycle was 2.7 g/m2 in the SOP group and 2.1 g/m2 in the intervention group. All patients with acute lymphoblastic leukemia received HD‐MTX as a continuous infusion over 24 hours, whereas in all other indications, MTX was administered as an infusion over 3–4 hours.
In 51 of 332 HD‐MTX cycles (15.2%) within the SOP group, MTX clearance was delayed. In contrast, delayed MTX clearance was only observed in 11 of 414 treatment cycles of the intervention group (2.6%, p < .001)
Acute kidney injury occurred in 6.3% of cycles (n = 21) within the SOP group and in only 0.7% of cycles (n = 3) in the intervention group (p < .001).
One patient with acute renal failure in the SOP group underwent hemodialysis. In all patients experiencing acute kidney injury, kidney damage was reversible and did not induce chronic renal impairment.
HD‐MTX therapy was permanently discontinued because of toxicity in five patients of the SOP group and in one patient of the intervention group. Five patients of the SOP group and two patients within the intervention group received carboxypeptidase because of acute renal failure and insufficient MTX clearance. The indication for carboxypeptidase was evaluated according to international recommendations [6, 13]. There were no treatment‐related deaths.
A review of potential reasons for complications in the SOP group by analysis of all treatment cycles with acute kidney injury and/or delayed MTX clearance revealed potential pharmacokinetic drug–drug interactions in 17 treatment cycles and inadequate control of urine alkalinization in 5 treatment cycles.
In the 21 treatment cycles of the SOP group that resulted in acute kidney injury, a potential drug–drug interaction was present in eight cases and inadequate urine alkalinization was present in five cycles. Other causes for nephrotoxicity were one case of tumor lysis syndrome and two patients with pretherapeutic renal impairment.
In the intervention cohort, administration of potentially interacting drugs could be successfully avoided. Specifically, in the three cases of acute kidney injury in the intervention group, no interfering medication was given. Table 2 summarizes the analysis of underlying causes for acute kidney injury in both treatment groups.
Table 2 Analysis of patients with acute kidney injury after high‐dose MTX
Potential reason for MTX toxicity Intervention group (n = 3) SOP group (n = 21)
Concomitant medication 0 8
Tumor lysis syndrome 0 1
Urinary retention due to bladder obstruction 1 0
Insufficient urine alkalinization 0 5
Preexisting renal impairment 0 2
Unknown 2 12
Abbreviations: MTX, methotrexate; SOP, standard operating procedure.
Discussion
Herein, we demonstrate that standardized documentation protocols for supportive care significantly reduce the rate of adverse events during HD‐MTX therapy by using a simplified and structured guidance consisting of only two single‐page documents (checklist and urine alkalinization protocol). Implementation of these measures was performed with high acceptance by physicians and nurses, as both the checklist and the alkalinization protocol were successfully applied in all patients within the intervention group for every treatment course.
Even slight deviations in supportive care may lead to acute kidney failure and subsequent toxicities of HD‐MTX. In clinical practice, strict adherence to these requirements can be challenging, and errors may occur. Optimal supportive care has been previously demonstrated to reduce the risk of HD‐MTX toxicity [4, 6, 13, 14].
Pharmacokinetic interactions between concomitant medications and MTX with significantly delayed MTX elimination have been previously described [8, 9, 10, 11, 15]. Therefore, avoidance of such pharmacokinetic interactions is imperative to administer HD‐MTX safely. The use of a checklist containing information on potential pharmacokinetic interactions can assist in preventing these adverse events.
For instance, we observed a case of acute renal failure necessitating hemodialysis in our SOP group after intravenous administration of a single dose of 40 mg pantoprazole only a few hours after infusion of HD‐MTX. As this example demonstrates, supportive care prior, during, and after HD‐MTX administration has to follow strict rules to avoid serious toxicity.
The important role of pharmacokinetic interactions for HD‐MTX toxicity is also supported by the finding of potentially interacting medication in about one third of the 21 cycles leading to acute kidney injury within the SOP group. In contrast, no patient within the intervention group had received interacting medications.
Previously, the rate of renal failure after HD‐MTX despite adequate, nonstandardized supportive care was reported to be 1.8% [6]. In another retrospective analysis in patients with lymphoma receiving HD‐MTX, the rate of renal injury was about 9% [16]. The reason for these different findings are presumably patient‐related factors like age and comorbidities.
In our intervention group, the overall rate of any degree of acute kidney injury (according to the AKIN classification) could be reduced from 6.3% (SOP group) to 0.7%. This finding demonstrates the high efficacy of standardized supportive care documentation to prevent acute renal failure during HD‐MTX treatment. The low rate of nephrotoxicity in our intervention group also shows the importance of effective and continuous urine alkalinization to prevent kidney damage during HD‐MTX treatment. The crucial role of urine alkalinization for adequate HD‐MTX clearance was also reported by other studies [7, 14].
The use of a standardized urine alkalinization protocol is an effective approach to optimize urine alkalinization during HD‐MTX therapy.
We decided to use a checklist for control of supportive care because previously, the usage of checklist‐based interventions was proven to be highly effective for improving the quality of routine clinical care and to ensure adherence to guidelines in clinical practice [17]. The low rate of adverse events in our intervention group demonstrates that the checklist‐based control of supportive care can improve the safety of HD‐MTX therapy. As outlined before, the most important element of this checklist is presumably the prevention of pharmacokinetic drug–drug interactions.
Another advantage of the checklist‐based documentation for supportive care during HD‐MTX therapy is that this approach enables a comprehensive, transparent overview of all important supportive care measures. Thus, the risk of insufficient supportive care is minimized while clinicians and nurses require less time and effort to control whether all necessary preparations for HD‐MTX are present.
Regarding the risk profile for adverse events in the SOP and intervention groups, the average age in both groups was about 53 years. The average MTX dose was slightly higher in the SOP cohort (2.7 vs. 2.1 g/m2). There was also a higher proportion of patients receiving 24‐hour infusional MTX within the intervention cohort. However, although both lower MTX dose and longer infusion times may reduce the overall risk of MTX toxicity, insufficient supportive care is still a major risk factor for adverse events in such circumstances. In comparison with the findings in our intervention group, other studies have reported comparable or even significantly higher rates of acute kidney injury for HD‐MTX in patients with childhood acute lymphoblastic leukemia [18, 19].
Limitations of our study are its retrospective, nonrandomized design and the evaluation within a single treatment center. However, our intervention of standardized supportive care documentation for HD‐MTX was effective in a broad, nonselected real‐world patient population, which warrants confirmation in further prospective clinical trials.
Our drug–drug interaction list did not include tyrosine kinase inhibitors like imatinib and dasatinib. However, it has been recently reported that such drugs may reduce MTX clearance and should therefore also be avoided during HD‐MTX treatment [20, 21].
Conclusion
The use of a standardized, checklist‐based documentation for supportive care significantly improves the safety of HD‐MTX treatment. These tools are able to minimize the risk of pharmacokinetic drug–drug interactions and insufficient urine alkalinization, leading to a low rate of adverse events. We therefore highly recommend implementation of such adjunctive measures for all patients receiving HD‐MTX. In our experience, the use of a checklist and urine alkalinization protocol is very efficient and can be easily implemented into clinical practice.
Author Contributions
Conception/design: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Provision of study material or patients: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Collection and/or assembly of data: Claudia Langebrake, Winfried Alsdorf, Christian Frenzel
Data analysis and interpretation: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Manuscript writing: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Final approval of manuscript: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Disclosures
Panagiotis Karagiannis: Abbvie Inc. (OI); Carsten Bokemeyer: Sanofi Aventis, Novartis, Merck Sharpe & Dohme, Bristol‐Myers Squibb, Eli Lilly & Co/Imclone, GSO Hamburg, AOK Health Insurance, Merck Darmstadt, Roche, Bayer Healthcare (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33215763 | 19,172,964 | 2021-02 |
What was the dosage of drug 'SODIUM BICARBONATE'? | Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment.
High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy.
The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP).
In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group.
The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events.
High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX.
Introduction
High‐dose (HD) methotrexate (MTX; defined as MTX dose >500 mg/m2) has been used for several decades as an important backbone in treatment protocols for acute lymphoblastic leukemia, osteosarcoma, and lymphoma [1, 2, 3]. MTX acts as folate antimetabolite and inhibits DNA synthesis by blocking the enzyme dihydrofolate reductase. High doses of MTX are feasible by using folinic acid (syn, leucovorin, the reduced form of folic acid) to reduce the toxic effects upon nonmalignant cells as a “leucovorin rescue.”
Notable toxicities of HD‐MTX are mucositis, myelosuppression, renal failure, liver injury, and neurotoxicity [4]. The risk of HD‐MTX toxicity is especially increased in the case of therapy‐induced renal failure because impaired renal function leads to reduced MTX renal clearance, which is the major route (90%) of MTX elimination [5]. Prolonged exposure to toxic MTX levels can induce severe myelosuppression and mucositis and is a life‐threatening condition. Avoidance of renal injury and the consecutive risk of impaired MTX clearance is therefore paramount to prevent MTX toxicity.
HD‐MTX administration demands specialized supportive care to prevent adverse events. This includes strict urine alkalinization and hyperhydration to increase MTX elimination and to prevent kidney damage as well as administration of leucovorin to reduce mucositis and myelosuppression [4, 6].
Urine alkalinization has been identified as a crucial aspect of MTX clearance and prevention of renal toxicity. At a urine pH of 5, the solubility of MTX is very low, and it can precipitate within renal tubuli, which induces severe kidney damage with the consequence of acute renal failure. In some cases, this condition will require hemodialysis. By raising the urine pH from 5 to 7.5, solubility of MTX increases about 20‐fold [4, 5, 6, 7]. Therefore, permanent and effective urine alkalinization and hyperhydration are absolutely mandatory for safe HD‐MTX treatment.
As MTX can accumulate in third‐space fluids like ascites and pleural effusions, thereby leading to prolonged MTX clearance due to distribution processes, the presence of such third‐space fluids prior to HD‐MTX needs to be ruled out. This is usually performed by sonography.
Furthermore, pharmacokinetic interactions between several drugs (i.e., proton‐pump inhibitors, β‐lactam antibiotics, nonsteroidal anti‐inflammatory drugs like indomethacin and naproxen) and MTX have been previously identified as reason for delayed MTX elimination and subsequent toxicity [4, 8, 9, 10, 11]. Avoidance of such interactions is another important part of supportive care during HD‐MTX therapy.
Even slight deviations from optimal supportive therapy may lead to profound toxicities of HD‐MTX. Therefore, strict adherence to supportive measures during HD‐MTX is vital for patient safety. As HD‐MTX is often used in curative treatment settings (i.e., acute lymphoblastic leukemia, lymphoma), toxicity of HD‐MTX needs to be minimized to prevent treatment delays as this may impair the overall prognosis.
We hypothesized that supportive care for HD‐MTX can be significantly improved by implementing standardized protocols for all relevant elements of supportive treatment.
Materials and Methods
Additional tools for supportive care during HD‐MTX therapy including a checklist for supportive care and a urine alkalinization protocol were implemented in our clinic, a tertiary comprehensive cancer center.
The checklist contains several elements of supportive care and treatment preparation during HD‐MTX (Fig. 1). Important items of the checklist are sonographic detection of third‐space fluids, correct intravenous fluid administration, proper urine alkalinization before the start of MTX infusion, preparation of a leucovorin rescue protocol, and evaluation of possible pharmacokinetic interactions.
Figure 1 Checklist for high‐dose MTX therapy. Abbreviation: ASS, acetylsalicyclic acid; MTX, methotrexate; NSAID, nonsteroidal anti‐inflammatory drug.
A protocol for measurement and recording of urine pH values as well as documentation of alkalinization therapy was designed to ensure proper urinary alkalinization (Fig. 2).
Figure 2 Protocol for urine pH measurement and urine alkalinization during HD‐MTX. Abbreviations: HD‐MTX, high‐dose methotrexate.
The use of both the checklist and the alkalinization protocol was implemented in all patients receiving HD‐MTX starting in April 2017. These two documents were individually used for every single HD‐MTX treatment course in every patient. Both physicians and the nursing staff were responsible for using this documentation system. To assess the efficacy of this intervention, treatment data of 118 patients receiving HD‐MTX from April 2017 to April 2019 were analyzed (intervention group).
Prior to implementation of this standardized documentation, supportive care for HD‐MTX in our clinic was performed as recommended by international guidelines [4, 6], with modifications according to local practice following a dedicated standard operating procedure (SOP). This included urine alkalinization and hyperhydration, leucovorin rescue, detection of third‐space fluids, and avoidance of pharmacokinetic interactions. Urine alkalinization was achieved by intravenous application of sodium bicarbonate, and a urine pH of 8 was defined as target value. Fluid administration and leucovorin rescue were performed according to standardized chemotherapy treatment protocols. Documentation of supportive care was done in electronic patient records but was not standardized.
Predefined adverse events (acute kidney injury, prolongation of MTX clearance) were retrospectively assessed in a cohort of 108 patients treated from January 2015 to March 2017. In this control group, supportive care was delivered following the SOP but without standardized documentation tools.
Delayed MTX clearance was defined as failure to reach prespecified thresholds (<0.2 μmol/L at 72 hours after therapy) and if prolonged leucovorin rescue was necessary.
Acute kidney injury was defined according to the AKIN classification [12]. The threshold for definition of acute kidney injury was AKIN stage 1. By definition, this finding is made in patients with an absolute serum creatinine increase of 0.3 mg/dL or greater, an increase of 1.5‐fold or greater above the baseline serum creatinine, or onset of oliguria (urine output <0.5 mL/kg per hour lasting 6–12 hours).
For statistical comparison of adverse events between the treatment groups, the Fisher‐Yates test was used. A p value < .05 was defined as statistically significant.
This study was conducted after review by the local ethics committee of the Hamburg chamber of physicians, Germany (Ref. no. WF106‐20).
Results
In the intervention group, 118 patients were treated with 414 cycles of HD‐MTX. The SOP group consisted of 108 patients who received 332 cycles of HD‐MTX (Table 1). The most common indications for HD‐MTX in both groups were central nervous system lymphoma (43 patients in both groups), acute lymphoblastic leukemia (36 patients in the intervention and 23 in the SOP group), and non‐Hodgkin lymphoma (16 patients in the intervention and 18 in the SOP group).
Table 1 Characteristics of SOP and intervention groups and frequency of adverse events
Characteristic SOP group Intervention group
p value
No. of patients 108 118
No. of treatment cycles 332 414
Mean age (range), yr 53 (18–85) 52 (18–83)
Burkitt lymphoma, n
16 19
CNS lymphoma, n
43 43
Osteosarcoma, n
8 2
Choriocarcinoma, n
0 2
Acute lymphoblastic leukemia, n
23 36
Non‐Hodgkin Lymphoma, n
18 16
MTX dose, mean (range), g/m2
2.7 (0.5–12) 2.1 (0.5–12)
No. of cycles with delayed MTX clearance (%) 51 (15.2) 11 (2.6) <.001
Acute kidney injury, n (%) 21 (6.2.) 3 (0.7) <.001
No. of cycles with use of carboxypeptidase (%)
5 (1.47) 2 (0.48) .25
Abbreviations: CNS, central nervous system; MTX, methotrexate; SOP, standard operating procedure.
The average MTX dose per treatment cycle was 2.7 g/m2 in the SOP group and 2.1 g/m2 in the intervention group. All patients with acute lymphoblastic leukemia received HD‐MTX as a continuous infusion over 24 hours, whereas in all other indications, MTX was administered as an infusion over 3–4 hours.
In 51 of 332 HD‐MTX cycles (15.2%) within the SOP group, MTX clearance was delayed. In contrast, delayed MTX clearance was only observed in 11 of 414 treatment cycles of the intervention group (2.6%, p < .001)
Acute kidney injury occurred in 6.3% of cycles (n = 21) within the SOP group and in only 0.7% of cycles (n = 3) in the intervention group (p < .001).
One patient with acute renal failure in the SOP group underwent hemodialysis. In all patients experiencing acute kidney injury, kidney damage was reversible and did not induce chronic renal impairment.
HD‐MTX therapy was permanently discontinued because of toxicity in five patients of the SOP group and in one patient of the intervention group. Five patients of the SOP group and two patients within the intervention group received carboxypeptidase because of acute renal failure and insufficient MTX clearance. The indication for carboxypeptidase was evaluated according to international recommendations [6, 13]. There were no treatment‐related deaths.
A review of potential reasons for complications in the SOP group by analysis of all treatment cycles with acute kidney injury and/or delayed MTX clearance revealed potential pharmacokinetic drug–drug interactions in 17 treatment cycles and inadequate control of urine alkalinization in 5 treatment cycles.
In the 21 treatment cycles of the SOP group that resulted in acute kidney injury, a potential drug–drug interaction was present in eight cases and inadequate urine alkalinization was present in five cycles. Other causes for nephrotoxicity were one case of tumor lysis syndrome and two patients with pretherapeutic renal impairment.
In the intervention cohort, administration of potentially interacting drugs could be successfully avoided. Specifically, in the three cases of acute kidney injury in the intervention group, no interfering medication was given. Table 2 summarizes the analysis of underlying causes for acute kidney injury in both treatment groups.
Table 2 Analysis of patients with acute kidney injury after high‐dose MTX
Potential reason for MTX toxicity Intervention group (n = 3) SOP group (n = 21)
Concomitant medication 0 8
Tumor lysis syndrome 0 1
Urinary retention due to bladder obstruction 1 0
Insufficient urine alkalinization 0 5
Preexisting renal impairment 0 2
Unknown 2 12
Abbreviations: MTX, methotrexate; SOP, standard operating procedure.
Discussion
Herein, we demonstrate that standardized documentation protocols for supportive care significantly reduce the rate of adverse events during HD‐MTX therapy by using a simplified and structured guidance consisting of only two single‐page documents (checklist and urine alkalinization protocol). Implementation of these measures was performed with high acceptance by physicians and nurses, as both the checklist and the alkalinization protocol were successfully applied in all patients within the intervention group for every treatment course.
Even slight deviations in supportive care may lead to acute kidney failure and subsequent toxicities of HD‐MTX. In clinical practice, strict adherence to these requirements can be challenging, and errors may occur. Optimal supportive care has been previously demonstrated to reduce the risk of HD‐MTX toxicity [4, 6, 13, 14].
Pharmacokinetic interactions between concomitant medications and MTX with significantly delayed MTX elimination have been previously described [8, 9, 10, 11, 15]. Therefore, avoidance of such pharmacokinetic interactions is imperative to administer HD‐MTX safely. The use of a checklist containing information on potential pharmacokinetic interactions can assist in preventing these adverse events.
For instance, we observed a case of acute renal failure necessitating hemodialysis in our SOP group after intravenous administration of a single dose of 40 mg pantoprazole only a few hours after infusion of HD‐MTX. As this example demonstrates, supportive care prior, during, and after HD‐MTX administration has to follow strict rules to avoid serious toxicity.
The important role of pharmacokinetic interactions for HD‐MTX toxicity is also supported by the finding of potentially interacting medication in about one third of the 21 cycles leading to acute kidney injury within the SOP group. In contrast, no patient within the intervention group had received interacting medications.
Previously, the rate of renal failure after HD‐MTX despite adequate, nonstandardized supportive care was reported to be 1.8% [6]. In another retrospective analysis in patients with lymphoma receiving HD‐MTX, the rate of renal injury was about 9% [16]. The reason for these different findings are presumably patient‐related factors like age and comorbidities.
In our intervention group, the overall rate of any degree of acute kidney injury (according to the AKIN classification) could be reduced from 6.3% (SOP group) to 0.7%. This finding demonstrates the high efficacy of standardized supportive care documentation to prevent acute renal failure during HD‐MTX treatment. The low rate of nephrotoxicity in our intervention group also shows the importance of effective and continuous urine alkalinization to prevent kidney damage during HD‐MTX treatment. The crucial role of urine alkalinization for adequate HD‐MTX clearance was also reported by other studies [7, 14].
The use of a standardized urine alkalinization protocol is an effective approach to optimize urine alkalinization during HD‐MTX therapy.
We decided to use a checklist for control of supportive care because previously, the usage of checklist‐based interventions was proven to be highly effective for improving the quality of routine clinical care and to ensure adherence to guidelines in clinical practice [17]. The low rate of adverse events in our intervention group demonstrates that the checklist‐based control of supportive care can improve the safety of HD‐MTX therapy. As outlined before, the most important element of this checklist is presumably the prevention of pharmacokinetic drug–drug interactions.
Another advantage of the checklist‐based documentation for supportive care during HD‐MTX therapy is that this approach enables a comprehensive, transparent overview of all important supportive care measures. Thus, the risk of insufficient supportive care is minimized while clinicians and nurses require less time and effort to control whether all necessary preparations for HD‐MTX are present.
Regarding the risk profile for adverse events in the SOP and intervention groups, the average age in both groups was about 53 years. The average MTX dose was slightly higher in the SOP cohort (2.7 vs. 2.1 g/m2). There was also a higher proportion of patients receiving 24‐hour infusional MTX within the intervention cohort. However, although both lower MTX dose and longer infusion times may reduce the overall risk of MTX toxicity, insufficient supportive care is still a major risk factor for adverse events in such circumstances. In comparison with the findings in our intervention group, other studies have reported comparable or even significantly higher rates of acute kidney injury for HD‐MTX in patients with childhood acute lymphoblastic leukemia [18, 19].
Limitations of our study are its retrospective, nonrandomized design and the evaluation within a single treatment center. However, our intervention of standardized supportive care documentation for HD‐MTX was effective in a broad, nonselected real‐world patient population, which warrants confirmation in further prospective clinical trials.
Our drug–drug interaction list did not include tyrosine kinase inhibitors like imatinib and dasatinib. However, it has been recently reported that such drugs may reduce MTX clearance and should therefore also be avoided during HD‐MTX treatment [20, 21].
Conclusion
The use of a standardized, checklist‐based documentation for supportive care significantly improves the safety of HD‐MTX treatment. These tools are able to minimize the risk of pharmacokinetic drug–drug interactions and insufficient urine alkalinization, leading to a low rate of adverse events. We therefore highly recommend implementation of such adjunctive measures for all patients receiving HD‐MTX. In our experience, the use of a checklist and urine alkalinization protocol is very efficient and can be easily implemented into clinical practice.
Author Contributions
Conception/design: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Provision of study material or patients: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Collection and/or assembly of data: Claudia Langebrake, Winfried Alsdorf, Christian Frenzel
Data analysis and interpretation: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Manuscript writing: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Final approval of manuscript: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Disclosures
Panagiotis Karagiannis: Abbvie Inc. (OI); Carsten Bokemeyer: Sanofi Aventis, Novartis, Merck Sharpe & Dohme, Bristol‐Myers Squibb, Eli Lilly & Co/Imclone, GSO Hamburg, AOK Health Insurance, Merck Darmstadt, Roche, Bayer Healthcare (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board | CYCLICAL | DrugDosageText | CC BY-NC-ND | 33215763 | 19,172,964 | 2021-02 |
What was the outcome of reaction 'Acute kidney injury'? | Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment.
High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy.
The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP).
In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group.
The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events.
High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX.
Introduction
High‐dose (HD) methotrexate (MTX; defined as MTX dose >500 mg/m2) has been used for several decades as an important backbone in treatment protocols for acute lymphoblastic leukemia, osteosarcoma, and lymphoma [1, 2, 3]. MTX acts as folate antimetabolite and inhibits DNA synthesis by blocking the enzyme dihydrofolate reductase. High doses of MTX are feasible by using folinic acid (syn, leucovorin, the reduced form of folic acid) to reduce the toxic effects upon nonmalignant cells as a “leucovorin rescue.”
Notable toxicities of HD‐MTX are mucositis, myelosuppression, renal failure, liver injury, and neurotoxicity [4]. The risk of HD‐MTX toxicity is especially increased in the case of therapy‐induced renal failure because impaired renal function leads to reduced MTX renal clearance, which is the major route (90%) of MTX elimination [5]. Prolonged exposure to toxic MTX levels can induce severe myelosuppression and mucositis and is a life‐threatening condition. Avoidance of renal injury and the consecutive risk of impaired MTX clearance is therefore paramount to prevent MTX toxicity.
HD‐MTX administration demands specialized supportive care to prevent adverse events. This includes strict urine alkalinization and hyperhydration to increase MTX elimination and to prevent kidney damage as well as administration of leucovorin to reduce mucositis and myelosuppression [4, 6].
Urine alkalinization has been identified as a crucial aspect of MTX clearance and prevention of renal toxicity. At a urine pH of 5, the solubility of MTX is very low, and it can precipitate within renal tubuli, which induces severe kidney damage with the consequence of acute renal failure. In some cases, this condition will require hemodialysis. By raising the urine pH from 5 to 7.5, solubility of MTX increases about 20‐fold [4, 5, 6, 7]. Therefore, permanent and effective urine alkalinization and hyperhydration are absolutely mandatory for safe HD‐MTX treatment.
As MTX can accumulate in third‐space fluids like ascites and pleural effusions, thereby leading to prolonged MTX clearance due to distribution processes, the presence of such third‐space fluids prior to HD‐MTX needs to be ruled out. This is usually performed by sonography.
Furthermore, pharmacokinetic interactions between several drugs (i.e., proton‐pump inhibitors, β‐lactam antibiotics, nonsteroidal anti‐inflammatory drugs like indomethacin and naproxen) and MTX have been previously identified as reason for delayed MTX elimination and subsequent toxicity [4, 8, 9, 10, 11]. Avoidance of such interactions is another important part of supportive care during HD‐MTX therapy.
Even slight deviations from optimal supportive therapy may lead to profound toxicities of HD‐MTX. Therefore, strict adherence to supportive measures during HD‐MTX is vital for patient safety. As HD‐MTX is often used in curative treatment settings (i.e., acute lymphoblastic leukemia, lymphoma), toxicity of HD‐MTX needs to be minimized to prevent treatment delays as this may impair the overall prognosis.
We hypothesized that supportive care for HD‐MTX can be significantly improved by implementing standardized protocols for all relevant elements of supportive treatment.
Materials and Methods
Additional tools for supportive care during HD‐MTX therapy including a checklist for supportive care and a urine alkalinization protocol were implemented in our clinic, a tertiary comprehensive cancer center.
The checklist contains several elements of supportive care and treatment preparation during HD‐MTX (Fig. 1). Important items of the checklist are sonographic detection of third‐space fluids, correct intravenous fluid administration, proper urine alkalinization before the start of MTX infusion, preparation of a leucovorin rescue protocol, and evaluation of possible pharmacokinetic interactions.
Figure 1 Checklist for high‐dose MTX therapy. Abbreviation: ASS, acetylsalicyclic acid; MTX, methotrexate; NSAID, nonsteroidal anti‐inflammatory drug.
A protocol for measurement and recording of urine pH values as well as documentation of alkalinization therapy was designed to ensure proper urinary alkalinization (Fig. 2).
Figure 2 Protocol for urine pH measurement and urine alkalinization during HD‐MTX. Abbreviations: HD‐MTX, high‐dose methotrexate.
The use of both the checklist and the alkalinization protocol was implemented in all patients receiving HD‐MTX starting in April 2017. These two documents were individually used for every single HD‐MTX treatment course in every patient. Both physicians and the nursing staff were responsible for using this documentation system. To assess the efficacy of this intervention, treatment data of 118 patients receiving HD‐MTX from April 2017 to April 2019 were analyzed (intervention group).
Prior to implementation of this standardized documentation, supportive care for HD‐MTX in our clinic was performed as recommended by international guidelines [4, 6], with modifications according to local practice following a dedicated standard operating procedure (SOP). This included urine alkalinization and hyperhydration, leucovorin rescue, detection of third‐space fluids, and avoidance of pharmacokinetic interactions. Urine alkalinization was achieved by intravenous application of sodium bicarbonate, and a urine pH of 8 was defined as target value. Fluid administration and leucovorin rescue were performed according to standardized chemotherapy treatment protocols. Documentation of supportive care was done in electronic patient records but was not standardized.
Predefined adverse events (acute kidney injury, prolongation of MTX clearance) were retrospectively assessed in a cohort of 108 patients treated from January 2015 to March 2017. In this control group, supportive care was delivered following the SOP but without standardized documentation tools.
Delayed MTX clearance was defined as failure to reach prespecified thresholds (<0.2 μmol/L at 72 hours after therapy) and if prolonged leucovorin rescue was necessary.
Acute kidney injury was defined according to the AKIN classification [12]. The threshold for definition of acute kidney injury was AKIN stage 1. By definition, this finding is made in patients with an absolute serum creatinine increase of 0.3 mg/dL or greater, an increase of 1.5‐fold or greater above the baseline serum creatinine, or onset of oliguria (urine output <0.5 mL/kg per hour lasting 6–12 hours).
For statistical comparison of adverse events between the treatment groups, the Fisher‐Yates test was used. A p value < .05 was defined as statistically significant.
This study was conducted after review by the local ethics committee of the Hamburg chamber of physicians, Germany (Ref. no. WF106‐20).
Results
In the intervention group, 118 patients were treated with 414 cycles of HD‐MTX. The SOP group consisted of 108 patients who received 332 cycles of HD‐MTX (Table 1). The most common indications for HD‐MTX in both groups were central nervous system lymphoma (43 patients in both groups), acute lymphoblastic leukemia (36 patients in the intervention and 23 in the SOP group), and non‐Hodgkin lymphoma (16 patients in the intervention and 18 in the SOP group).
Table 1 Characteristics of SOP and intervention groups and frequency of adverse events
Characteristic SOP group Intervention group
p value
No. of patients 108 118
No. of treatment cycles 332 414
Mean age (range), yr 53 (18–85) 52 (18–83)
Burkitt lymphoma, n
16 19
CNS lymphoma, n
43 43
Osteosarcoma, n
8 2
Choriocarcinoma, n
0 2
Acute lymphoblastic leukemia, n
23 36
Non‐Hodgkin Lymphoma, n
18 16
MTX dose, mean (range), g/m2
2.7 (0.5–12) 2.1 (0.5–12)
No. of cycles with delayed MTX clearance (%) 51 (15.2) 11 (2.6) <.001
Acute kidney injury, n (%) 21 (6.2.) 3 (0.7) <.001
No. of cycles with use of carboxypeptidase (%)
5 (1.47) 2 (0.48) .25
Abbreviations: CNS, central nervous system; MTX, methotrexate; SOP, standard operating procedure.
The average MTX dose per treatment cycle was 2.7 g/m2 in the SOP group and 2.1 g/m2 in the intervention group. All patients with acute lymphoblastic leukemia received HD‐MTX as a continuous infusion over 24 hours, whereas in all other indications, MTX was administered as an infusion over 3–4 hours.
In 51 of 332 HD‐MTX cycles (15.2%) within the SOP group, MTX clearance was delayed. In contrast, delayed MTX clearance was only observed in 11 of 414 treatment cycles of the intervention group (2.6%, p < .001)
Acute kidney injury occurred in 6.3% of cycles (n = 21) within the SOP group and in only 0.7% of cycles (n = 3) in the intervention group (p < .001).
One patient with acute renal failure in the SOP group underwent hemodialysis. In all patients experiencing acute kidney injury, kidney damage was reversible and did not induce chronic renal impairment.
HD‐MTX therapy was permanently discontinued because of toxicity in five patients of the SOP group and in one patient of the intervention group. Five patients of the SOP group and two patients within the intervention group received carboxypeptidase because of acute renal failure and insufficient MTX clearance. The indication for carboxypeptidase was evaluated according to international recommendations [6, 13]. There were no treatment‐related deaths.
A review of potential reasons for complications in the SOP group by analysis of all treatment cycles with acute kidney injury and/or delayed MTX clearance revealed potential pharmacokinetic drug–drug interactions in 17 treatment cycles and inadequate control of urine alkalinization in 5 treatment cycles.
In the 21 treatment cycles of the SOP group that resulted in acute kidney injury, a potential drug–drug interaction was present in eight cases and inadequate urine alkalinization was present in five cycles. Other causes for nephrotoxicity were one case of tumor lysis syndrome and two patients with pretherapeutic renal impairment.
In the intervention cohort, administration of potentially interacting drugs could be successfully avoided. Specifically, in the three cases of acute kidney injury in the intervention group, no interfering medication was given. Table 2 summarizes the analysis of underlying causes for acute kidney injury in both treatment groups.
Table 2 Analysis of patients with acute kidney injury after high‐dose MTX
Potential reason for MTX toxicity Intervention group (n = 3) SOP group (n = 21)
Concomitant medication 0 8
Tumor lysis syndrome 0 1
Urinary retention due to bladder obstruction 1 0
Insufficient urine alkalinization 0 5
Preexisting renal impairment 0 2
Unknown 2 12
Abbreviations: MTX, methotrexate; SOP, standard operating procedure.
Discussion
Herein, we demonstrate that standardized documentation protocols for supportive care significantly reduce the rate of adverse events during HD‐MTX therapy by using a simplified and structured guidance consisting of only two single‐page documents (checklist and urine alkalinization protocol). Implementation of these measures was performed with high acceptance by physicians and nurses, as both the checklist and the alkalinization protocol were successfully applied in all patients within the intervention group for every treatment course.
Even slight deviations in supportive care may lead to acute kidney failure and subsequent toxicities of HD‐MTX. In clinical practice, strict adherence to these requirements can be challenging, and errors may occur. Optimal supportive care has been previously demonstrated to reduce the risk of HD‐MTX toxicity [4, 6, 13, 14].
Pharmacokinetic interactions between concomitant medications and MTX with significantly delayed MTX elimination have been previously described [8, 9, 10, 11, 15]. Therefore, avoidance of such pharmacokinetic interactions is imperative to administer HD‐MTX safely. The use of a checklist containing information on potential pharmacokinetic interactions can assist in preventing these adverse events.
For instance, we observed a case of acute renal failure necessitating hemodialysis in our SOP group after intravenous administration of a single dose of 40 mg pantoprazole only a few hours after infusion of HD‐MTX. As this example demonstrates, supportive care prior, during, and after HD‐MTX administration has to follow strict rules to avoid serious toxicity.
The important role of pharmacokinetic interactions for HD‐MTX toxicity is also supported by the finding of potentially interacting medication in about one third of the 21 cycles leading to acute kidney injury within the SOP group. In contrast, no patient within the intervention group had received interacting medications.
Previously, the rate of renal failure after HD‐MTX despite adequate, nonstandardized supportive care was reported to be 1.8% [6]. In another retrospective analysis in patients with lymphoma receiving HD‐MTX, the rate of renal injury was about 9% [16]. The reason for these different findings are presumably patient‐related factors like age and comorbidities.
In our intervention group, the overall rate of any degree of acute kidney injury (according to the AKIN classification) could be reduced from 6.3% (SOP group) to 0.7%. This finding demonstrates the high efficacy of standardized supportive care documentation to prevent acute renal failure during HD‐MTX treatment. The low rate of nephrotoxicity in our intervention group also shows the importance of effective and continuous urine alkalinization to prevent kidney damage during HD‐MTX treatment. The crucial role of urine alkalinization for adequate HD‐MTX clearance was also reported by other studies [7, 14].
The use of a standardized urine alkalinization protocol is an effective approach to optimize urine alkalinization during HD‐MTX therapy.
We decided to use a checklist for control of supportive care because previously, the usage of checklist‐based interventions was proven to be highly effective for improving the quality of routine clinical care and to ensure adherence to guidelines in clinical practice [17]. The low rate of adverse events in our intervention group demonstrates that the checklist‐based control of supportive care can improve the safety of HD‐MTX therapy. As outlined before, the most important element of this checklist is presumably the prevention of pharmacokinetic drug–drug interactions.
Another advantage of the checklist‐based documentation for supportive care during HD‐MTX therapy is that this approach enables a comprehensive, transparent overview of all important supportive care measures. Thus, the risk of insufficient supportive care is minimized while clinicians and nurses require less time and effort to control whether all necessary preparations for HD‐MTX are present.
Regarding the risk profile for adverse events in the SOP and intervention groups, the average age in both groups was about 53 years. The average MTX dose was slightly higher in the SOP cohort (2.7 vs. 2.1 g/m2). There was also a higher proportion of patients receiving 24‐hour infusional MTX within the intervention cohort. However, although both lower MTX dose and longer infusion times may reduce the overall risk of MTX toxicity, insufficient supportive care is still a major risk factor for adverse events in such circumstances. In comparison with the findings in our intervention group, other studies have reported comparable or even significantly higher rates of acute kidney injury for HD‐MTX in patients with childhood acute lymphoblastic leukemia [18, 19].
Limitations of our study are its retrospective, nonrandomized design and the evaluation within a single treatment center. However, our intervention of standardized supportive care documentation for HD‐MTX was effective in a broad, nonselected real‐world patient population, which warrants confirmation in further prospective clinical trials.
Our drug–drug interaction list did not include tyrosine kinase inhibitors like imatinib and dasatinib. However, it has been recently reported that such drugs may reduce MTX clearance and should therefore also be avoided during HD‐MTX treatment [20, 21].
Conclusion
The use of a standardized, checklist‐based documentation for supportive care significantly improves the safety of HD‐MTX treatment. These tools are able to minimize the risk of pharmacokinetic drug–drug interactions and insufficient urine alkalinization, leading to a low rate of adverse events. We therefore highly recommend implementation of such adjunctive measures for all patients receiving HD‐MTX. In our experience, the use of a checklist and urine alkalinization protocol is very efficient and can be easily implemented into clinical practice.
Author Contributions
Conception/design: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Provision of study material or patients: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Collection and/or assembly of data: Claudia Langebrake, Winfried Alsdorf, Christian Frenzel
Data analysis and interpretation: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Manuscript writing: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Final approval of manuscript: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Disclosures
Panagiotis Karagiannis: Abbvie Inc. (OI); Carsten Bokemeyer: Sanofi Aventis, Novartis, Merck Sharpe & Dohme, Bristol‐Myers Squibb, Eli Lilly & Co/Imclone, GSO Hamburg, AOK Health Insurance, Merck Darmstadt, Roche, Bayer Healthcare (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board | Recovered | ReactionOutcome | CC BY-NC-ND | 33215763 | 19,172,964 | 2021-02 |
What was the outcome of reaction 'Labelled drug-drug interaction medication error'? | Standardized Supportive Care Documentation Improves Safety of High-Dose Methotrexate Treatment.
High-dose (HD) methotrexate (MTX) is an essential component of treatment protocols in acute lymphoblastic leukemia, aggressive lymphoma, and osteosarcoma. However, delayed MTX clearance may lead to life-threatening toxicities. Administration of supportive therapy for HD-MTX is complex, and insufficient supportive care increases the risk of MTX toxicity. To improve patient safety, we investigated the implementation of a checklist and urine alkalinization protocol in addition to standard supportive care during HD-MTX therapy.
The intervention included individualized patient checklists for control of adequate supportive care for every HD-MTX treatment cycle and a urine alkalinization protocol for documentation and guidance during urine alkalinization therapy. The impact of these tools on the rate of adverse events (acute renal injury, delayed MTX clearance) was retrospectively assessed in patients treated from April 2017 to April 2019 (intervention group) and compared with patients treated from January 2015 to March 2017 who received standard supportive care for HD-MTX according to a standard operating procedure (SOP).
In total, 118 patients received 414 HD-MTX cycles in the intervention group compared with 108 patients with 332 treatment cycles in the SOP group. Delayed MTX clearance was observed in 2.6% of treatment cycles in the intervention cohort opposed to 15.2% of cycles in the SOP group. The rate of acute kidney injury was also significantly reduced in the intervention group (6.2%. vs. 0.7%). The use of carboxypeptidase as rescue treatment for severe renal impairment and insufficient MTX clearance was necessary in five cases in the SOP group and in only two cycles within the intervention group.
The use of standardized documentation for supportive care during HD-MTX therapy is recommended to minimize the risk of adverse events.
High-dose methotrexate (HD-MTX) is a commonly used treatment in several cancer types. Distinct supportive measures are necessary to minimize the risk of HD-MTX side effects, which can be life-threatening. Supportive care consists of certain examinations and interventions before starting HD-MTX and permanent alkalinization of the urine, as this greatly increases the elimination of MTX and decreases the risk of kidney injury. After implementing a checklist for control of supportive care and a urine alkalinization protocol to optimize urine alkalinization, a significant decrease of side effects was observed in comparison to the standard of care; therefore, the use of a safety checklist and alkalinization protocol is recommended for all patients who receive HD-MTX.
Introduction
High‐dose (HD) methotrexate (MTX; defined as MTX dose >500 mg/m2) has been used for several decades as an important backbone in treatment protocols for acute lymphoblastic leukemia, osteosarcoma, and lymphoma [1, 2, 3]. MTX acts as folate antimetabolite and inhibits DNA synthesis by blocking the enzyme dihydrofolate reductase. High doses of MTX are feasible by using folinic acid (syn, leucovorin, the reduced form of folic acid) to reduce the toxic effects upon nonmalignant cells as a “leucovorin rescue.”
Notable toxicities of HD‐MTX are mucositis, myelosuppression, renal failure, liver injury, and neurotoxicity [4]. The risk of HD‐MTX toxicity is especially increased in the case of therapy‐induced renal failure because impaired renal function leads to reduced MTX renal clearance, which is the major route (90%) of MTX elimination [5]. Prolonged exposure to toxic MTX levels can induce severe myelosuppression and mucositis and is a life‐threatening condition. Avoidance of renal injury and the consecutive risk of impaired MTX clearance is therefore paramount to prevent MTX toxicity.
HD‐MTX administration demands specialized supportive care to prevent adverse events. This includes strict urine alkalinization and hyperhydration to increase MTX elimination and to prevent kidney damage as well as administration of leucovorin to reduce mucositis and myelosuppression [4, 6].
Urine alkalinization has been identified as a crucial aspect of MTX clearance and prevention of renal toxicity. At a urine pH of 5, the solubility of MTX is very low, and it can precipitate within renal tubuli, which induces severe kidney damage with the consequence of acute renal failure. In some cases, this condition will require hemodialysis. By raising the urine pH from 5 to 7.5, solubility of MTX increases about 20‐fold [4, 5, 6, 7]. Therefore, permanent and effective urine alkalinization and hyperhydration are absolutely mandatory for safe HD‐MTX treatment.
As MTX can accumulate in third‐space fluids like ascites and pleural effusions, thereby leading to prolonged MTX clearance due to distribution processes, the presence of such third‐space fluids prior to HD‐MTX needs to be ruled out. This is usually performed by sonography.
Furthermore, pharmacokinetic interactions between several drugs (i.e., proton‐pump inhibitors, β‐lactam antibiotics, nonsteroidal anti‐inflammatory drugs like indomethacin and naproxen) and MTX have been previously identified as reason for delayed MTX elimination and subsequent toxicity [4, 8, 9, 10, 11]. Avoidance of such interactions is another important part of supportive care during HD‐MTX therapy.
Even slight deviations from optimal supportive therapy may lead to profound toxicities of HD‐MTX. Therefore, strict adherence to supportive measures during HD‐MTX is vital for patient safety. As HD‐MTX is often used in curative treatment settings (i.e., acute lymphoblastic leukemia, lymphoma), toxicity of HD‐MTX needs to be minimized to prevent treatment delays as this may impair the overall prognosis.
We hypothesized that supportive care for HD‐MTX can be significantly improved by implementing standardized protocols for all relevant elements of supportive treatment.
Materials and Methods
Additional tools for supportive care during HD‐MTX therapy including a checklist for supportive care and a urine alkalinization protocol were implemented in our clinic, a tertiary comprehensive cancer center.
The checklist contains several elements of supportive care and treatment preparation during HD‐MTX (Fig. 1). Important items of the checklist are sonographic detection of third‐space fluids, correct intravenous fluid administration, proper urine alkalinization before the start of MTX infusion, preparation of a leucovorin rescue protocol, and evaluation of possible pharmacokinetic interactions.
Figure 1 Checklist for high‐dose MTX therapy. Abbreviation: ASS, acetylsalicyclic acid; MTX, methotrexate; NSAID, nonsteroidal anti‐inflammatory drug.
A protocol for measurement and recording of urine pH values as well as documentation of alkalinization therapy was designed to ensure proper urinary alkalinization (Fig. 2).
Figure 2 Protocol for urine pH measurement and urine alkalinization during HD‐MTX. Abbreviations: HD‐MTX, high‐dose methotrexate.
The use of both the checklist and the alkalinization protocol was implemented in all patients receiving HD‐MTX starting in April 2017. These two documents were individually used for every single HD‐MTX treatment course in every patient. Both physicians and the nursing staff were responsible for using this documentation system. To assess the efficacy of this intervention, treatment data of 118 patients receiving HD‐MTX from April 2017 to April 2019 were analyzed (intervention group).
Prior to implementation of this standardized documentation, supportive care for HD‐MTX in our clinic was performed as recommended by international guidelines [4, 6], with modifications according to local practice following a dedicated standard operating procedure (SOP). This included urine alkalinization and hyperhydration, leucovorin rescue, detection of third‐space fluids, and avoidance of pharmacokinetic interactions. Urine alkalinization was achieved by intravenous application of sodium bicarbonate, and a urine pH of 8 was defined as target value. Fluid administration and leucovorin rescue were performed according to standardized chemotherapy treatment protocols. Documentation of supportive care was done in electronic patient records but was not standardized.
Predefined adverse events (acute kidney injury, prolongation of MTX clearance) were retrospectively assessed in a cohort of 108 patients treated from January 2015 to March 2017. In this control group, supportive care was delivered following the SOP but without standardized documentation tools.
Delayed MTX clearance was defined as failure to reach prespecified thresholds (<0.2 μmol/L at 72 hours after therapy) and if prolonged leucovorin rescue was necessary.
Acute kidney injury was defined according to the AKIN classification [12]. The threshold for definition of acute kidney injury was AKIN stage 1. By definition, this finding is made in patients with an absolute serum creatinine increase of 0.3 mg/dL or greater, an increase of 1.5‐fold or greater above the baseline serum creatinine, or onset of oliguria (urine output <0.5 mL/kg per hour lasting 6–12 hours).
For statistical comparison of adverse events between the treatment groups, the Fisher‐Yates test was used. A p value < .05 was defined as statistically significant.
This study was conducted after review by the local ethics committee of the Hamburg chamber of physicians, Germany (Ref. no. WF106‐20).
Results
In the intervention group, 118 patients were treated with 414 cycles of HD‐MTX. The SOP group consisted of 108 patients who received 332 cycles of HD‐MTX (Table 1). The most common indications for HD‐MTX in both groups were central nervous system lymphoma (43 patients in both groups), acute lymphoblastic leukemia (36 patients in the intervention and 23 in the SOP group), and non‐Hodgkin lymphoma (16 patients in the intervention and 18 in the SOP group).
Table 1 Characteristics of SOP and intervention groups and frequency of adverse events
Characteristic SOP group Intervention group
p value
No. of patients 108 118
No. of treatment cycles 332 414
Mean age (range), yr 53 (18–85) 52 (18–83)
Burkitt lymphoma, n
16 19
CNS lymphoma, n
43 43
Osteosarcoma, n
8 2
Choriocarcinoma, n
0 2
Acute lymphoblastic leukemia, n
23 36
Non‐Hodgkin Lymphoma, n
18 16
MTX dose, mean (range), g/m2
2.7 (0.5–12) 2.1 (0.5–12)
No. of cycles with delayed MTX clearance (%) 51 (15.2) 11 (2.6) <.001
Acute kidney injury, n (%) 21 (6.2.) 3 (0.7) <.001
No. of cycles with use of carboxypeptidase (%)
5 (1.47) 2 (0.48) .25
Abbreviations: CNS, central nervous system; MTX, methotrexate; SOP, standard operating procedure.
The average MTX dose per treatment cycle was 2.7 g/m2 in the SOP group and 2.1 g/m2 in the intervention group. All patients with acute lymphoblastic leukemia received HD‐MTX as a continuous infusion over 24 hours, whereas in all other indications, MTX was administered as an infusion over 3–4 hours.
In 51 of 332 HD‐MTX cycles (15.2%) within the SOP group, MTX clearance was delayed. In contrast, delayed MTX clearance was only observed in 11 of 414 treatment cycles of the intervention group (2.6%, p < .001)
Acute kidney injury occurred in 6.3% of cycles (n = 21) within the SOP group and in only 0.7% of cycles (n = 3) in the intervention group (p < .001).
One patient with acute renal failure in the SOP group underwent hemodialysis. In all patients experiencing acute kidney injury, kidney damage was reversible and did not induce chronic renal impairment.
HD‐MTX therapy was permanently discontinued because of toxicity in five patients of the SOP group and in one patient of the intervention group. Five patients of the SOP group and two patients within the intervention group received carboxypeptidase because of acute renal failure and insufficient MTX clearance. The indication for carboxypeptidase was evaluated according to international recommendations [6, 13]. There were no treatment‐related deaths.
A review of potential reasons for complications in the SOP group by analysis of all treatment cycles with acute kidney injury and/or delayed MTX clearance revealed potential pharmacokinetic drug–drug interactions in 17 treatment cycles and inadequate control of urine alkalinization in 5 treatment cycles.
In the 21 treatment cycles of the SOP group that resulted in acute kidney injury, a potential drug–drug interaction was present in eight cases and inadequate urine alkalinization was present in five cycles. Other causes for nephrotoxicity were one case of tumor lysis syndrome and two patients with pretherapeutic renal impairment.
In the intervention cohort, administration of potentially interacting drugs could be successfully avoided. Specifically, in the three cases of acute kidney injury in the intervention group, no interfering medication was given. Table 2 summarizes the analysis of underlying causes for acute kidney injury in both treatment groups.
Table 2 Analysis of patients with acute kidney injury after high‐dose MTX
Potential reason for MTX toxicity Intervention group (n = 3) SOP group (n = 21)
Concomitant medication 0 8
Tumor lysis syndrome 0 1
Urinary retention due to bladder obstruction 1 0
Insufficient urine alkalinization 0 5
Preexisting renal impairment 0 2
Unknown 2 12
Abbreviations: MTX, methotrexate; SOP, standard operating procedure.
Discussion
Herein, we demonstrate that standardized documentation protocols for supportive care significantly reduce the rate of adverse events during HD‐MTX therapy by using a simplified and structured guidance consisting of only two single‐page documents (checklist and urine alkalinization protocol). Implementation of these measures was performed with high acceptance by physicians and nurses, as both the checklist and the alkalinization protocol were successfully applied in all patients within the intervention group for every treatment course.
Even slight deviations in supportive care may lead to acute kidney failure and subsequent toxicities of HD‐MTX. In clinical practice, strict adherence to these requirements can be challenging, and errors may occur. Optimal supportive care has been previously demonstrated to reduce the risk of HD‐MTX toxicity [4, 6, 13, 14].
Pharmacokinetic interactions between concomitant medications and MTX with significantly delayed MTX elimination have been previously described [8, 9, 10, 11, 15]. Therefore, avoidance of such pharmacokinetic interactions is imperative to administer HD‐MTX safely. The use of a checklist containing information on potential pharmacokinetic interactions can assist in preventing these adverse events.
For instance, we observed a case of acute renal failure necessitating hemodialysis in our SOP group after intravenous administration of a single dose of 40 mg pantoprazole only a few hours after infusion of HD‐MTX. As this example demonstrates, supportive care prior, during, and after HD‐MTX administration has to follow strict rules to avoid serious toxicity.
The important role of pharmacokinetic interactions for HD‐MTX toxicity is also supported by the finding of potentially interacting medication in about one third of the 21 cycles leading to acute kidney injury within the SOP group. In contrast, no patient within the intervention group had received interacting medications.
Previously, the rate of renal failure after HD‐MTX despite adequate, nonstandardized supportive care was reported to be 1.8% [6]. In another retrospective analysis in patients with lymphoma receiving HD‐MTX, the rate of renal injury was about 9% [16]. The reason for these different findings are presumably patient‐related factors like age and comorbidities.
In our intervention group, the overall rate of any degree of acute kidney injury (according to the AKIN classification) could be reduced from 6.3% (SOP group) to 0.7%. This finding demonstrates the high efficacy of standardized supportive care documentation to prevent acute renal failure during HD‐MTX treatment. The low rate of nephrotoxicity in our intervention group also shows the importance of effective and continuous urine alkalinization to prevent kidney damage during HD‐MTX treatment. The crucial role of urine alkalinization for adequate HD‐MTX clearance was also reported by other studies [7, 14].
The use of a standardized urine alkalinization protocol is an effective approach to optimize urine alkalinization during HD‐MTX therapy.
We decided to use a checklist for control of supportive care because previously, the usage of checklist‐based interventions was proven to be highly effective for improving the quality of routine clinical care and to ensure adherence to guidelines in clinical practice [17]. The low rate of adverse events in our intervention group demonstrates that the checklist‐based control of supportive care can improve the safety of HD‐MTX therapy. As outlined before, the most important element of this checklist is presumably the prevention of pharmacokinetic drug–drug interactions.
Another advantage of the checklist‐based documentation for supportive care during HD‐MTX therapy is that this approach enables a comprehensive, transparent overview of all important supportive care measures. Thus, the risk of insufficient supportive care is minimized while clinicians and nurses require less time and effort to control whether all necessary preparations for HD‐MTX are present.
Regarding the risk profile for adverse events in the SOP and intervention groups, the average age in both groups was about 53 years. The average MTX dose was slightly higher in the SOP cohort (2.7 vs. 2.1 g/m2). There was also a higher proportion of patients receiving 24‐hour infusional MTX within the intervention cohort. However, although both lower MTX dose and longer infusion times may reduce the overall risk of MTX toxicity, insufficient supportive care is still a major risk factor for adverse events in such circumstances. In comparison with the findings in our intervention group, other studies have reported comparable or even significantly higher rates of acute kidney injury for HD‐MTX in patients with childhood acute lymphoblastic leukemia [18, 19].
Limitations of our study are its retrospective, nonrandomized design and the evaluation within a single treatment center. However, our intervention of standardized supportive care documentation for HD‐MTX was effective in a broad, nonselected real‐world patient population, which warrants confirmation in further prospective clinical trials.
Our drug–drug interaction list did not include tyrosine kinase inhibitors like imatinib and dasatinib. However, it has been recently reported that such drugs may reduce MTX clearance and should therefore also be avoided during HD‐MTX treatment [20, 21].
Conclusion
The use of a standardized, checklist‐based documentation for supportive care significantly improves the safety of HD‐MTX treatment. These tools are able to minimize the risk of pharmacokinetic drug–drug interactions and insufficient urine alkalinization, leading to a low rate of adverse events. We therefore highly recommend implementation of such adjunctive measures for all patients receiving HD‐MTX. In our experience, the use of a checklist and urine alkalinization protocol is very efficient and can be easily implemented into clinical practice.
Author Contributions
Conception/design: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Provision of study material or patients: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Collection and/or assembly of data: Claudia Langebrake, Winfried Alsdorf, Christian Frenzel
Data analysis and interpretation: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Manuscript writing: Winfried H. Alsdorf, Claudia Langebrake, Carsten Bokemeyer
Final approval of manuscript: Winfried H. Alsdorf, Panagiotis Karagiannis, Claudia Langebrake, Carsten Bokemeyer, Christian Frenzel
Disclosures
Panagiotis Karagiannis: Abbvie Inc. (OI); Carsten Bokemeyer: Sanofi Aventis, Novartis, Merck Sharpe & Dohme, Bristol‐Myers Squibb, Eli Lilly & Co/Imclone, GSO Hamburg, AOK Health Insurance, Merck Darmstadt, Roche, Bayer Healthcare (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board | Recovered | ReactionOutcome | CC BY-NC-ND | 33215763 | 19,172,964 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | DABRAFENIB MESYLATE, TRAMETINIB DIMETHYL SULFOXIDE | DrugsGivenReaction | CC BY | 33215864 | 18,545,980 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood alkaline phosphatase increased'. | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | DABRAFENIB MESYLATE, TRAMETINIB DIMETHYL SULFOXIDE | DrugsGivenReaction | CC BY | 33215864 | 18,545,980 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | DABRAFENIB, FUROSEMIDE, TRAMETINIB | DrugsGivenReaction | CC BY | 33215864 | 19,564,673 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | DABRAFENIB, FUROSEMIDE, TRAMETINIB | DrugsGivenReaction | CC BY | 33215864 | 19,564,673 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'General physical health deterioration'. | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | DABRAFENIB MESYLATE, TRAMETINIB DIMETHYL SULFOXIDE | DrugsGivenReaction | CC BY | 33215864 | 18,545,980 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic function abnormal'. | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | DABRAFENIB MESYLATE, TRAMETINIB DIMETHYL SULFOXIDE | DrugsGivenReaction | CC BY | 33215864 | 18,545,980 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Interstitial lung disease'. | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | DABRAFENIB MESYLATE, TRAMETINIB DIMETHYL SULFOXIDE | DrugsGivenReaction | CC BY | 33215864 | 18,545,980 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia bacterial'. | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | DABRAFENIB MESYLATE, TRAMETINIB DIMETHYL SULFOXIDE | DrugsGivenReaction | CC BY | 33215864 | 18,545,980 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'. | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | DABRAFENIB, FUROSEMIDE, TRAMETINIB | DrugsGivenReaction | CC BY | 33215864 | 19,564,673 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | DABRAFENIB MESYLATE, TRAMETINIB DIMETHYL SULFOXIDE | DrugsGivenReaction | CC BY | 33215864 | 18,545,980 | 2021-01 |
What was the administration route of drug 'DABRAFENIB MESYLATE'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | Oral | DrugAdministrationRoute | CC BY | 33215864 | 18,545,980 | 2021-01 |
What was the administration route of drug 'DABRAFENIB'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | Oral | DrugAdministrationRoute | CC BY | 33215864 | 19,564,673 | 2021-01 |
What was the administration route of drug 'FUROSEMIDE'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | Oral | DrugAdministrationRoute | CC BY | 33215864 | 19,564,673 | 2021-01 |
What was the administration route of drug 'TRAMETINIB DIMETHYL SULFOXIDE'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | Oral | DrugAdministrationRoute | CC BY | 33215864 | 18,545,980 | 2021-01 |
What was the administration route of drug 'TRAMETINIB'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | Oral | DrugAdministrationRoute | CC BY | 33215864 | 19,564,673 | 2021-01 |
What was the dosage of drug 'DABRAFENIB'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | 150 mg (milligrams). | DrugDosage | CC BY | 33215864 | 19,564,673 | 2021-01 |
What was the outcome of reaction 'Condition aggravated'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | Recovering | ReactionOutcome | CC BY | 33215864 | 19,564,673 | 2021-01 |
What was the outcome of reaction 'General physical health deterioration'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | Recovering | ReactionOutcome | CC BY | 33215864 | 18,545,980 | 2021-01 |
What was the outcome of reaction 'Hypoalbuminaemia'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | Recovering | ReactionOutcome | CC BY | 33215864 | 18,545,980 | 2021-01 |
What was the outcome of reaction 'Interstitial lung disease'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | Recovering | ReactionOutcome | CC BY | 33215864 | 18,545,980 | 2021-01 |
What was the outcome of reaction 'Pneumonia'? | Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.
Introduction
The v‐raf murine sarcoma viral oncogene homolog B1 (BRAF) gene has been found to function as a driver oncogene through mitogen‐activated protein kinase (MAPK) signaling
1
in patients with non‐small cell lung cancer (NSCLC). BRAF mutations occur in approximately 1%–4% of cases of NSCLC, and the most common BRAF mutation is V600E, which results in glutamate being substituted for valine at codon 600.
1
,
2
The efficacy of dual BRAF and meiotic chromosome‐axis‐associated kinase (MEK) inhibitors has been evaluated in previously treated and untreated patients with BRAF V600E‐mutant metastatic NSCLC, in whom it achieved overall response rates of 63%–64% and complete response rates of 4%–6%.
3
,
4
However, the ages of the subjects of these studies ranged from 58–71 and from 62–74 years, respectively, and the efficacy and safety of combination therapy for such disease in elderly patients remain unclear. Here, we describe a case, in which an elderly (“oldest old”) patient with BRAF V600E‐mutant NSCLC adenocarcinoma was treated with dabrafenib and trametinib. Although the treatment brought durable tumor shrinkage and symptom relief, it had to be terminated due to the occurrence of marked hypoalbuminemia and edema. Informed consent from the patient and the permission of ethics committee of Nagasaki University Hospital (Permission Number 20081733) were obtained to publish the report and accompanying images.
Case report
An 86‐year‐old male patient with a history of smoking, one pack per day from the age of 20 to 70 years of age, was referred to our hospital with dyspnea. A computed tomography (CT) scan revealed a lesion in the right lower lobe together with pleural effusion (Fig 1a,d) and multiple mediastinal lymphadenopathy. Positron emission tomography/computed tomography (PET/CT) also showed increased metabolic activity in the bilateral adrenal glands. Radiographic and pathological evaluations resulted in a diagnosis of advanced lung adenocarcinoma (cT4N2M1c, stage IVB). Next‐generation sequencing (NGS) revealed a BRAF V600E mutation in exon 15 (c.1799>A). The tumor sample was negative for other driver mutations, and immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Laboratory analyses revealed the following: leukocyte count: 7100/μL, hemoglobin level: 11.5 g/dL, C‐reactive protein level: 1.56 mg/dL, total protein level: 8.6 g/dL, albumin level: 2.4 g/dL, blood urea nitrogen level: 18 mg/dL, serum creatinine level: 0.85 mg/dL, and albuminuria score: 1+. These laboratory findings were indicative of mild hypoalbuminemia. Although the patient was “oldest old”, he had an Eastern Cooperative Oncology Group performance status (PS) of 1 and was treated with dabrafenib and trametinib combination targeted therapy. Dabrafenib was administered orally at a dose of 150 mg twice daily, and 2 mg trametinib was administered orally once daily.
Figure 1 Chest X‐rays and computed tomography scans obtained (a) (d) before and (b) (e) two weeks and (c) (f) seven weeks after the start of the dabrafenib plus trametinib treatment.
After two weeks of targeted therapy, a chest X‐ray and CT scan revealed a reduction in the right pleural effusion and shrinkage of the primary mass (Fig 1b,e). During this period, the patient did not experience dyspnea, and his PS improved. Four weeks after the initiation of dabrafenib plus trametinib therapy, he developed peripheral leg edema and hypoalbuminemia (Fig 2). Ultrasound cardiography showed that his cardiac function had been preserved, and that he was not suffering from renal dysfunction, which suggested that the peripheral edema was related to the dabrafenib plus trametinib therapy. The peripheral edema created some problems for the patient during daily living activities and he was classified as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The dabrafenib plus trametinib treatment was interrupted, and oral administration of the diuretic furosemide was initiated. The peripheral edema had not improved one week after the interruption of treatment, and so treatment was not recommenced. A CT scan performed seven weeks after the initiation of treatment revealed further tumor shrinkage; however, it also showed pneumonia that was either infection or drug‐induced, although the patient did not experience any symptoms. Thus, he was hospitalized and treated with intravenous antibiotics, albumin injections, and a branched‐chain amino acid preparation, and his pneumonia and hypoalbuminemia gradually improved. The blood albumin levels of the patient are shown in Figure 3. Dabrafenib and trametinib treatment was discontinued because of the risk of life‐threatening adverse events, and best supportive care was initiated. The duration of the dabrafenib and trametinib treatment was in total 40 days. Tumor shrinkage continued to be seen on radiological imaging (Fig 1c,f), and the patient was able to maintain his quality of life (QOL) for at least six weeks after treatment interruption.
Figure 2 Peripheral pitting edema seen four weeks after the initiation of dabrafenib plus trametinib therapy.
Figure 3 Timeline of the patient's serum albumin level. D/T: Dabrafenib plus trametinib.
Discussion
This report describes the case of an “oldest old” patient with BRAF V600E‐mutated NSCLC, who received dabrafenib plus trametinib treatment. Although it induced a marked response, the patient was unable to continue to receive combination treatment because he developed grade 3 hypoalbuminemia and peripheral edema and was subsequently switched to supportive care. As targeted therapies for patients with NSCLC are usually expected to have marked therapeutic effects with only mild adverse events, even in elderly patients, this combination therapy might have caused relatively strong adverse events or the patient might have been too old. We consider that these observations will be helpful for clinicians facing similar situations in the future.
Targeted therapies have been previously reported to show marked antitumor effects against advanced NSCLC that express molecular driver oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c‐Ros oncogene 1 (ROS1),
5
,
6
,
7
,
8
including in elderly populations, resulting in the development of individualized treatment strategies. BRAF is a serine/threonine kinase, which is mediated by the RAS‐RAF‐MEK‐ERK signaling pathway,
1
and BRAF mutations have been previously observed in about 1%–5% of lung adenocarcinomas.
2
,
9
,
10
Targeting BRAF V600‐mutant tumors with selective BRAF and MEK inhibitors is the current standard treatment for patients with metastatic melanoma, in which the BRAF V600E mutation is more common than in NSCLC.
11
Phase II trials of combined BRAF and MEK inhibition in patients with previously treated and untreated NSCLC achieved overall response rates of 63% and 64% and median response durations of 9.7 and 10.4 months, respectively.
3
,
4
Therefore, dabrafenib plus trametinib is the current standard treatment for patients with BRAF V600‐mutated advanced NSCLC, and was very appropriate for the present case.
There is limited clinical information about patients harboring BRAF mutations, especially in elderly patients and those with poor PS, because BRAF mutations are only found in a few populations. Intensive treatment, such as combination chemotherapy or combined modality, does not usually produce a survival benefit in patients aged >70 or 75 years.
12
,
13
,
14
On the other hand, the use of therapies targeting other driver oncogenes is recommended, regardless of the patient's age and general condition, because of the marked responses they induce and their mild toxicities.
15
,
16
,
17
However, the patient in the present case was 86 years old, which is classified as “oldest old”, and the supportive care rates in this age group range from 55%–67%.
18
,
19
Despite this, it seems that the treatment caused an improvement in QOL and prolonged the patient's life by shrinking the tumor, and thus, it had meaningful effects.
The most common adverse events of dabrafenib and trametinib therapy for NSCLC have been reported to be pyrexia, elevated alanine aminotransferase levels, hypertension, anemia, a confused state, decreased appetite, hemoptysis, hypercalcemia, nausea, vomiting, neutropenia, hyponatremia, and a reduction in the ejection fraction.
3
,
4
Previous trials have reported that 52% of melanoma patients that were treated with combination therapy had grade 3 or 4 side effects, and the frequencies of adverse events that led to dose reduction and treatment interruption were 33% and 55%, respectively.
20
Therefore, clinicians must always keep in mind that the toxicities of combination therapy are relatively serious. In addition, the characteristics of the adverse events seen in patients treated with combination therapy often differ from those of other targeted therapies. Peripheral edema is a common adverse event and has been reported to occur in 28%–36% of cases of BRAF V600E‐mutant NSCLC,
3
,
21
but most patients experienced mild (grade 1 or 2) peripheral edema. To the best of our knowledge, there have been no reports about peripheral edema due to combination therapy that led to dose reduction or treatment interruption or discontinuance in NSCLC. However, in the present case the peripheral edema caused by hypoalbuminemia triggered a decline in the patient's QOL, which could be intolerable for some patients. In addition, when peripheral edema is observed, clinicians must always exclude a reduction in the left ventricular ejection fraction and cardiac tamponade using ultrasound cardiography.
22
Liver dysfunction did not occur in the present case; thus, hypoalbuminemia was not derived from liver toxicity. As the ability to assimilate nutrients decreases, tumor‐induced inflammation increases, and the clearing of necrotic tumor cells from the body after durable treatment becomes less effective with age, and it might be necessary to monitor patients for chemotherapy‐induced hypoalbuminemia and peripheral edema when chemotherapy is administered to “oldest old” patients. Patients with bilateral adrenal metastases and adrenal insufficiency might also present with hypoalbuminemia. During the patient's clinical course, pneumonia also appeared for a period of time, and the possibility of drug‐induced pneumonitis was feared. The presence of fibrosis on chest CT before treatment has been reported to predict the appearance of anticancer drug‐induced pneumonia,
23
,
24
but this was not seen before treatment in the case reported here, and the patient's pneumonia improved with antibacterial treatment and drug suspension; therefore, drug‐induced pneumonia could not be completely ruled out with no retreatment. If the tumor had not possessed the BRAF V600E mutation, no other treatment strategies would have been available for the patient due to his age. Thus, we consider that the combination therapy administered in this patient had many benefits. A previous study reported that a reduced dose of combination therapy prevented toxicities and maintained antitumor effects
25
; therefore, dose reduction from the beginning of treatment might be a better option for elderly patients, as it might allow combination therapy to be continued successfully.
Immunohistochemistry (clone 22C3) demonstrated high programmed death‐ligand 1 expression (TPS 90%). Regarding the issue which is better about targeted drug or immune check point inhibitor for elderly patients with both BRAF mutation and high expression of PD‐L1 more than 90% TPS. It was considered that immunotherapy may be less effective for driver gene positive cancer and in elderly people; in addition, it has also been previously reported that there is a risk of increased drug‐induced pneumonia after immunotherapy there is a risk of drug‐induced pneumonia of EGFR‐TKI such as osimertinib.
26
Therefore, we decided to first administer targeted therapy. The patient did not use immunotherapy after all, but if he was fine with a good PS, immunotherapy was considered the option after targeted therapy.
In conclusion, dabrafenib and trametinib caused marked tumor shrinkage, improvements in QOL, and prolonged survival when administered to an “oldest old” patient with BRAF V600E‐mutant NSCLC. Active targeted therapy may therefore be considered instead of conservative treatment even if the patient is extremely old. In such cases, careful management, including treatment interruption and dose reduction, is required to manage adverse events such as hypoalbuminemia and peripheral edema derived from the decline of the patient's physical condition,
Disclosure
The authors report no conflicts of interest related to this work.
Acknowledgments
We are grateful the patient and his family for their cooperation in this paper. | Recovering | ReactionOutcome | CC BY | 33215864 | 19,564,673 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhage'. | Direct oral anticoagulants (DOAC) for prevention of recurrent arterial or venous thromboembolic events (ATE/VTE) in myeloproliferative neoplasms.
In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial or venous thromboembolic events (ATE/VTE) are a major burden. In order to control these complications, vitamin K antagonists (VKA) are widely used. There is no robust evidence supporting the use of direct oral anticoagulants (DOAC) in MPN patients. We therefore compared the efficacy and safety of both anticoagulants in 71 cases from a cohort of 782 MPN patients. Seventy-one of 782 MPN patients (9.1%) had ATE/VTE with nine ATE (12.7%) and 62 VTE (87.3%). Forty-five of 71 ATE/VTE (63.4%) were treated with VKA and 26 (36.6%) with DOAC. The duration of anticoagulation therapy (p = 0.984), the number of patients receiving additional aspirin (p = 1.0), and the proportion of patients receiving cytoreductive therapy (p = 0.807) did not differ significantly between the VKA and DOAC groups. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1-20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. For all bleeding events (p = 0.516) or major bleeding (p = 1.0), no significant differences were observed between VKA and DOAC. In our experience, the use of DOAC was as effective and safe as VKA, possibly even potentially beneficial with a lower number of recurrences and no increased risk for bleedings. However, further and larger studies are required before DOAC can be routinely used in MPN patients.
Introduction
In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial and venous thromboembolic events (ATE/VTE) occur frequently and have a significant impact on morbidity and mortality [1–3]. Several studies reported up to 10 times higher incidence of such complications compared to the healthy population [4–12].
Vitamin K antagonists (VKA) are widely used for both primary therapy and secondary prevention of MPN-associated ATE/VTE [13–15]. The introduction of direct oral anticoagulants (DOAC) provides a new treatment option [14, 16–20] with data comparable to the VKA [16–21]. However, the DOAC have no drug approval for patients with cancer or hematological malignancies, and published experience with its use in MPN-associated vascular events is currently very limited.
Curto-Garcia et al. [22] retrospectively reported on the results of 32 MPN patients with 38 venous thromboembolism and DOAC treatment. During a median follow-up period of 2.1 years, neither VTE recurrences nor major bleedings were observed.
Ianotto et al. [21] reported on the retrospective course of 25 MPN patients under DOAC treatment. During a median follow-up time of 2.1 years, two arterial thromboembolic and three bleeding events were observed. A case-control comparison of 25 MPN patients treated with low-dose aspirin (ASS) showed no difference in efficacy and safety [21].
Preliminary and retrospective data from Fedorov et al. [23] reported 22 DOAC- and 31 VKA-treated MPN patients with comparable incidences of recurrence and bleeding events.
However, there is no robust evidence supporting the use of DOAC in MPN, including a direct comparison with VKA treatment. Therefore, at our center, we retrospectively evaluated 71 MPN patients with 71 ATE/VTE treated with VKA (n = 45) or DOAC (n = 26) to compare the efficacy and safety of both anticoagulants.
Patients and methods
Clinical data of all MPN patients, who regularly present in our university department, were collected from June 2007 to April 2020 (time of last data cut-off April 1, 2020). All MPN were diagnosed according to the WHO 2008 criteria [24–26]. A total of 782 MPN patients (478 female, 61.1%, and 304 males, 38.9%) are currently registered in our outpatient clinic specializing in MPN. The median age is 50.5 years (range: 11.0–88.9), and the median follow-up time is 1.8 years (range: 0.1–28.4). The different MPN subtypes within the whole group are essential thrombocythemia (ET), n = 254 (32.5%); polycythemia vera (PV), n = 264 (33.8%); myelofibrosis (MF) including primary and secondary myelofibrosis, n = 238 (30.4%); and MPN unclassifiable, n = 26 (3.3%). The driver mutations are distributed within the 782 MPN patients as follows: JAK2 mutation, 534 (68.3%); CALR mutation, 110 (14.1%); MPL mutation, 19 (2.4%); triple negative, 42 (5.4%); and unknown 70 (9.0%).
The main objective of this retrospective, non-interventional, single-center study was to compare VKA with DOAC therapy in MPN patients. Of particular interest was the efficacy in ATE/VTE treatment, the prevention of ATE/VTE relapses, and the subsequent risk of bleeding complications under both anticoagulants. The data were collected in an electronic system. The Ethics Committee of our center approved the study. We focused on each patient with at least one MPN-associated arterial (ATE) or venous (VTE) thromboembolic event treated with VKA or DOAC. In line with previous studies, we defined an ATE or VTE associated with MPN if it occurred within 2 years prior to MPN diagnosis or after [27, 28].
The follow-up time was defined as the time between the first occurrence of an ATE/VTE and last visit to our center. Treatment time was defined as the time between the start of anticoagulation (= after the first ATE/VTE) and the end of anticoagulation or the last visit to our center (if anticoagulation was not stopped) or first relapse (whichever came first).
For each MPN patient with an ATE/VTE and anticoagulation with VKA or DOAC, we collected demographic data, mutational profile, method of objective diagnosis of ATE/VTE, and presence of cardiovascular (CV) risk factors. In addition, further details on ATE/VTE such as localization, total number, PT (prothrombin time)-INR (international normalized ratio), time of diagnosis and other cytoreductive or antiplatelet therapy were collected. Cytoreductive treatment was defined as the use of hydroxyurea, busulfan, anagrelide, interferon-alpha, ruxolitinib, and/or other JAK inhibitors at the time of ATE/VTE or within 6 months thereafter. Finally, time intervals regarding anticoagulation treatment, duration of treatment, occurrence of bleeding complications, and the number of relapses that occurred during or after completion of anticoagulation were recorded. The diagnosis of an ATE/VTE event required objective diagnostic procedures such as ultrasound, computed tomography, angiography, or scintigraphy.
The severity of bleeding complications was defined according to the criteria of the International Society on Thrombosis and Hemostasis [29]. According to these criteria, we considered a bleeding greater than II° (e.g., transfusion-related anemia, central nervous system involvement, or other life-threatening bleeding) to be clinically relevant.
Statistical methods
For continuous variables, the median and range are provided. The annual incidence of ATE/VTE recurrences was calculated by dividing the number of events by the sum of patient-years. Differences in the proportions were estimated using Fisher’s exact test, Chi-square test, Mann-Whitney U test (statistical significance threshold set at p < 0.05), or log-rank test (Mantel-Haenszel test).
Results
Of the total 71 MPN-associated ATE/VTE, nine (12.7%) were ATE and 62 (87.3%) VTE. Table 1 provides an overview of demographic data and clinical characteristics of all 71 patients diagnosed with 71 initial ATE/VTE. Most ATE/VTE patients were female (n = 49, 69.0%) and were diagnosed as PV (n = 30, 42.3%), followed by MF (n = 20, 28.2%) or ET (n = 19, 26.8%). Two MPN patients with ATE/VTE were found to have a MPN at bone marrow biopsy, but both could not be further classified and were referred to as MPN unclassifiable. The JAK2 V617F mutation was the most frequent driver mutation (n = 63, 88.7%). The median age at ATE/VTE diagnosis was 54.0 years (22.0–82.0).Table 1 Overview of demographic data and clinical features of 71 MPN patients with 71 arterial and venous thromboembolic events (ATE/VTE) treated with either VKA or DOAC
Male/female; n (%) 22/49 (31.0/69.0)
Median age at first ATE/VTE; years (range) 54.0 (22.0–82.0)
Median follow-up time from first ATE/VTE; years (range) 3.2 (0.1–20.4)
MPN diagnosis
Polycythemia vera (PV); n (%) 30 (42.3)
Myelofibrosis (MF); n (%) 20 (28.2)
Essential thrombocythemia (ET); n (%) 19 (26.8)
MPN unclassifiable; n (%) 2 (2.8)
Driver mutations
JAK2; n (%) 63 (88.7)
CALR; n (%) 3 (4.2)
MPL; n (%) 1 (1.4)
Triple negative; n (%) 2 (2.8)
Unknown; n (%) 2 (2.8)
ATE/VTE
VTE; n (%) 62 (87.3)
ATE; n (%) 9 (12.7)
The localizations of all 71 ATE/VTE events together with corresponding localizations of ATE/VTE in VKA- or DOAC-treated MPN patients are shown in Table 2. Most ATE (6/9 = 67%) consisted of transient ischemic attacks (n = 2) or a stroke (n = 4). The remaining three had two embolisms each on a lower limb (n = 2, 2.8%) and an arterial splenic infarction (n = 1, 1.4%). About half VTE (28/62 = 45%) were atypical with 22 splanchnic and six sinus vein thromboses. Deep vein thrombosis simultaneously with pulmonary embolism was observed in nine MPN patients (n = 9, 12.7%). Isolated deep vein thrombosis or pulmonary embolism occurred in 14 (19.7%) and nine (n = 9, 12.7%) MPN cases with VTE, respectively. The two remaining VTE were each thrombophlebitis (n = 1, 1.4%) and arm vein thromboses (n = 1, 1.4%).Table 2 Localization of all first arterial and venous thromboembolic events (ATE/VTE, n = 71) with corresponding localizations of ATE/VTE in DOAC (n = 26) or VKA (n = 45) treated MPN patients together with localization of first ATE/VTE recurrences (n = 26)
First ATE/VTE event (n = 71) First ATE/VTE treated with DOAC (n = 26) First ATE/VTE treated with VKA (n = 45) ATE/VTE recurrences (n = 26) ATE/VTE recurrences after DOAC therapy (n = 4) ATE/VTE recurrence during or after VKA therapy (n = 22)
Localization
Arterial thromboembolic events (ATE); n (%) 9 (12.7) 3 (11.5) 6 (13.3) 12 (46.2) 1 (25.0) 11 (50.0)
Transient ischemic attack (TIA); n (%) 2 (2.8) - 2 (4.4) 1 (3.8) - 1 (4.5)
Angina pectoris; n (%) - - - 1 (3.8) - 1 (4.5)
Stroke; n (%) 4 (5.6) 1 (3.8) 3 (6.7) 2 (7.7) - 2 (9.1)
Arterial embolism of lower limb; n (%) 2 (2.8) 1 (3.8) 1 (2.2) 3 (11.5) - 3 (13.6)
Renal infarction; n (%) - - - 1 (3.8) 1 (25.0) -
Splenic infarction; n (%) 1 (1.4) 1 (3.8) - 4 (15.4) - 4 (18.2)
Venous thromboembolic events (VTE) 62 (87.3) 23 (88.5%) 39 (86.7) 14 (53.8) 3 (75.0) 11 (50.0)
Deep vein thrombosis; n (%) 14 (19.7) 5 (19.2) 9 (20.0) 6 (23.1) 1 (25.0) 5 (22.7)
Pulmonary embolism; n (%) 9 (12.7) 6 (23.1) 3 (6.7) 1 (3.8) 1 (25.0) -
Deep vein thrombosis simultaneous to pulmonary embolism; n (%) 9 (12.7) 4 (15.4) 5 (11.1) - - -
Splanchnic vein thrombosis; n (%) 22 (31.0) 5 (19.2) 17 (37.8) 4 (15.4) - 4 (18.2)
Thrombophlebitis; n (%) 1 (1.4) 1 (3.8) - 1 (3.8) 1 (25.0) -
Sinus vein thrombosis; n (%) 6 (8.5) 2 (7.7) 4 (8.9) 2 (7.7) - 2 (9.1)
Arm vein thrombosis; n (%) 1 (1.4) - - - - -
No recurrences were observed during DOAC therapy, but there were four recurrences after stopping DOAC. 22 recurrences occurred during or after VKA therapy
All 71 patients had a median total follow-up time of 3.2 years (range: 0.1–20.4) with an incidence rate for all 71 ATE/VTE of 3.4% per patient/year. The corresponding rates for ATE and for VTE were 0.4% and 3.0% per patient/year, respectively.
Out of 71 MPN with a first ATE/VTE, 45 (63.4%) were treated with VKA and 26 (36.6%) with DOAC. Most patients with DOAC received rivaroxaban (n = 21), and the remaining were treated with apixaban (n = 5). The median duration on anticoagulation was 1.0 years (range 0.1–20.4) with a median time on VKA of 1.0 years (range 0.1–20.4) and a median time on DOAC of 1.3 years (range 0.2–7.3). During the entire anticoagulation period, low-dose acetylsalicylic acid was additionally used in the 71 ATE/VTE in seven patients with VKA therapy (7/45, 9.9%) and in four patients with DOAC treatment (4/26, 5.5%). Cytoreductive treatment was initiated in 39 MPN patients (39/71, 63.9%) simultaneously or within 6 months after ATE/VTE. In the VKA group 22 of 45 patients (48.9%) and in the DOAC group 17 of 26 patients (65.4%) additionally received cytoreductive drugs.
Within a median time of 1.5 years (range: 0.1–8.5), 26 first ATE/VTE recurrences were observed in 26 patients. This corresponds to an ATE /VTE recurrence rate of 8.0% per patient/year. No recurrence was observed in 45 patients (63.4%). The localizations of the first 26 recurrences together with the corresponding localizations of recurrent ATE/VTE in VKA- or DOAC-treated MPN patients are shown in Table 2. Of 26 first recurrences, 12 (12/26 = 46.2%) were ATE and 14 (14/26 = 53.8%) were VTE. After a median time of 0.9 years (range: 0.1–8.5), 16 ATE/VTE recurrences occurred during anticoagulation with VKA therapy (16/26 = 61.5%). No recurrences were observed during DOAC therapy. This difference is statistically significant (p = 0.0003) (Fig. 1).Fig. 1 First ATE/VTE recurrences (n = 26) during follow-up time: significantly more recurrences (p = 0.0003) occurred during VKA (n = 16) compared to no recurrences during DOAC (n = 0) treatment (red). After termination of anticoagulation, four of 26 DOAC and six of 45 VKA-treated patients had ATE/VTE recurrences (green). Overall, significantly more recurrences were recorded in patients with VKA treatment (n = 22) compared to DOAC (n = 4) (p = 0.0053)
In 17 out of 45 patients (38%) treated with VKA, sufficient PT (prothrombin time) and/or INR (international normalized ratio) values were documented during anticoagulation, and 53% of these were in the therapeutic range. At the time of relapse, seven out of 22 patients treated with VKA had documented PT and/or INR values, and four (57%) were in the therapeutic range.
During the entire follow-up time, 22 recurrences occurred in VKA-treated (n = 22, 84.6%) and four in DOAC-treated (n = 4, 15.4%) patients. In the latter group, all four recurrences were recorded within a median time of 0.7 years (range: 0.3–1.3) after termination of DOAC treatment. Sixteen of all 22 VKA-associated ATE/VTE recurrences (16/22 = 72.7%) were observed during VKA anticoagulation therapy. The remaining six recurrences (6/22 = 27.3%) were observed within a median time of 0.9 years (range: 0.4–4.0) after termination of the VKA. Comparing the total number of recurrences in VKA-treated patients (n = 22) with the recurrences registered in patients treated with DOAC (n = 4) shows a statistically significant difference during the follow-up time (p = 0.0053) (Fig. 1).
After comparing the absolute number of ATE/VTE recurrences, an analysis was performed that considered the probability of “recurrence-free” survival during the follow-up time. In this analysis, the difference between VKA- and DOAC-treated patients was not statistically different (Fig. 2, p = 0.2). The incidence rate of ATE/VTE recurrences in VKA-treated patients was 8.1% per patient/year and 7.2% per patient/year in DOAC-treated patients. This difference was also not statistically different (alpha = 5%).Fig. 2 Probability of recurrence-free survival: the cumulative probability of the ATE/VTE recurrence-free survival in 71 MPN patients treated with DOAC (n = 26, red curve) or VKA (n = 45, blue curve) was statistically not significantly different (p = 0.2)
Bleedings
During anticoagulation with either VKA or DOAC, 10 of 71 patients (14.1%) experienced 11 bleeding complications over a median period of 1.6 years (range: 0.1–6.8). Six out of 11 bleedings (54.5%) were classified as severe bleedings.
In the VKA group, seven bleeding complications (63.6%), including four major bleeding complications, were recorded after a median time of 1.6 years (range: 0.1–6.8). Three out of four major bleedings (one esophageal varicose vein bleeding and two severe epistaxis episodes) occurred during VKA use alone (without low-dose acetylsalicylic acid). One patient underwent a combination therapy of VKA and low-dose acetylsalicylic acid and experienced major postoperative bleeding 1 day after total hip replacement implantation. During VKA treatment, three minor bleedings occurred (a menorrhagia, an episode with bloody semen, and an unspecified bleeding tendency).
During DOAC therapy, two minor and two major bleeding complications (n = 4, 36.4%) occurred after a median time of 0.5 years (range: 0.3–1.6). Both major bleeding episodes under DOAC anticoagulation (without low-dose acetylsalicylic acid) were gastrointestinal bleedings of unknown localization. The remaining two minor bleedings were epistaxis and petechial bleeding during DOAC therapy.
Overall, no significant differences were observed between DOAC and VKA anticoagulation therapy for both overall (p = 0.516) or major bleeding (p = 1.0). A comparison regarding different clinical and laboratory parameters between VKA- and DOAC-treated patients is shown in Table 3. In the VKA group, only the total follow-up time (p = 0.0005) and number of ATE/VTE recurrences (p = 0.0053) were statistically different.Table 3 Comparison of different clinical and laboratory parameters between DOAC- (n = 26) and VKA-treated MPN patients (n = 45)
Parameters DOAC VKA p
Number of pts.* 26 45
Median age at MPN diagnosis; years (range) 55.5 (24.0–81.0) 50.0 (22.0–82.0) 0.131
Median age at first ATE/VTE event; years (range) 57.5 (27.0–88.0) 53.0 (22.0–81.0) 0.070
Gender (male/female) 8/18 14/31 0.976
Essential thrombocythemia 8 11 0.816
Polycythemia vera 10 20
Myelofibrosis 7 13
JAK2 Mutation 24 39 0.701
Cardiovascular risk factors (yes/no) 15/11 30/15 0.450
ATE 3 6 1.0
VTE 23 39
Median treatment time; years (range) 1.3 (0.2–7.3) 1.0 (0.1–20.4) 0.984
Median total follow up time; years (range) 1.7 (0.2–7.3) 4.8 (0.6–20.4) 0.0005**
ATE/VTE recurrences 4 22 0.0053**
Combined ASS use*** 4 7 1.0
Cytoreductive therapy for first ATE/VTE**** 17 22 0.22
Bleeding events total 4 7 1.0
Major bleeding events 2 4 1.0
Deaths 1 3 1.0
*Pts. = patients
**Significantly different
***During time on anticoagulation after first ATE/VTE
****Begin at time of ATE/VTE or within 6 months thereafter
Discussion
Myeloproliferative neoplasm (MPN) patients have an increased risk of arterial and venous thromboembolic events (ATE/VTE). In larger MPN cohorts, the proportion of patients suffering from ATE/VTE is reported to be 10 to 30% [22]. Accordingly, vascular events occurred in 9.1% (71/782) of our 782 MPN patients. The incidence rate for the first 71 ATE/VTE was 3.4% per patient/year with a VTE rate of 3.0% per patient/year. Prospective studies in MPN observed comparable VTE rates of 0.5–3.7% [6, 7]. The ATE incidence rate of 0.4% per patient/year in our MPN patients was also similar to the reported ATE rates of 0.2 to 1.5% [5, 11].
In recent decades, anticoagulation with vitamin K antagonists (VKA) has been the treatment of choice to prevent ATE/VTE recurrences in MPN patients. Hernández-Boluda et al. [14] reported a 2.8-fold risk reduction for recurrence in 150 ET and PV patients with ATE/VTE and VKA treatment. In 206 MPN patients, De Stefano et al. [15] also found a reduction in the recurrence rate of VTE with VKA. The incidence rate of recurrent VTE was 5.3% per patient/year among patients with long-term VKA and 12.8% per patient/year after VKA discontinuation (p = 0.008). The VTE recurrence rate in our cohort was comparable at 8.0% per patient/year.
As far as anticoagulation with direct oral anticoagulants (DOAC) is concerned, there are few studies in MPN that indicate good efficacy with sufficient safety. In a retrospective study by Curto-Garcia et al. [22] in 32 MPN patients receiving DOAC for MPN-associated venous thromboembolism treated with DOAC, no VTE relapse but one ATE occurred. No major and three minor bleedings were reported. Ianotto et al. [21] retrospectively reported two ATE and no VTE recurrences in a cohort of 25 DOAC-treated MPN patients. Three major and two minor bleedings were observed. Curto-Garcia et al. [22] reported a median age of 49.9 years and a median follow-up of 2.1 years in their publication. The median follow-up time in the study of Ianotto et al. [21] was quite similar with 2.1 years. However, both studies did not compare DOAC treatment with VKA in their cohort [21, 22]. Fedorov et al. [23] reported preliminary data on recurrence rates and bleeding complications in 22 DOAC- and 31 VKA-treated MPN patients. During a short follow-up of 8 months, the number of ATE/VTE recurrences (DOAC, n = 5 versus VKA, n = 6) and of all bleeding complications (DOAC, n = 5 versus VKA, n = 11) were not significantly different.
The median age of our 71 MPN patients at the time of ATE/VTE was 54 years and was comparable to the studies of Curto-Garcia et al. and Ianotto et al. [21, 22]. The median duration of anticoagulation was lower at 1.0 years for VKA and 1.3 for DOAC. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1–20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. This is mainly due to the significantly longer follow-up time for VKA patients (p = 0.0005). The corresponding recurrence rates for VKA and DOAC treatment (during and after discontinuation of anticoagulation) did not differ significantly either.
During anticoagulation with VKA, 53% and at the time of relapse, 57% of patients treated with VKA were in the therapeutic range with PT-INR. A major disadvantage of the VKA is the narrow therapeutic range and the time patients spend in the therapeutic range (TTR, “time in therapeutic range”). Even in well-conducted comparative studies of VKA and DOAK, the TTR was on average only between 55 and 65% [17, 20, 30, 31].
As in the studies mentioned above, we have not observed any increased bleeding propensity under DOAC. In particular, the rate of major bleeding was not higher under DOAC compared to VKA. Regarding bleeding complications with anticoagulation, the German MPN Registry of the Leukemia Study Alliance [32] reported bleeding in 437 MPN patients, including eight with DOAC (rivaroxaban) treatment. In a multivariate analysis, the risk of bleeding during DOAC treatment was slightly reduced compared to VKA.
In summary, our results complement the currently limited literature [21–23, 32] on the efficacy and safety of DOAC-treated MPN patients. Despite the limitations—small number of patients, retrospective analysis, and short treatment time—our data suggest that the use of DOAC was as effective and safe as VKA. However, further and larger studies are required before DOAC can be routinely used in MPN patients.
Authors’ contributions
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Karlo Huenerbein. The first draft of the manuscript was written by Karlo Huenerbein and Dr. Kai Wille, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
Ethical approval was waived by the local Ethics Committee of the Ruhr University Bochum in view of the retrospective nature of the study, and all the procedures being performed were part of the routine care.
Consent to participate/for publication
Informed consent was obtained from all individual participants included in the study. Patients signed informed consent regarding publishing their data and photographs.
Code availability
Not applicable.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ASPIRIN | DrugsGivenReaction | CC BY | 33216197 | 19,808,389 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Post procedural haemorrhage'. | Direct oral anticoagulants (DOAC) for prevention of recurrent arterial or venous thromboembolic events (ATE/VTE) in myeloproliferative neoplasms.
In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial or venous thromboembolic events (ATE/VTE) are a major burden. In order to control these complications, vitamin K antagonists (VKA) are widely used. There is no robust evidence supporting the use of direct oral anticoagulants (DOAC) in MPN patients. We therefore compared the efficacy and safety of both anticoagulants in 71 cases from a cohort of 782 MPN patients. Seventy-one of 782 MPN patients (9.1%) had ATE/VTE with nine ATE (12.7%) and 62 VTE (87.3%). Forty-five of 71 ATE/VTE (63.4%) were treated with VKA and 26 (36.6%) with DOAC. The duration of anticoagulation therapy (p = 0.984), the number of patients receiving additional aspirin (p = 1.0), and the proportion of patients receiving cytoreductive therapy (p = 0.807) did not differ significantly between the VKA and DOAC groups. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1-20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. For all bleeding events (p = 0.516) or major bleeding (p = 1.0), no significant differences were observed between VKA and DOAC. In our experience, the use of DOAC was as effective and safe as VKA, possibly even potentially beneficial with a lower number of recurrences and no increased risk for bleedings. However, further and larger studies are required before DOAC can be routinely used in MPN patients.
Introduction
In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial and venous thromboembolic events (ATE/VTE) occur frequently and have a significant impact on morbidity and mortality [1–3]. Several studies reported up to 10 times higher incidence of such complications compared to the healthy population [4–12].
Vitamin K antagonists (VKA) are widely used for both primary therapy and secondary prevention of MPN-associated ATE/VTE [13–15]. The introduction of direct oral anticoagulants (DOAC) provides a new treatment option [14, 16–20] with data comparable to the VKA [16–21]. However, the DOAC have no drug approval for patients with cancer or hematological malignancies, and published experience with its use in MPN-associated vascular events is currently very limited.
Curto-Garcia et al. [22] retrospectively reported on the results of 32 MPN patients with 38 venous thromboembolism and DOAC treatment. During a median follow-up period of 2.1 years, neither VTE recurrences nor major bleedings were observed.
Ianotto et al. [21] reported on the retrospective course of 25 MPN patients under DOAC treatment. During a median follow-up time of 2.1 years, two arterial thromboembolic and three bleeding events were observed. A case-control comparison of 25 MPN patients treated with low-dose aspirin (ASS) showed no difference in efficacy and safety [21].
Preliminary and retrospective data from Fedorov et al. [23] reported 22 DOAC- and 31 VKA-treated MPN patients with comparable incidences of recurrence and bleeding events.
However, there is no robust evidence supporting the use of DOAC in MPN, including a direct comparison with VKA treatment. Therefore, at our center, we retrospectively evaluated 71 MPN patients with 71 ATE/VTE treated with VKA (n = 45) or DOAC (n = 26) to compare the efficacy and safety of both anticoagulants.
Patients and methods
Clinical data of all MPN patients, who regularly present in our university department, were collected from June 2007 to April 2020 (time of last data cut-off April 1, 2020). All MPN were diagnosed according to the WHO 2008 criteria [24–26]. A total of 782 MPN patients (478 female, 61.1%, and 304 males, 38.9%) are currently registered in our outpatient clinic specializing in MPN. The median age is 50.5 years (range: 11.0–88.9), and the median follow-up time is 1.8 years (range: 0.1–28.4). The different MPN subtypes within the whole group are essential thrombocythemia (ET), n = 254 (32.5%); polycythemia vera (PV), n = 264 (33.8%); myelofibrosis (MF) including primary and secondary myelofibrosis, n = 238 (30.4%); and MPN unclassifiable, n = 26 (3.3%). The driver mutations are distributed within the 782 MPN patients as follows: JAK2 mutation, 534 (68.3%); CALR mutation, 110 (14.1%); MPL mutation, 19 (2.4%); triple negative, 42 (5.4%); and unknown 70 (9.0%).
The main objective of this retrospective, non-interventional, single-center study was to compare VKA with DOAC therapy in MPN patients. Of particular interest was the efficacy in ATE/VTE treatment, the prevention of ATE/VTE relapses, and the subsequent risk of bleeding complications under both anticoagulants. The data were collected in an electronic system. The Ethics Committee of our center approved the study. We focused on each patient with at least one MPN-associated arterial (ATE) or venous (VTE) thromboembolic event treated with VKA or DOAC. In line with previous studies, we defined an ATE or VTE associated with MPN if it occurred within 2 years prior to MPN diagnosis or after [27, 28].
The follow-up time was defined as the time between the first occurrence of an ATE/VTE and last visit to our center. Treatment time was defined as the time between the start of anticoagulation (= after the first ATE/VTE) and the end of anticoagulation or the last visit to our center (if anticoagulation was not stopped) or first relapse (whichever came first).
For each MPN patient with an ATE/VTE and anticoagulation with VKA or DOAC, we collected demographic data, mutational profile, method of objective diagnosis of ATE/VTE, and presence of cardiovascular (CV) risk factors. In addition, further details on ATE/VTE such as localization, total number, PT (prothrombin time)-INR (international normalized ratio), time of diagnosis and other cytoreductive or antiplatelet therapy were collected. Cytoreductive treatment was defined as the use of hydroxyurea, busulfan, anagrelide, interferon-alpha, ruxolitinib, and/or other JAK inhibitors at the time of ATE/VTE or within 6 months thereafter. Finally, time intervals regarding anticoagulation treatment, duration of treatment, occurrence of bleeding complications, and the number of relapses that occurred during or after completion of anticoagulation were recorded. The diagnosis of an ATE/VTE event required objective diagnostic procedures such as ultrasound, computed tomography, angiography, or scintigraphy.
The severity of bleeding complications was defined according to the criteria of the International Society on Thrombosis and Hemostasis [29]. According to these criteria, we considered a bleeding greater than II° (e.g., transfusion-related anemia, central nervous system involvement, or other life-threatening bleeding) to be clinically relevant.
Statistical methods
For continuous variables, the median and range are provided. The annual incidence of ATE/VTE recurrences was calculated by dividing the number of events by the sum of patient-years. Differences in the proportions were estimated using Fisher’s exact test, Chi-square test, Mann-Whitney U test (statistical significance threshold set at p < 0.05), or log-rank test (Mantel-Haenszel test).
Results
Of the total 71 MPN-associated ATE/VTE, nine (12.7%) were ATE and 62 (87.3%) VTE. Table 1 provides an overview of demographic data and clinical characteristics of all 71 patients diagnosed with 71 initial ATE/VTE. Most ATE/VTE patients were female (n = 49, 69.0%) and were diagnosed as PV (n = 30, 42.3%), followed by MF (n = 20, 28.2%) or ET (n = 19, 26.8%). Two MPN patients with ATE/VTE were found to have a MPN at bone marrow biopsy, but both could not be further classified and were referred to as MPN unclassifiable. The JAK2 V617F mutation was the most frequent driver mutation (n = 63, 88.7%). The median age at ATE/VTE diagnosis was 54.0 years (22.0–82.0).Table 1 Overview of demographic data and clinical features of 71 MPN patients with 71 arterial and venous thromboembolic events (ATE/VTE) treated with either VKA or DOAC
Male/female; n (%) 22/49 (31.0/69.0)
Median age at first ATE/VTE; years (range) 54.0 (22.0–82.0)
Median follow-up time from first ATE/VTE; years (range) 3.2 (0.1–20.4)
MPN diagnosis
Polycythemia vera (PV); n (%) 30 (42.3)
Myelofibrosis (MF); n (%) 20 (28.2)
Essential thrombocythemia (ET); n (%) 19 (26.8)
MPN unclassifiable; n (%) 2 (2.8)
Driver mutations
JAK2; n (%) 63 (88.7)
CALR; n (%) 3 (4.2)
MPL; n (%) 1 (1.4)
Triple negative; n (%) 2 (2.8)
Unknown; n (%) 2 (2.8)
ATE/VTE
VTE; n (%) 62 (87.3)
ATE; n (%) 9 (12.7)
The localizations of all 71 ATE/VTE events together with corresponding localizations of ATE/VTE in VKA- or DOAC-treated MPN patients are shown in Table 2. Most ATE (6/9 = 67%) consisted of transient ischemic attacks (n = 2) or a stroke (n = 4). The remaining three had two embolisms each on a lower limb (n = 2, 2.8%) and an arterial splenic infarction (n = 1, 1.4%). About half VTE (28/62 = 45%) were atypical with 22 splanchnic and six sinus vein thromboses. Deep vein thrombosis simultaneously with pulmonary embolism was observed in nine MPN patients (n = 9, 12.7%). Isolated deep vein thrombosis or pulmonary embolism occurred in 14 (19.7%) and nine (n = 9, 12.7%) MPN cases with VTE, respectively. The two remaining VTE were each thrombophlebitis (n = 1, 1.4%) and arm vein thromboses (n = 1, 1.4%).Table 2 Localization of all first arterial and venous thromboembolic events (ATE/VTE, n = 71) with corresponding localizations of ATE/VTE in DOAC (n = 26) or VKA (n = 45) treated MPN patients together with localization of first ATE/VTE recurrences (n = 26)
First ATE/VTE event (n = 71) First ATE/VTE treated with DOAC (n = 26) First ATE/VTE treated with VKA (n = 45) ATE/VTE recurrences (n = 26) ATE/VTE recurrences after DOAC therapy (n = 4) ATE/VTE recurrence during or after VKA therapy (n = 22)
Localization
Arterial thromboembolic events (ATE); n (%) 9 (12.7) 3 (11.5) 6 (13.3) 12 (46.2) 1 (25.0) 11 (50.0)
Transient ischemic attack (TIA); n (%) 2 (2.8) - 2 (4.4) 1 (3.8) - 1 (4.5)
Angina pectoris; n (%) - - - 1 (3.8) - 1 (4.5)
Stroke; n (%) 4 (5.6) 1 (3.8) 3 (6.7) 2 (7.7) - 2 (9.1)
Arterial embolism of lower limb; n (%) 2 (2.8) 1 (3.8) 1 (2.2) 3 (11.5) - 3 (13.6)
Renal infarction; n (%) - - - 1 (3.8) 1 (25.0) -
Splenic infarction; n (%) 1 (1.4) 1 (3.8) - 4 (15.4) - 4 (18.2)
Venous thromboembolic events (VTE) 62 (87.3) 23 (88.5%) 39 (86.7) 14 (53.8) 3 (75.0) 11 (50.0)
Deep vein thrombosis; n (%) 14 (19.7) 5 (19.2) 9 (20.0) 6 (23.1) 1 (25.0) 5 (22.7)
Pulmonary embolism; n (%) 9 (12.7) 6 (23.1) 3 (6.7) 1 (3.8) 1 (25.0) -
Deep vein thrombosis simultaneous to pulmonary embolism; n (%) 9 (12.7) 4 (15.4) 5 (11.1) - - -
Splanchnic vein thrombosis; n (%) 22 (31.0) 5 (19.2) 17 (37.8) 4 (15.4) - 4 (18.2)
Thrombophlebitis; n (%) 1 (1.4) 1 (3.8) - 1 (3.8) 1 (25.0) -
Sinus vein thrombosis; n (%) 6 (8.5) 2 (7.7) 4 (8.9) 2 (7.7) - 2 (9.1)
Arm vein thrombosis; n (%) 1 (1.4) - - - - -
No recurrences were observed during DOAC therapy, but there were four recurrences after stopping DOAC. 22 recurrences occurred during or after VKA therapy
All 71 patients had a median total follow-up time of 3.2 years (range: 0.1–20.4) with an incidence rate for all 71 ATE/VTE of 3.4% per patient/year. The corresponding rates for ATE and for VTE were 0.4% and 3.0% per patient/year, respectively.
Out of 71 MPN with a first ATE/VTE, 45 (63.4%) were treated with VKA and 26 (36.6%) with DOAC. Most patients with DOAC received rivaroxaban (n = 21), and the remaining were treated with apixaban (n = 5). The median duration on anticoagulation was 1.0 years (range 0.1–20.4) with a median time on VKA of 1.0 years (range 0.1–20.4) and a median time on DOAC of 1.3 years (range 0.2–7.3). During the entire anticoagulation period, low-dose acetylsalicylic acid was additionally used in the 71 ATE/VTE in seven patients with VKA therapy (7/45, 9.9%) and in four patients with DOAC treatment (4/26, 5.5%). Cytoreductive treatment was initiated in 39 MPN patients (39/71, 63.9%) simultaneously or within 6 months after ATE/VTE. In the VKA group 22 of 45 patients (48.9%) and in the DOAC group 17 of 26 patients (65.4%) additionally received cytoreductive drugs.
Within a median time of 1.5 years (range: 0.1–8.5), 26 first ATE/VTE recurrences were observed in 26 patients. This corresponds to an ATE /VTE recurrence rate of 8.0% per patient/year. No recurrence was observed in 45 patients (63.4%). The localizations of the first 26 recurrences together with the corresponding localizations of recurrent ATE/VTE in VKA- or DOAC-treated MPN patients are shown in Table 2. Of 26 first recurrences, 12 (12/26 = 46.2%) were ATE and 14 (14/26 = 53.8%) were VTE. After a median time of 0.9 years (range: 0.1–8.5), 16 ATE/VTE recurrences occurred during anticoagulation with VKA therapy (16/26 = 61.5%). No recurrences were observed during DOAC therapy. This difference is statistically significant (p = 0.0003) (Fig. 1).Fig. 1 First ATE/VTE recurrences (n = 26) during follow-up time: significantly more recurrences (p = 0.0003) occurred during VKA (n = 16) compared to no recurrences during DOAC (n = 0) treatment (red). After termination of anticoagulation, four of 26 DOAC and six of 45 VKA-treated patients had ATE/VTE recurrences (green). Overall, significantly more recurrences were recorded in patients with VKA treatment (n = 22) compared to DOAC (n = 4) (p = 0.0053)
In 17 out of 45 patients (38%) treated with VKA, sufficient PT (prothrombin time) and/or INR (international normalized ratio) values were documented during anticoagulation, and 53% of these were in the therapeutic range. At the time of relapse, seven out of 22 patients treated with VKA had documented PT and/or INR values, and four (57%) were in the therapeutic range.
During the entire follow-up time, 22 recurrences occurred in VKA-treated (n = 22, 84.6%) and four in DOAC-treated (n = 4, 15.4%) patients. In the latter group, all four recurrences were recorded within a median time of 0.7 years (range: 0.3–1.3) after termination of DOAC treatment. Sixteen of all 22 VKA-associated ATE/VTE recurrences (16/22 = 72.7%) were observed during VKA anticoagulation therapy. The remaining six recurrences (6/22 = 27.3%) were observed within a median time of 0.9 years (range: 0.4–4.0) after termination of the VKA. Comparing the total number of recurrences in VKA-treated patients (n = 22) with the recurrences registered in patients treated with DOAC (n = 4) shows a statistically significant difference during the follow-up time (p = 0.0053) (Fig. 1).
After comparing the absolute number of ATE/VTE recurrences, an analysis was performed that considered the probability of “recurrence-free” survival during the follow-up time. In this analysis, the difference between VKA- and DOAC-treated patients was not statistically different (Fig. 2, p = 0.2). The incidence rate of ATE/VTE recurrences in VKA-treated patients was 8.1% per patient/year and 7.2% per patient/year in DOAC-treated patients. This difference was also not statistically different (alpha = 5%).Fig. 2 Probability of recurrence-free survival: the cumulative probability of the ATE/VTE recurrence-free survival in 71 MPN patients treated with DOAC (n = 26, red curve) or VKA (n = 45, blue curve) was statistically not significantly different (p = 0.2)
Bleedings
During anticoagulation with either VKA or DOAC, 10 of 71 patients (14.1%) experienced 11 bleeding complications over a median period of 1.6 years (range: 0.1–6.8). Six out of 11 bleedings (54.5%) were classified as severe bleedings.
In the VKA group, seven bleeding complications (63.6%), including four major bleeding complications, were recorded after a median time of 1.6 years (range: 0.1–6.8). Three out of four major bleedings (one esophageal varicose vein bleeding and two severe epistaxis episodes) occurred during VKA use alone (without low-dose acetylsalicylic acid). One patient underwent a combination therapy of VKA and low-dose acetylsalicylic acid and experienced major postoperative bleeding 1 day after total hip replacement implantation. During VKA treatment, three minor bleedings occurred (a menorrhagia, an episode with bloody semen, and an unspecified bleeding tendency).
During DOAC therapy, two minor and two major bleeding complications (n = 4, 36.4%) occurred after a median time of 0.5 years (range: 0.3–1.6). Both major bleeding episodes under DOAC anticoagulation (without low-dose acetylsalicylic acid) were gastrointestinal bleedings of unknown localization. The remaining two minor bleedings were epistaxis and petechial bleeding during DOAC therapy.
Overall, no significant differences were observed between DOAC and VKA anticoagulation therapy for both overall (p = 0.516) or major bleeding (p = 1.0). A comparison regarding different clinical and laboratory parameters between VKA- and DOAC-treated patients is shown in Table 3. In the VKA group, only the total follow-up time (p = 0.0005) and number of ATE/VTE recurrences (p = 0.0053) were statistically different.Table 3 Comparison of different clinical and laboratory parameters between DOAC- (n = 26) and VKA-treated MPN patients (n = 45)
Parameters DOAC VKA p
Number of pts.* 26 45
Median age at MPN diagnosis; years (range) 55.5 (24.0–81.0) 50.0 (22.0–82.0) 0.131
Median age at first ATE/VTE event; years (range) 57.5 (27.0–88.0) 53.0 (22.0–81.0) 0.070
Gender (male/female) 8/18 14/31 0.976
Essential thrombocythemia 8 11 0.816
Polycythemia vera 10 20
Myelofibrosis 7 13
JAK2 Mutation 24 39 0.701
Cardiovascular risk factors (yes/no) 15/11 30/15 0.450
ATE 3 6 1.0
VTE 23 39
Median treatment time; years (range) 1.3 (0.2–7.3) 1.0 (0.1–20.4) 0.984
Median total follow up time; years (range) 1.7 (0.2–7.3) 4.8 (0.6–20.4) 0.0005**
ATE/VTE recurrences 4 22 0.0053**
Combined ASS use*** 4 7 1.0
Cytoreductive therapy for first ATE/VTE**** 17 22 0.22
Bleeding events total 4 7 1.0
Major bleeding events 2 4 1.0
Deaths 1 3 1.0
*Pts. = patients
**Significantly different
***During time on anticoagulation after first ATE/VTE
****Begin at time of ATE/VTE or within 6 months thereafter
Discussion
Myeloproliferative neoplasm (MPN) patients have an increased risk of arterial and venous thromboembolic events (ATE/VTE). In larger MPN cohorts, the proportion of patients suffering from ATE/VTE is reported to be 10 to 30% [22]. Accordingly, vascular events occurred in 9.1% (71/782) of our 782 MPN patients. The incidence rate for the first 71 ATE/VTE was 3.4% per patient/year with a VTE rate of 3.0% per patient/year. Prospective studies in MPN observed comparable VTE rates of 0.5–3.7% [6, 7]. The ATE incidence rate of 0.4% per patient/year in our MPN patients was also similar to the reported ATE rates of 0.2 to 1.5% [5, 11].
In recent decades, anticoagulation with vitamin K antagonists (VKA) has been the treatment of choice to prevent ATE/VTE recurrences in MPN patients. Hernández-Boluda et al. [14] reported a 2.8-fold risk reduction for recurrence in 150 ET and PV patients with ATE/VTE and VKA treatment. In 206 MPN patients, De Stefano et al. [15] also found a reduction in the recurrence rate of VTE with VKA. The incidence rate of recurrent VTE was 5.3% per patient/year among patients with long-term VKA and 12.8% per patient/year after VKA discontinuation (p = 0.008). The VTE recurrence rate in our cohort was comparable at 8.0% per patient/year.
As far as anticoagulation with direct oral anticoagulants (DOAC) is concerned, there are few studies in MPN that indicate good efficacy with sufficient safety. In a retrospective study by Curto-Garcia et al. [22] in 32 MPN patients receiving DOAC for MPN-associated venous thromboembolism treated with DOAC, no VTE relapse but one ATE occurred. No major and three minor bleedings were reported. Ianotto et al. [21] retrospectively reported two ATE and no VTE recurrences in a cohort of 25 DOAC-treated MPN patients. Three major and two minor bleedings were observed. Curto-Garcia et al. [22] reported a median age of 49.9 years and a median follow-up of 2.1 years in their publication. The median follow-up time in the study of Ianotto et al. [21] was quite similar with 2.1 years. However, both studies did not compare DOAC treatment with VKA in their cohort [21, 22]. Fedorov et al. [23] reported preliminary data on recurrence rates and bleeding complications in 22 DOAC- and 31 VKA-treated MPN patients. During a short follow-up of 8 months, the number of ATE/VTE recurrences (DOAC, n = 5 versus VKA, n = 6) and of all bleeding complications (DOAC, n = 5 versus VKA, n = 11) were not significantly different.
The median age of our 71 MPN patients at the time of ATE/VTE was 54 years and was comparable to the studies of Curto-Garcia et al. and Ianotto et al. [21, 22]. The median duration of anticoagulation was lower at 1.0 years for VKA and 1.3 for DOAC. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1–20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. This is mainly due to the significantly longer follow-up time for VKA patients (p = 0.0005). The corresponding recurrence rates for VKA and DOAC treatment (during and after discontinuation of anticoagulation) did not differ significantly either.
During anticoagulation with VKA, 53% and at the time of relapse, 57% of patients treated with VKA were in the therapeutic range with PT-INR. A major disadvantage of the VKA is the narrow therapeutic range and the time patients spend in the therapeutic range (TTR, “time in therapeutic range”). Even in well-conducted comparative studies of VKA and DOAK, the TTR was on average only between 55 and 65% [17, 20, 30, 31].
As in the studies mentioned above, we have not observed any increased bleeding propensity under DOAC. In particular, the rate of major bleeding was not higher under DOAC compared to VKA. Regarding bleeding complications with anticoagulation, the German MPN Registry of the Leukemia Study Alliance [32] reported bleeding in 437 MPN patients, including eight with DOAC (rivaroxaban) treatment. In a multivariate analysis, the risk of bleeding during DOAC treatment was slightly reduced compared to VKA.
In summary, our results complement the currently limited literature [21–23, 32] on the efficacy and safety of DOAC-treated MPN patients. Despite the limitations—small number of patients, retrospective analysis, and short treatment time—our data suggest that the use of DOAC was as effective and safe as VKA. However, further and larger studies are required before DOAC can be routinely used in MPN patients.
Authors’ contributions
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Karlo Huenerbein. The first draft of the manuscript was written by Karlo Huenerbein and Dr. Kai Wille, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
Ethical approval was waived by the local Ethics Committee of the Ruhr University Bochum in view of the retrospective nature of the study, and all the procedures being performed were part of the routine care.
Consent to participate/for publication
Informed consent was obtained from all individual participants included in the study. Patients signed informed consent regarding publishing their data and photographs.
Code availability
Not applicable.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ASPIRIN | DrugsGivenReaction | CC BY | 33216197 | 19,808,389 | 2021-08 |
What was the dosage of drug 'ASPIRIN'? | Direct oral anticoagulants (DOAC) for prevention of recurrent arterial or venous thromboembolic events (ATE/VTE) in myeloproliferative neoplasms.
In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial or venous thromboembolic events (ATE/VTE) are a major burden. In order to control these complications, vitamin K antagonists (VKA) are widely used. There is no robust evidence supporting the use of direct oral anticoagulants (DOAC) in MPN patients. We therefore compared the efficacy and safety of both anticoagulants in 71 cases from a cohort of 782 MPN patients. Seventy-one of 782 MPN patients (9.1%) had ATE/VTE with nine ATE (12.7%) and 62 VTE (87.3%). Forty-five of 71 ATE/VTE (63.4%) were treated with VKA and 26 (36.6%) with DOAC. The duration of anticoagulation therapy (p = 0.984), the number of patients receiving additional aspirin (p = 1.0), and the proportion of patients receiving cytoreductive therapy (p = 0.807) did not differ significantly between the VKA and DOAC groups. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1-20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. For all bleeding events (p = 0.516) or major bleeding (p = 1.0), no significant differences were observed between VKA and DOAC. In our experience, the use of DOAC was as effective and safe as VKA, possibly even potentially beneficial with a lower number of recurrences and no increased risk for bleedings. However, further and larger studies are required before DOAC can be routinely used in MPN patients.
Introduction
In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial and venous thromboembolic events (ATE/VTE) occur frequently and have a significant impact on morbidity and mortality [1–3]. Several studies reported up to 10 times higher incidence of such complications compared to the healthy population [4–12].
Vitamin K antagonists (VKA) are widely used for both primary therapy and secondary prevention of MPN-associated ATE/VTE [13–15]. The introduction of direct oral anticoagulants (DOAC) provides a new treatment option [14, 16–20] with data comparable to the VKA [16–21]. However, the DOAC have no drug approval for patients with cancer or hematological malignancies, and published experience with its use in MPN-associated vascular events is currently very limited.
Curto-Garcia et al. [22] retrospectively reported on the results of 32 MPN patients with 38 venous thromboembolism and DOAC treatment. During a median follow-up period of 2.1 years, neither VTE recurrences nor major bleedings were observed.
Ianotto et al. [21] reported on the retrospective course of 25 MPN patients under DOAC treatment. During a median follow-up time of 2.1 years, two arterial thromboembolic and three bleeding events were observed. A case-control comparison of 25 MPN patients treated with low-dose aspirin (ASS) showed no difference in efficacy and safety [21].
Preliminary and retrospective data from Fedorov et al. [23] reported 22 DOAC- and 31 VKA-treated MPN patients with comparable incidences of recurrence and bleeding events.
However, there is no robust evidence supporting the use of DOAC in MPN, including a direct comparison with VKA treatment. Therefore, at our center, we retrospectively evaluated 71 MPN patients with 71 ATE/VTE treated with VKA (n = 45) or DOAC (n = 26) to compare the efficacy and safety of both anticoagulants.
Patients and methods
Clinical data of all MPN patients, who regularly present in our university department, were collected from June 2007 to April 2020 (time of last data cut-off April 1, 2020). All MPN were diagnosed according to the WHO 2008 criteria [24–26]. A total of 782 MPN patients (478 female, 61.1%, and 304 males, 38.9%) are currently registered in our outpatient clinic specializing in MPN. The median age is 50.5 years (range: 11.0–88.9), and the median follow-up time is 1.8 years (range: 0.1–28.4). The different MPN subtypes within the whole group are essential thrombocythemia (ET), n = 254 (32.5%); polycythemia vera (PV), n = 264 (33.8%); myelofibrosis (MF) including primary and secondary myelofibrosis, n = 238 (30.4%); and MPN unclassifiable, n = 26 (3.3%). The driver mutations are distributed within the 782 MPN patients as follows: JAK2 mutation, 534 (68.3%); CALR mutation, 110 (14.1%); MPL mutation, 19 (2.4%); triple negative, 42 (5.4%); and unknown 70 (9.0%).
The main objective of this retrospective, non-interventional, single-center study was to compare VKA with DOAC therapy in MPN patients. Of particular interest was the efficacy in ATE/VTE treatment, the prevention of ATE/VTE relapses, and the subsequent risk of bleeding complications under both anticoagulants. The data were collected in an electronic system. The Ethics Committee of our center approved the study. We focused on each patient with at least one MPN-associated arterial (ATE) or venous (VTE) thromboembolic event treated with VKA or DOAC. In line with previous studies, we defined an ATE or VTE associated with MPN if it occurred within 2 years prior to MPN diagnosis or after [27, 28].
The follow-up time was defined as the time between the first occurrence of an ATE/VTE and last visit to our center. Treatment time was defined as the time between the start of anticoagulation (= after the first ATE/VTE) and the end of anticoagulation or the last visit to our center (if anticoagulation was not stopped) or first relapse (whichever came first).
For each MPN patient with an ATE/VTE and anticoagulation with VKA or DOAC, we collected demographic data, mutational profile, method of objective diagnosis of ATE/VTE, and presence of cardiovascular (CV) risk factors. In addition, further details on ATE/VTE such as localization, total number, PT (prothrombin time)-INR (international normalized ratio), time of diagnosis and other cytoreductive or antiplatelet therapy were collected. Cytoreductive treatment was defined as the use of hydroxyurea, busulfan, anagrelide, interferon-alpha, ruxolitinib, and/or other JAK inhibitors at the time of ATE/VTE or within 6 months thereafter. Finally, time intervals regarding anticoagulation treatment, duration of treatment, occurrence of bleeding complications, and the number of relapses that occurred during or after completion of anticoagulation were recorded. The diagnosis of an ATE/VTE event required objective diagnostic procedures such as ultrasound, computed tomography, angiography, or scintigraphy.
The severity of bleeding complications was defined according to the criteria of the International Society on Thrombosis and Hemostasis [29]. According to these criteria, we considered a bleeding greater than II° (e.g., transfusion-related anemia, central nervous system involvement, or other life-threatening bleeding) to be clinically relevant.
Statistical methods
For continuous variables, the median and range are provided. The annual incidence of ATE/VTE recurrences was calculated by dividing the number of events by the sum of patient-years. Differences in the proportions were estimated using Fisher’s exact test, Chi-square test, Mann-Whitney U test (statistical significance threshold set at p < 0.05), or log-rank test (Mantel-Haenszel test).
Results
Of the total 71 MPN-associated ATE/VTE, nine (12.7%) were ATE and 62 (87.3%) VTE. Table 1 provides an overview of demographic data and clinical characteristics of all 71 patients diagnosed with 71 initial ATE/VTE. Most ATE/VTE patients were female (n = 49, 69.0%) and were diagnosed as PV (n = 30, 42.3%), followed by MF (n = 20, 28.2%) or ET (n = 19, 26.8%). Two MPN patients with ATE/VTE were found to have a MPN at bone marrow biopsy, but both could not be further classified and were referred to as MPN unclassifiable. The JAK2 V617F mutation was the most frequent driver mutation (n = 63, 88.7%). The median age at ATE/VTE diagnosis was 54.0 years (22.0–82.0).Table 1 Overview of demographic data and clinical features of 71 MPN patients with 71 arterial and venous thromboembolic events (ATE/VTE) treated with either VKA or DOAC
Male/female; n (%) 22/49 (31.0/69.0)
Median age at first ATE/VTE; years (range) 54.0 (22.0–82.0)
Median follow-up time from first ATE/VTE; years (range) 3.2 (0.1–20.4)
MPN diagnosis
Polycythemia vera (PV); n (%) 30 (42.3)
Myelofibrosis (MF); n (%) 20 (28.2)
Essential thrombocythemia (ET); n (%) 19 (26.8)
MPN unclassifiable; n (%) 2 (2.8)
Driver mutations
JAK2; n (%) 63 (88.7)
CALR; n (%) 3 (4.2)
MPL; n (%) 1 (1.4)
Triple negative; n (%) 2 (2.8)
Unknown; n (%) 2 (2.8)
ATE/VTE
VTE; n (%) 62 (87.3)
ATE; n (%) 9 (12.7)
The localizations of all 71 ATE/VTE events together with corresponding localizations of ATE/VTE in VKA- or DOAC-treated MPN patients are shown in Table 2. Most ATE (6/9 = 67%) consisted of transient ischemic attacks (n = 2) or a stroke (n = 4). The remaining three had two embolisms each on a lower limb (n = 2, 2.8%) and an arterial splenic infarction (n = 1, 1.4%). About half VTE (28/62 = 45%) were atypical with 22 splanchnic and six sinus vein thromboses. Deep vein thrombosis simultaneously with pulmonary embolism was observed in nine MPN patients (n = 9, 12.7%). Isolated deep vein thrombosis or pulmonary embolism occurred in 14 (19.7%) and nine (n = 9, 12.7%) MPN cases with VTE, respectively. The two remaining VTE were each thrombophlebitis (n = 1, 1.4%) and arm vein thromboses (n = 1, 1.4%).Table 2 Localization of all first arterial and venous thromboembolic events (ATE/VTE, n = 71) with corresponding localizations of ATE/VTE in DOAC (n = 26) or VKA (n = 45) treated MPN patients together with localization of first ATE/VTE recurrences (n = 26)
First ATE/VTE event (n = 71) First ATE/VTE treated with DOAC (n = 26) First ATE/VTE treated with VKA (n = 45) ATE/VTE recurrences (n = 26) ATE/VTE recurrences after DOAC therapy (n = 4) ATE/VTE recurrence during or after VKA therapy (n = 22)
Localization
Arterial thromboembolic events (ATE); n (%) 9 (12.7) 3 (11.5) 6 (13.3) 12 (46.2) 1 (25.0) 11 (50.0)
Transient ischemic attack (TIA); n (%) 2 (2.8) - 2 (4.4) 1 (3.8) - 1 (4.5)
Angina pectoris; n (%) - - - 1 (3.8) - 1 (4.5)
Stroke; n (%) 4 (5.6) 1 (3.8) 3 (6.7) 2 (7.7) - 2 (9.1)
Arterial embolism of lower limb; n (%) 2 (2.8) 1 (3.8) 1 (2.2) 3 (11.5) - 3 (13.6)
Renal infarction; n (%) - - - 1 (3.8) 1 (25.0) -
Splenic infarction; n (%) 1 (1.4) 1 (3.8) - 4 (15.4) - 4 (18.2)
Venous thromboembolic events (VTE) 62 (87.3) 23 (88.5%) 39 (86.7) 14 (53.8) 3 (75.0) 11 (50.0)
Deep vein thrombosis; n (%) 14 (19.7) 5 (19.2) 9 (20.0) 6 (23.1) 1 (25.0) 5 (22.7)
Pulmonary embolism; n (%) 9 (12.7) 6 (23.1) 3 (6.7) 1 (3.8) 1 (25.0) -
Deep vein thrombosis simultaneous to pulmonary embolism; n (%) 9 (12.7) 4 (15.4) 5 (11.1) - - -
Splanchnic vein thrombosis; n (%) 22 (31.0) 5 (19.2) 17 (37.8) 4 (15.4) - 4 (18.2)
Thrombophlebitis; n (%) 1 (1.4) 1 (3.8) - 1 (3.8) 1 (25.0) -
Sinus vein thrombosis; n (%) 6 (8.5) 2 (7.7) 4 (8.9) 2 (7.7) - 2 (9.1)
Arm vein thrombosis; n (%) 1 (1.4) - - - - -
No recurrences were observed during DOAC therapy, but there were four recurrences after stopping DOAC. 22 recurrences occurred during or after VKA therapy
All 71 patients had a median total follow-up time of 3.2 years (range: 0.1–20.4) with an incidence rate for all 71 ATE/VTE of 3.4% per patient/year. The corresponding rates for ATE and for VTE were 0.4% and 3.0% per patient/year, respectively.
Out of 71 MPN with a first ATE/VTE, 45 (63.4%) were treated with VKA and 26 (36.6%) with DOAC. Most patients with DOAC received rivaroxaban (n = 21), and the remaining were treated with apixaban (n = 5). The median duration on anticoagulation was 1.0 years (range 0.1–20.4) with a median time on VKA of 1.0 years (range 0.1–20.4) and a median time on DOAC of 1.3 years (range 0.2–7.3). During the entire anticoagulation period, low-dose acetylsalicylic acid was additionally used in the 71 ATE/VTE in seven patients with VKA therapy (7/45, 9.9%) and in four patients with DOAC treatment (4/26, 5.5%). Cytoreductive treatment was initiated in 39 MPN patients (39/71, 63.9%) simultaneously or within 6 months after ATE/VTE. In the VKA group 22 of 45 patients (48.9%) and in the DOAC group 17 of 26 patients (65.4%) additionally received cytoreductive drugs.
Within a median time of 1.5 years (range: 0.1–8.5), 26 first ATE/VTE recurrences were observed in 26 patients. This corresponds to an ATE /VTE recurrence rate of 8.0% per patient/year. No recurrence was observed in 45 patients (63.4%). The localizations of the first 26 recurrences together with the corresponding localizations of recurrent ATE/VTE in VKA- or DOAC-treated MPN patients are shown in Table 2. Of 26 first recurrences, 12 (12/26 = 46.2%) were ATE and 14 (14/26 = 53.8%) were VTE. After a median time of 0.9 years (range: 0.1–8.5), 16 ATE/VTE recurrences occurred during anticoagulation with VKA therapy (16/26 = 61.5%). No recurrences were observed during DOAC therapy. This difference is statistically significant (p = 0.0003) (Fig. 1).Fig. 1 First ATE/VTE recurrences (n = 26) during follow-up time: significantly more recurrences (p = 0.0003) occurred during VKA (n = 16) compared to no recurrences during DOAC (n = 0) treatment (red). After termination of anticoagulation, four of 26 DOAC and six of 45 VKA-treated patients had ATE/VTE recurrences (green). Overall, significantly more recurrences were recorded in patients with VKA treatment (n = 22) compared to DOAC (n = 4) (p = 0.0053)
In 17 out of 45 patients (38%) treated with VKA, sufficient PT (prothrombin time) and/or INR (international normalized ratio) values were documented during anticoagulation, and 53% of these were in the therapeutic range. At the time of relapse, seven out of 22 patients treated with VKA had documented PT and/or INR values, and four (57%) were in the therapeutic range.
During the entire follow-up time, 22 recurrences occurred in VKA-treated (n = 22, 84.6%) and four in DOAC-treated (n = 4, 15.4%) patients. In the latter group, all four recurrences were recorded within a median time of 0.7 years (range: 0.3–1.3) after termination of DOAC treatment. Sixteen of all 22 VKA-associated ATE/VTE recurrences (16/22 = 72.7%) were observed during VKA anticoagulation therapy. The remaining six recurrences (6/22 = 27.3%) were observed within a median time of 0.9 years (range: 0.4–4.0) after termination of the VKA. Comparing the total number of recurrences in VKA-treated patients (n = 22) with the recurrences registered in patients treated with DOAC (n = 4) shows a statistically significant difference during the follow-up time (p = 0.0053) (Fig. 1).
After comparing the absolute number of ATE/VTE recurrences, an analysis was performed that considered the probability of “recurrence-free” survival during the follow-up time. In this analysis, the difference between VKA- and DOAC-treated patients was not statistically different (Fig. 2, p = 0.2). The incidence rate of ATE/VTE recurrences in VKA-treated patients was 8.1% per patient/year and 7.2% per patient/year in DOAC-treated patients. This difference was also not statistically different (alpha = 5%).Fig. 2 Probability of recurrence-free survival: the cumulative probability of the ATE/VTE recurrence-free survival in 71 MPN patients treated with DOAC (n = 26, red curve) or VKA (n = 45, blue curve) was statistically not significantly different (p = 0.2)
Bleedings
During anticoagulation with either VKA or DOAC, 10 of 71 patients (14.1%) experienced 11 bleeding complications over a median period of 1.6 years (range: 0.1–6.8). Six out of 11 bleedings (54.5%) were classified as severe bleedings.
In the VKA group, seven bleeding complications (63.6%), including four major bleeding complications, were recorded after a median time of 1.6 years (range: 0.1–6.8). Three out of four major bleedings (one esophageal varicose vein bleeding and two severe epistaxis episodes) occurred during VKA use alone (without low-dose acetylsalicylic acid). One patient underwent a combination therapy of VKA and low-dose acetylsalicylic acid and experienced major postoperative bleeding 1 day after total hip replacement implantation. During VKA treatment, three minor bleedings occurred (a menorrhagia, an episode with bloody semen, and an unspecified bleeding tendency).
During DOAC therapy, two minor and two major bleeding complications (n = 4, 36.4%) occurred after a median time of 0.5 years (range: 0.3–1.6). Both major bleeding episodes under DOAC anticoagulation (without low-dose acetylsalicylic acid) were gastrointestinal bleedings of unknown localization. The remaining two minor bleedings were epistaxis and petechial bleeding during DOAC therapy.
Overall, no significant differences were observed between DOAC and VKA anticoagulation therapy for both overall (p = 0.516) or major bleeding (p = 1.0). A comparison regarding different clinical and laboratory parameters between VKA- and DOAC-treated patients is shown in Table 3. In the VKA group, only the total follow-up time (p = 0.0005) and number of ATE/VTE recurrences (p = 0.0053) were statistically different.Table 3 Comparison of different clinical and laboratory parameters between DOAC- (n = 26) and VKA-treated MPN patients (n = 45)
Parameters DOAC VKA p
Number of pts.* 26 45
Median age at MPN diagnosis; years (range) 55.5 (24.0–81.0) 50.0 (22.0–82.0) 0.131
Median age at first ATE/VTE event; years (range) 57.5 (27.0–88.0) 53.0 (22.0–81.0) 0.070
Gender (male/female) 8/18 14/31 0.976
Essential thrombocythemia 8 11 0.816
Polycythemia vera 10 20
Myelofibrosis 7 13
JAK2 Mutation 24 39 0.701
Cardiovascular risk factors (yes/no) 15/11 30/15 0.450
ATE 3 6 1.0
VTE 23 39
Median treatment time; years (range) 1.3 (0.2–7.3) 1.0 (0.1–20.4) 0.984
Median total follow up time; years (range) 1.7 (0.2–7.3) 4.8 (0.6–20.4) 0.0005**
ATE/VTE recurrences 4 22 0.0053**
Combined ASS use*** 4 7 1.0
Cytoreductive therapy for first ATE/VTE**** 17 22 0.22
Bleeding events total 4 7 1.0
Major bleeding events 2 4 1.0
Deaths 1 3 1.0
*Pts. = patients
**Significantly different
***During time on anticoagulation after first ATE/VTE
****Begin at time of ATE/VTE or within 6 months thereafter
Discussion
Myeloproliferative neoplasm (MPN) patients have an increased risk of arterial and venous thromboembolic events (ATE/VTE). In larger MPN cohorts, the proportion of patients suffering from ATE/VTE is reported to be 10 to 30% [22]. Accordingly, vascular events occurred in 9.1% (71/782) of our 782 MPN patients. The incidence rate for the first 71 ATE/VTE was 3.4% per patient/year with a VTE rate of 3.0% per patient/year. Prospective studies in MPN observed comparable VTE rates of 0.5–3.7% [6, 7]. The ATE incidence rate of 0.4% per patient/year in our MPN patients was also similar to the reported ATE rates of 0.2 to 1.5% [5, 11].
In recent decades, anticoagulation with vitamin K antagonists (VKA) has been the treatment of choice to prevent ATE/VTE recurrences in MPN patients. Hernández-Boluda et al. [14] reported a 2.8-fold risk reduction for recurrence in 150 ET and PV patients with ATE/VTE and VKA treatment. In 206 MPN patients, De Stefano et al. [15] also found a reduction in the recurrence rate of VTE with VKA. The incidence rate of recurrent VTE was 5.3% per patient/year among patients with long-term VKA and 12.8% per patient/year after VKA discontinuation (p = 0.008). The VTE recurrence rate in our cohort was comparable at 8.0% per patient/year.
As far as anticoagulation with direct oral anticoagulants (DOAC) is concerned, there are few studies in MPN that indicate good efficacy with sufficient safety. In a retrospective study by Curto-Garcia et al. [22] in 32 MPN patients receiving DOAC for MPN-associated venous thromboembolism treated with DOAC, no VTE relapse but one ATE occurred. No major and three minor bleedings were reported. Ianotto et al. [21] retrospectively reported two ATE and no VTE recurrences in a cohort of 25 DOAC-treated MPN patients. Three major and two minor bleedings were observed. Curto-Garcia et al. [22] reported a median age of 49.9 years and a median follow-up of 2.1 years in their publication. The median follow-up time in the study of Ianotto et al. [21] was quite similar with 2.1 years. However, both studies did not compare DOAC treatment with VKA in their cohort [21, 22]. Fedorov et al. [23] reported preliminary data on recurrence rates and bleeding complications in 22 DOAC- and 31 VKA-treated MPN patients. During a short follow-up of 8 months, the number of ATE/VTE recurrences (DOAC, n = 5 versus VKA, n = 6) and of all bleeding complications (DOAC, n = 5 versus VKA, n = 11) were not significantly different.
The median age of our 71 MPN patients at the time of ATE/VTE was 54 years and was comparable to the studies of Curto-Garcia et al. and Ianotto et al. [21, 22]. The median duration of anticoagulation was lower at 1.0 years for VKA and 1.3 for DOAC. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1–20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. This is mainly due to the significantly longer follow-up time for VKA patients (p = 0.0005). The corresponding recurrence rates for VKA and DOAC treatment (during and after discontinuation of anticoagulation) did not differ significantly either.
During anticoagulation with VKA, 53% and at the time of relapse, 57% of patients treated with VKA were in the therapeutic range with PT-INR. A major disadvantage of the VKA is the narrow therapeutic range and the time patients spend in the therapeutic range (TTR, “time in therapeutic range”). Even in well-conducted comparative studies of VKA and DOAK, the TTR was on average only between 55 and 65% [17, 20, 30, 31].
As in the studies mentioned above, we have not observed any increased bleeding propensity under DOAC. In particular, the rate of major bleeding was not higher under DOAC compared to VKA. Regarding bleeding complications with anticoagulation, the German MPN Registry of the Leukemia Study Alliance [32] reported bleeding in 437 MPN patients, including eight with DOAC (rivaroxaban) treatment. In a multivariate analysis, the risk of bleeding during DOAC treatment was slightly reduced compared to VKA.
In summary, our results complement the currently limited literature [21–23, 32] on the efficacy and safety of DOAC-treated MPN patients. Despite the limitations—small number of patients, retrospective analysis, and short treatment time—our data suggest that the use of DOAC was as effective and safe as VKA. However, further and larger studies are required before DOAC can be routinely used in MPN patients.
Authors’ contributions
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Karlo Huenerbein. The first draft of the manuscript was written by Karlo Huenerbein and Dr. Kai Wille, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics approval
Ethical approval was waived by the local Ethics Committee of the Ruhr University Bochum in view of the retrospective nature of the study, and all the procedures being performed were part of the routine care.
Consent to participate/for publication
Informed consent was obtained from all individual participants included in the study. Patients signed informed consent regarding publishing their data and photographs.
Code availability
Not applicable.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | LOW DOSE | DrugDosageText | CC BY | 33216197 | 19,808,389 | 2021-08 |
What was the administration route of drug 'AMIODARONE'? | Recurrent autoimmune myocarditis in a young woman during the coronavirus disease 2019 pandemic.
We report a unique case of a young woman with recurrent immune-mediated (virus-negative) lymphocytic fulminant myocarditis during the coronavirus disease 2019 pandemic. At the first endomyocardial biopsy (EMB)-proven episode, she had concomitant pneumonia, and a temporary biventricular assist device implant was followed by complete and long-lasting cardiac recovery. Five years later, she was re-admitted for relapsing cardiogenic shock with a recent history of pneumonia. She was treated with extracorporeal life support with apical venting for left ventricular unloading, and full recovery was achieved. Despite negative seriate nasopharyngeal swabs and EMB during hospitalization, an antibody positivity for severe acute respiratory syndrome coronavirus 2 was discovered after 4 weeks from discharge. This is the first report of an EMB-proven, immune-mediated (virus-negative) recurrence of fulminant myocarditis. We hypothesize that in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune-mediated hyper-response.
Introduction
Fulminant myocarditis (FM) is characterized by sudden onset with haemodynamic compromise requiring immediate inotropic therapy and/or mechanical circulatory support (MCS). 1 , 2 , 3 In FM, endomyocardial biopsy (EMB) is mandatory to achieve certainty in diagnosis and guide aetiology‐directed therapy. 2
Case report
In February 2015, a 40‐year‐old female and mother of two young children presented to the emergency department (ED) complaining of fatigue and chest pain without any relevant clinical history. She had no family history of cardiomyopathy or autoimmune disease. Computed tomography (CT) scan ruled out pulmonary embolism but showed right lung pneumonia. Severe left ventricular (LV) systolic dysfunction [LV ejection fraction (LVEF) < 20%] and unobstructed coronary arteries were detected ( Video S1 , 0:05). Despite inotropic support, the patient needed percutaneous veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) support. After 48 h with no clinical improvement, the patient was referred to our centre. Through a left mini‐thoracotomy in the fifth intercostal space, the cardiac apex was approached for inflow LV assist device (LVAD) implantation, and a myocardial sample was taken for histological analysis. With the use of a right mini‐thoracotomy in the second intercostal space, a vascular prosthesis was anastomosed to the aorta as outflow line. A right ventricular assist device (RVAD) was implanted using the left femoral vein and the pulmonary artery through a left mini‐thoracotomy in the second intercostal space. A diagnosis of virus‐negative lymphocytic myocarditis was made on the basis of EMB (Figure 1A and 1B ). Serum tested weakly positive for anti‐heart and anti‐intercalated disk autoantibodies. Although the diagnosis consisted of a lymphocytic immune‐mediated (virus‐negative) myocarditis with severe systolic dysfunction, the patient was not put on immunosuppression because of pneumonia. She was progressively weaned from RVAD, which was removed after 6 days. Twenty days later, the LVAD was also removed, as a complete LV recovery was achieved. The patient's stay in the intensive care unit (ICU) was prolonged (37 days) owing to nosocomial pneumonia, acute renal failure needing 14 days of continuous veno‐venous haemodialysis, positive blood cultures for Candida utilis and Enterococcus faecium, and presence of Enterovirus on sputum. LVEF was 50% at discharge (102 days). After the first hospitalization, the patient developed an amiodarone‐related thyroid disease and chronic kidney disease for which she was followed up by the respective specialists. She was put on beta‐blocker therapy with carvedilol and aldosterone antagonist. Her newly developed Stage IV chronic kidney disease with a glomerular filtration rate between 15 and 20 mL/min was treated with additional sodium therapy for persistent hyponatremia. Three years later, after being hospitalized owing to severe hyponatremia, aldosterone antagonist administration was suspended. For the subsequent 5 years, the patient was asymptomatic and was followed up with echocardiograms ( Video S1 , 0:15), ECGs, and blood and troponin tests every 6 months.
Figure 1 Pathological findings in endomyocardial biopsy (EMB) at first episode. (A) EMB specimen showing extensive myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
In January 2020, the patient presented several times to the ED complaining of atypical chest pain and fever. ECG was unchanged, and troponin values were repeatedly normal; the echocardiogram also remained consistent ( Video S1 , 0:30). In March, she was re‐admitted to secondary care ED for dyspnoea and palpitations. ECG showed diffuse ST elevation with tombstone morphology; troponin was also markedly increased (peak TnI 83 000 ng/L, normal range 0–34 ng/L) (Figure 2A ). Because she presented during the coronavirus disease 2019 (COVID‐19) outbreak, she underwent a nasopharyngeal swab test for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which resulted negative. A bedside echocardiogram showed severe LV dysfunction with healthy coronary arteries ( Video S1 , 0:40). She was then transferred to our institution. On arrival, she developed haemodynamic and electrical instability consisting of an arrhythmic storm and cardiac arrest, requiring emergent femoral–femoral V‐A ECMO. One hour later, following severe haemodynamic instability, we decided to unload the LV by placing an apical venting through the previous left mini‐thoracotomy in the fifth intercostal space; an EMB was again performed at the LV apex. A 4 L/min support was commenced; better organ perfusion was evidenced by lactate reduction and pH improvement. Complex incessant arrhythmias persisted despite i.v. amiodarone, lidocaine, and esmolol administration. The EMB showed a virus‐negative lymphocytic myocarditis (Figure 3A and 3B ). Immunosuppressive therapy with steroids (methylprednisolone, 1 g i.v. bolus OD for the first 3 days, then 100 mg i.v. OD for the first week followed by progressive tapering in the subsequent days) was then immediately started; azathioprine (50 mg per os b.i.d.) was also added. A progressive normalization of ECG and biventricular contractility was observed (Figure 2B ). In the following days, there was a rapid recovery of cardiac function with a decreasing need for mechanical support. VA‐ECMO was removed on the ninth post‐operative day. She was transferred from the ICU on the 13th post‐operative day. Echocardiography at discharge showed mild LV dysfunction (LVEF 48%) ( Video S1 , 1:00). She was discharged home on Day 32, with a maintenance immunosuppressive therapy of oral methylprednisolone and azathioprine. Methylprednisolone was then tapered the following days with a weekly 25% reduction and a target of chronic 5 mg per day. Additionally, she is currently on alternating doses of azathioprine (100 mg per os 1 day and 150 mg the next day). Four weeks after discharge, once the test was introduced in Italy, an immunological assay for SARS‐CoV‐2 IgM and IgG was performed showing a weak positivity for specific antibodies while immunosuppressed.
Figure 2 (A) ECG at hospital admission showing a wide QRS complex. (B) ECG at discharge showing a restoration of the sinus rhythm; QRS waves narrowing with diffuse negative T waves; low voltages on all the precordial leads.
Figure 3 Pathological findings in endomyocardial biopsy (EMB) at recurrent fulminant myocarditis (FM) episode. (A) EMB specimen showing persistent myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
Discussion
This is the first report to show that lymphocytic virus‐negative FM relapses can be observed in the same patient with a similar presentation severity. Regardless of the MCS used, prompt LV unloading is critical for myocardial recovery; in addition, timely integration of MCS with tailored EMB‐guided immunosuppression was of critical importance in the treatment of our patient. Outcome of lymphocytic FM compared with non‐fulminant disease is controversial, reported as excellent 1 or bad. 2 So far, it is unclear whether the fulminant modality has independent negative prognostic value per se regardless of other known negative predictors such as the histology, giant cell vs. lymphocytic, and the degree of biventricular dysfunction. 2
FM is rare, and fulminant episodes of recurrences have already been reported in literature. 4 , 5 On the basis of serological tests, the aetiology of recurrent myocarditis in cases discussed by Matsue and Yoshimizu et al. is to be considered viral related, missing any EMB in both. In our case, immunohistochemical results of EMBs performed during the acute phase pointed to lymphocytic myocarditis. All serological and molecular tests on the samples obtained were negative for viruses, hence our definition of virus‐negative immune‐mediated lymphocytic myocarditis.
Although this is the first report of recurrent immune‐mediated lymphocytic FM with a fulminant relapse, our specific case keeps in line with the relapsing–remitting course of other autoimmune diseases. 2 In the first episode of FM for our patient, immunosuppression was withheld because of concomitant pneumonia and, after pneumonia resolution, because of the sustained recovery of ventricular function. The long‐lasting asymptomatic state of the patient with preserved biventricular function in the following 5 years confirmed that the first episode was indeed cured. During the strict echocardiographic follow‐up in the time preceding the recurrence, no clinical or instrumental evidence ever suggested the presence of a subclinical myocarditis, justifying the absence of further invasive examinations. The second episode highlights the importance of a timely combined surgical and medical approach; initial high dose i.v. steroids were highly effective in suppressing a life‐threatening arrhythmic storm.
Another interesting feature of this case was the presence of pneumonia as a prodromal event in both FM episodes. We hypothesize that, in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune‐mediated hyper‐response. 2 The patient had a history of pneumonia in the first months of 2020 during the initial spread of the COVID‐19 pandemic in Northern Italy. In the absence of severe symptomatology and the still dormant SARS‐CoV‐2 outbreak, a CT scan was not performed; the patient was discharged home on antibiotic therapy with a community‐acquired pneumonia diagnosis after a chest X‐ray. Nasopharyngeal swabs tests performed during hospitalization were negative, as was EMB‐based analysis of viral activity. It cannot be excluded that an autoimmune inflammatory process was triggered by the pneumonia prodromal episode 2 months prior. Unfortunately, the late introduction (May 2020) of serological assays for SARS‐CoV‐2 in the Italian market delayed our ability to make fully informed decisions regarding the treatment of this patient, who was already undergoing a heavy immunosuppressive regimen with steroid and azathioprine as a relapse maintenance therapy. Regardless, pathology studies up to date have yet to specifically address the myocardium and the burden of myocarditis in COVID‐19 patients, which remain to be established. 6 , 7
Funding
Departmental Strategic Investment (SID) 2020, BIRD205838, University of Padua.
Supporting information
Video S1. Transthoracic‐Echocardiogram 3 days post BiVAD implantation (0:05); Transthoracic‐Echocardiogram at discharge (0:15); Transthoracic‐Echocardiogram 5 years after the first episode (0:30); Transthoracic‐Echocardiogram and Coronary Angiography at admission for recurrent FM (0:40); Transthoracic‐Echocardiogram at discharge (1:00).
Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33225579 | 19,649,870 | 2021-02 |
What was the administration route of drug 'ESMOLOL HYDROCHLORIDE'? | Recurrent autoimmune myocarditis in a young woman during the coronavirus disease 2019 pandemic.
We report a unique case of a young woman with recurrent immune-mediated (virus-negative) lymphocytic fulminant myocarditis during the coronavirus disease 2019 pandemic. At the first endomyocardial biopsy (EMB)-proven episode, she had concomitant pneumonia, and a temporary biventricular assist device implant was followed by complete and long-lasting cardiac recovery. Five years later, she was re-admitted for relapsing cardiogenic shock with a recent history of pneumonia. She was treated with extracorporeal life support with apical venting for left ventricular unloading, and full recovery was achieved. Despite negative seriate nasopharyngeal swabs and EMB during hospitalization, an antibody positivity for severe acute respiratory syndrome coronavirus 2 was discovered after 4 weeks from discharge. This is the first report of an EMB-proven, immune-mediated (virus-negative) recurrence of fulminant myocarditis. We hypothesize that in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune-mediated hyper-response.
Introduction
Fulminant myocarditis (FM) is characterized by sudden onset with haemodynamic compromise requiring immediate inotropic therapy and/or mechanical circulatory support (MCS). 1 , 2 , 3 In FM, endomyocardial biopsy (EMB) is mandatory to achieve certainty in diagnosis and guide aetiology‐directed therapy. 2
Case report
In February 2015, a 40‐year‐old female and mother of two young children presented to the emergency department (ED) complaining of fatigue and chest pain without any relevant clinical history. She had no family history of cardiomyopathy or autoimmune disease. Computed tomography (CT) scan ruled out pulmonary embolism but showed right lung pneumonia. Severe left ventricular (LV) systolic dysfunction [LV ejection fraction (LVEF) < 20%] and unobstructed coronary arteries were detected ( Video S1 , 0:05). Despite inotropic support, the patient needed percutaneous veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) support. After 48 h with no clinical improvement, the patient was referred to our centre. Through a left mini‐thoracotomy in the fifth intercostal space, the cardiac apex was approached for inflow LV assist device (LVAD) implantation, and a myocardial sample was taken for histological analysis. With the use of a right mini‐thoracotomy in the second intercostal space, a vascular prosthesis was anastomosed to the aorta as outflow line. A right ventricular assist device (RVAD) was implanted using the left femoral vein and the pulmonary artery through a left mini‐thoracotomy in the second intercostal space. A diagnosis of virus‐negative lymphocytic myocarditis was made on the basis of EMB (Figure 1A and 1B ). Serum tested weakly positive for anti‐heart and anti‐intercalated disk autoantibodies. Although the diagnosis consisted of a lymphocytic immune‐mediated (virus‐negative) myocarditis with severe systolic dysfunction, the patient was not put on immunosuppression because of pneumonia. She was progressively weaned from RVAD, which was removed after 6 days. Twenty days later, the LVAD was also removed, as a complete LV recovery was achieved. The patient's stay in the intensive care unit (ICU) was prolonged (37 days) owing to nosocomial pneumonia, acute renal failure needing 14 days of continuous veno‐venous haemodialysis, positive blood cultures for Candida utilis and Enterococcus faecium, and presence of Enterovirus on sputum. LVEF was 50% at discharge (102 days). After the first hospitalization, the patient developed an amiodarone‐related thyroid disease and chronic kidney disease for which she was followed up by the respective specialists. She was put on beta‐blocker therapy with carvedilol and aldosterone antagonist. Her newly developed Stage IV chronic kidney disease with a glomerular filtration rate between 15 and 20 mL/min was treated with additional sodium therapy for persistent hyponatremia. Three years later, after being hospitalized owing to severe hyponatremia, aldosterone antagonist administration was suspended. For the subsequent 5 years, the patient was asymptomatic and was followed up with echocardiograms ( Video S1 , 0:15), ECGs, and blood and troponin tests every 6 months.
Figure 1 Pathological findings in endomyocardial biopsy (EMB) at first episode. (A) EMB specimen showing extensive myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
In January 2020, the patient presented several times to the ED complaining of atypical chest pain and fever. ECG was unchanged, and troponin values were repeatedly normal; the echocardiogram also remained consistent ( Video S1 , 0:30). In March, she was re‐admitted to secondary care ED for dyspnoea and palpitations. ECG showed diffuse ST elevation with tombstone morphology; troponin was also markedly increased (peak TnI 83 000 ng/L, normal range 0–34 ng/L) (Figure 2A ). Because she presented during the coronavirus disease 2019 (COVID‐19) outbreak, she underwent a nasopharyngeal swab test for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which resulted negative. A bedside echocardiogram showed severe LV dysfunction with healthy coronary arteries ( Video S1 , 0:40). She was then transferred to our institution. On arrival, she developed haemodynamic and electrical instability consisting of an arrhythmic storm and cardiac arrest, requiring emergent femoral–femoral V‐A ECMO. One hour later, following severe haemodynamic instability, we decided to unload the LV by placing an apical venting through the previous left mini‐thoracotomy in the fifth intercostal space; an EMB was again performed at the LV apex. A 4 L/min support was commenced; better organ perfusion was evidenced by lactate reduction and pH improvement. Complex incessant arrhythmias persisted despite i.v. amiodarone, lidocaine, and esmolol administration. The EMB showed a virus‐negative lymphocytic myocarditis (Figure 3A and 3B ). Immunosuppressive therapy with steroids (methylprednisolone, 1 g i.v. bolus OD for the first 3 days, then 100 mg i.v. OD for the first week followed by progressive tapering in the subsequent days) was then immediately started; azathioprine (50 mg per os b.i.d.) was also added. A progressive normalization of ECG and biventricular contractility was observed (Figure 2B ). In the following days, there was a rapid recovery of cardiac function with a decreasing need for mechanical support. VA‐ECMO was removed on the ninth post‐operative day. She was transferred from the ICU on the 13th post‐operative day. Echocardiography at discharge showed mild LV dysfunction (LVEF 48%) ( Video S1 , 1:00). She was discharged home on Day 32, with a maintenance immunosuppressive therapy of oral methylprednisolone and azathioprine. Methylprednisolone was then tapered the following days with a weekly 25% reduction and a target of chronic 5 mg per day. Additionally, she is currently on alternating doses of azathioprine (100 mg per os 1 day and 150 mg the next day). Four weeks after discharge, once the test was introduced in Italy, an immunological assay for SARS‐CoV‐2 IgM and IgG was performed showing a weak positivity for specific antibodies while immunosuppressed.
Figure 2 (A) ECG at hospital admission showing a wide QRS complex. (B) ECG at discharge showing a restoration of the sinus rhythm; QRS waves narrowing with diffuse negative T waves; low voltages on all the precordial leads.
Figure 3 Pathological findings in endomyocardial biopsy (EMB) at recurrent fulminant myocarditis (FM) episode. (A) EMB specimen showing persistent myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
Discussion
This is the first report to show that lymphocytic virus‐negative FM relapses can be observed in the same patient with a similar presentation severity. Regardless of the MCS used, prompt LV unloading is critical for myocardial recovery; in addition, timely integration of MCS with tailored EMB‐guided immunosuppression was of critical importance in the treatment of our patient. Outcome of lymphocytic FM compared with non‐fulminant disease is controversial, reported as excellent 1 or bad. 2 So far, it is unclear whether the fulminant modality has independent negative prognostic value per se regardless of other known negative predictors such as the histology, giant cell vs. lymphocytic, and the degree of biventricular dysfunction. 2
FM is rare, and fulminant episodes of recurrences have already been reported in literature. 4 , 5 On the basis of serological tests, the aetiology of recurrent myocarditis in cases discussed by Matsue and Yoshimizu et al. is to be considered viral related, missing any EMB in both. In our case, immunohistochemical results of EMBs performed during the acute phase pointed to lymphocytic myocarditis. All serological and molecular tests on the samples obtained were negative for viruses, hence our definition of virus‐negative immune‐mediated lymphocytic myocarditis.
Although this is the first report of recurrent immune‐mediated lymphocytic FM with a fulminant relapse, our specific case keeps in line with the relapsing–remitting course of other autoimmune diseases. 2 In the first episode of FM for our patient, immunosuppression was withheld because of concomitant pneumonia and, after pneumonia resolution, because of the sustained recovery of ventricular function. The long‐lasting asymptomatic state of the patient with preserved biventricular function in the following 5 years confirmed that the first episode was indeed cured. During the strict echocardiographic follow‐up in the time preceding the recurrence, no clinical or instrumental evidence ever suggested the presence of a subclinical myocarditis, justifying the absence of further invasive examinations. The second episode highlights the importance of a timely combined surgical and medical approach; initial high dose i.v. steroids were highly effective in suppressing a life‐threatening arrhythmic storm.
Another interesting feature of this case was the presence of pneumonia as a prodromal event in both FM episodes. We hypothesize that, in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune‐mediated hyper‐response. 2 The patient had a history of pneumonia in the first months of 2020 during the initial spread of the COVID‐19 pandemic in Northern Italy. In the absence of severe symptomatology and the still dormant SARS‐CoV‐2 outbreak, a CT scan was not performed; the patient was discharged home on antibiotic therapy with a community‐acquired pneumonia diagnosis after a chest X‐ray. Nasopharyngeal swabs tests performed during hospitalization were negative, as was EMB‐based analysis of viral activity. It cannot be excluded that an autoimmune inflammatory process was triggered by the pneumonia prodromal episode 2 months prior. Unfortunately, the late introduction (May 2020) of serological assays for SARS‐CoV‐2 in the Italian market delayed our ability to make fully informed decisions regarding the treatment of this patient, who was already undergoing a heavy immunosuppressive regimen with steroid and azathioprine as a relapse maintenance therapy. Regardless, pathology studies up to date have yet to specifically address the myocardium and the burden of myocarditis in COVID‐19 patients, which remain to be established. 6 , 7
Funding
Departmental Strategic Investment (SID) 2020, BIRD205838, University of Padua.
Supporting information
Video S1. Transthoracic‐Echocardiogram 3 days post BiVAD implantation (0:05); Transthoracic‐Echocardiogram at discharge (0:15); Transthoracic‐Echocardiogram 5 years after the first episode (0:30); Transthoracic‐Echocardiogram and Coronary Angiography at admission for recurrent FM (0:40); Transthoracic‐Echocardiogram at discharge (1:00).
Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33225579 | 19,625,863 | 2021-02 |
What was the administration route of drug 'LIDOCAINE HYDROCHLORIDE'? | Recurrent autoimmune myocarditis in a young woman during the coronavirus disease 2019 pandemic.
We report a unique case of a young woman with recurrent immune-mediated (virus-negative) lymphocytic fulminant myocarditis during the coronavirus disease 2019 pandemic. At the first endomyocardial biopsy (EMB)-proven episode, she had concomitant pneumonia, and a temporary biventricular assist device implant was followed by complete and long-lasting cardiac recovery. Five years later, she was re-admitted for relapsing cardiogenic shock with a recent history of pneumonia. She was treated with extracorporeal life support with apical venting for left ventricular unloading, and full recovery was achieved. Despite negative seriate nasopharyngeal swabs and EMB during hospitalization, an antibody positivity for severe acute respiratory syndrome coronavirus 2 was discovered after 4 weeks from discharge. This is the first report of an EMB-proven, immune-mediated (virus-negative) recurrence of fulminant myocarditis. We hypothesize that in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune-mediated hyper-response.
Introduction
Fulminant myocarditis (FM) is characterized by sudden onset with haemodynamic compromise requiring immediate inotropic therapy and/or mechanical circulatory support (MCS). 1 , 2 , 3 In FM, endomyocardial biopsy (EMB) is mandatory to achieve certainty in diagnosis and guide aetiology‐directed therapy. 2
Case report
In February 2015, a 40‐year‐old female and mother of two young children presented to the emergency department (ED) complaining of fatigue and chest pain without any relevant clinical history. She had no family history of cardiomyopathy or autoimmune disease. Computed tomography (CT) scan ruled out pulmonary embolism but showed right lung pneumonia. Severe left ventricular (LV) systolic dysfunction [LV ejection fraction (LVEF) < 20%] and unobstructed coronary arteries were detected ( Video S1 , 0:05). Despite inotropic support, the patient needed percutaneous veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) support. After 48 h with no clinical improvement, the patient was referred to our centre. Through a left mini‐thoracotomy in the fifth intercostal space, the cardiac apex was approached for inflow LV assist device (LVAD) implantation, and a myocardial sample was taken for histological analysis. With the use of a right mini‐thoracotomy in the second intercostal space, a vascular prosthesis was anastomosed to the aorta as outflow line. A right ventricular assist device (RVAD) was implanted using the left femoral vein and the pulmonary artery through a left mini‐thoracotomy in the second intercostal space. A diagnosis of virus‐negative lymphocytic myocarditis was made on the basis of EMB (Figure 1A and 1B ). Serum tested weakly positive for anti‐heart and anti‐intercalated disk autoantibodies. Although the diagnosis consisted of a lymphocytic immune‐mediated (virus‐negative) myocarditis with severe systolic dysfunction, the patient was not put on immunosuppression because of pneumonia. She was progressively weaned from RVAD, which was removed after 6 days. Twenty days later, the LVAD was also removed, as a complete LV recovery was achieved. The patient's stay in the intensive care unit (ICU) was prolonged (37 days) owing to nosocomial pneumonia, acute renal failure needing 14 days of continuous veno‐venous haemodialysis, positive blood cultures for Candida utilis and Enterococcus faecium, and presence of Enterovirus on sputum. LVEF was 50% at discharge (102 days). After the first hospitalization, the patient developed an amiodarone‐related thyroid disease and chronic kidney disease for which she was followed up by the respective specialists. She was put on beta‐blocker therapy with carvedilol and aldosterone antagonist. Her newly developed Stage IV chronic kidney disease with a glomerular filtration rate between 15 and 20 mL/min was treated with additional sodium therapy for persistent hyponatremia. Three years later, after being hospitalized owing to severe hyponatremia, aldosterone antagonist administration was suspended. For the subsequent 5 years, the patient was asymptomatic and was followed up with echocardiograms ( Video S1 , 0:15), ECGs, and blood and troponin tests every 6 months.
Figure 1 Pathological findings in endomyocardial biopsy (EMB) at first episode. (A) EMB specimen showing extensive myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
In January 2020, the patient presented several times to the ED complaining of atypical chest pain and fever. ECG was unchanged, and troponin values were repeatedly normal; the echocardiogram also remained consistent ( Video S1 , 0:30). In March, she was re‐admitted to secondary care ED for dyspnoea and palpitations. ECG showed diffuse ST elevation with tombstone morphology; troponin was also markedly increased (peak TnI 83 000 ng/L, normal range 0–34 ng/L) (Figure 2A ). Because she presented during the coronavirus disease 2019 (COVID‐19) outbreak, she underwent a nasopharyngeal swab test for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which resulted negative. A bedside echocardiogram showed severe LV dysfunction with healthy coronary arteries ( Video S1 , 0:40). She was then transferred to our institution. On arrival, she developed haemodynamic and electrical instability consisting of an arrhythmic storm and cardiac arrest, requiring emergent femoral–femoral V‐A ECMO. One hour later, following severe haemodynamic instability, we decided to unload the LV by placing an apical venting through the previous left mini‐thoracotomy in the fifth intercostal space; an EMB was again performed at the LV apex. A 4 L/min support was commenced; better organ perfusion was evidenced by lactate reduction and pH improvement. Complex incessant arrhythmias persisted despite i.v. amiodarone, lidocaine, and esmolol administration. The EMB showed a virus‐negative lymphocytic myocarditis (Figure 3A and 3B ). Immunosuppressive therapy with steroids (methylprednisolone, 1 g i.v. bolus OD for the first 3 days, then 100 mg i.v. OD for the first week followed by progressive tapering in the subsequent days) was then immediately started; azathioprine (50 mg per os b.i.d.) was also added. A progressive normalization of ECG and biventricular contractility was observed (Figure 2B ). In the following days, there was a rapid recovery of cardiac function with a decreasing need for mechanical support. VA‐ECMO was removed on the ninth post‐operative day. She was transferred from the ICU on the 13th post‐operative day. Echocardiography at discharge showed mild LV dysfunction (LVEF 48%) ( Video S1 , 1:00). She was discharged home on Day 32, with a maintenance immunosuppressive therapy of oral methylprednisolone and azathioprine. Methylprednisolone was then tapered the following days with a weekly 25% reduction and a target of chronic 5 mg per day. Additionally, she is currently on alternating doses of azathioprine (100 mg per os 1 day and 150 mg the next day). Four weeks after discharge, once the test was introduced in Italy, an immunological assay for SARS‐CoV‐2 IgM and IgG was performed showing a weak positivity for specific antibodies while immunosuppressed.
Figure 2 (A) ECG at hospital admission showing a wide QRS complex. (B) ECG at discharge showing a restoration of the sinus rhythm; QRS waves narrowing with diffuse negative T waves; low voltages on all the precordial leads.
Figure 3 Pathological findings in endomyocardial biopsy (EMB) at recurrent fulminant myocarditis (FM) episode. (A) EMB specimen showing persistent myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
Discussion
This is the first report to show that lymphocytic virus‐negative FM relapses can be observed in the same patient with a similar presentation severity. Regardless of the MCS used, prompt LV unloading is critical for myocardial recovery; in addition, timely integration of MCS with tailored EMB‐guided immunosuppression was of critical importance in the treatment of our patient. Outcome of lymphocytic FM compared with non‐fulminant disease is controversial, reported as excellent 1 or bad. 2 So far, it is unclear whether the fulminant modality has independent negative prognostic value per se regardless of other known negative predictors such as the histology, giant cell vs. lymphocytic, and the degree of biventricular dysfunction. 2
FM is rare, and fulminant episodes of recurrences have already been reported in literature. 4 , 5 On the basis of serological tests, the aetiology of recurrent myocarditis in cases discussed by Matsue and Yoshimizu et al. is to be considered viral related, missing any EMB in both. In our case, immunohistochemical results of EMBs performed during the acute phase pointed to lymphocytic myocarditis. All serological and molecular tests on the samples obtained were negative for viruses, hence our definition of virus‐negative immune‐mediated lymphocytic myocarditis.
Although this is the first report of recurrent immune‐mediated lymphocytic FM with a fulminant relapse, our specific case keeps in line with the relapsing–remitting course of other autoimmune diseases. 2 In the first episode of FM for our patient, immunosuppression was withheld because of concomitant pneumonia and, after pneumonia resolution, because of the sustained recovery of ventricular function. The long‐lasting asymptomatic state of the patient with preserved biventricular function in the following 5 years confirmed that the first episode was indeed cured. During the strict echocardiographic follow‐up in the time preceding the recurrence, no clinical or instrumental evidence ever suggested the presence of a subclinical myocarditis, justifying the absence of further invasive examinations. The second episode highlights the importance of a timely combined surgical and medical approach; initial high dose i.v. steroids were highly effective in suppressing a life‐threatening arrhythmic storm.
Another interesting feature of this case was the presence of pneumonia as a prodromal event in both FM episodes. We hypothesize that, in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune‐mediated hyper‐response. 2 The patient had a history of pneumonia in the first months of 2020 during the initial spread of the COVID‐19 pandemic in Northern Italy. In the absence of severe symptomatology and the still dormant SARS‐CoV‐2 outbreak, a CT scan was not performed; the patient was discharged home on antibiotic therapy with a community‐acquired pneumonia diagnosis after a chest X‐ray. Nasopharyngeal swabs tests performed during hospitalization were negative, as was EMB‐based analysis of viral activity. It cannot be excluded that an autoimmune inflammatory process was triggered by the pneumonia prodromal episode 2 months prior. Unfortunately, the late introduction (May 2020) of serological assays for SARS‐CoV‐2 in the Italian market delayed our ability to make fully informed decisions regarding the treatment of this patient, who was already undergoing a heavy immunosuppressive regimen with steroid and azathioprine as a relapse maintenance therapy. Regardless, pathology studies up to date have yet to specifically address the myocardium and the burden of myocarditis in COVID‐19 patients, which remain to be established. 6 , 7
Funding
Departmental Strategic Investment (SID) 2020, BIRD205838, University of Padua.
Supporting information
Video S1. Transthoracic‐Echocardiogram 3 days post BiVAD implantation (0:05); Transthoracic‐Echocardiogram at discharge (0:15); Transthoracic‐Echocardiogram 5 years after the first episode (0:30); Transthoracic‐Echocardiogram and Coronary Angiography at admission for recurrent FM (0:40); Transthoracic‐Echocardiogram at discharge (1:00).
Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33225579 | 19,649,870 | 2021-02 |
What was the administration route of drug 'LIDOCAINE'? | Recurrent autoimmune myocarditis in a young woman during the coronavirus disease 2019 pandemic.
We report a unique case of a young woman with recurrent immune-mediated (virus-negative) lymphocytic fulminant myocarditis during the coronavirus disease 2019 pandemic. At the first endomyocardial biopsy (EMB)-proven episode, she had concomitant pneumonia, and a temporary biventricular assist device implant was followed by complete and long-lasting cardiac recovery. Five years later, she was re-admitted for relapsing cardiogenic shock with a recent history of pneumonia. She was treated with extracorporeal life support with apical venting for left ventricular unloading, and full recovery was achieved. Despite negative seriate nasopharyngeal swabs and EMB during hospitalization, an antibody positivity for severe acute respiratory syndrome coronavirus 2 was discovered after 4 weeks from discharge. This is the first report of an EMB-proven, immune-mediated (virus-negative) recurrence of fulminant myocarditis. We hypothesize that in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune-mediated hyper-response.
Introduction
Fulminant myocarditis (FM) is characterized by sudden onset with haemodynamic compromise requiring immediate inotropic therapy and/or mechanical circulatory support (MCS). 1 , 2 , 3 In FM, endomyocardial biopsy (EMB) is mandatory to achieve certainty in diagnosis and guide aetiology‐directed therapy. 2
Case report
In February 2015, a 40‐year‐old female and mother of two young children presented to the emergency department (ED) complaining of fatigue and chest pain without any relevant clinical history. She had no family history of cardiomyopathy or autoimmune disease. Computed tomography (CT) scan ruled out pulmonary embolism but showed right lung pneumonia. Severe left ventricular (LV) systolic dysfunction [LV ejection fraction (LVEF) < 20%] and unobstructed coronary arteries were detected ( Video S1 , 0:05). Despite inotropic support, the patient needed percutaneous veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) support. After 48 h with no clinical improvement, the patient was referred to our centre. Through a left mini‐thoracotomy in the fifth intercostal space, the cardiac apex was approached for inflow LV assist device (LVAD) implantation, and a myocardial sample was taken for histological analysis. With the use of a right mini‐thoracotomy in the second intercostal space, a vascular prosthesis was anastomosed to the aorta as outflow line. A right ventricular assist device (RVAD) was implanted using the left femoral vein and the pulmonary artery through a left mini‐thoracotomy in the second intercostal space. A diagnosis of virus‐negative lymphocytic myocarditis was made on the basis of EMB (Figure 1A and 1B ). Serum tested weakly positive for anti‐heart and anti‐intercalated disk autoantibodies. Although the diagnosis consisted of a lymphocytic immune‐mediated (virus‐negative) myocarditis with severe systolic dysfunction, the patient was not put on immunosuppression because of pneumonia. She was progressively weaned from RVAD, which was removed after 6 days. Twenty days later, the LVAD was also removed, as a complete LV recovery was achieved. The patient's stay in the intensive care unit (ICU) was prolonged (37 days) owing to nosocomial pneumonia, acute renal failure needing 14 days of continuous veno‐venous haemodialysis, positive blood cultures for Candida utilis and Enterococcus faecium, and presence of Enterovirus on sputum. LVEF was 50% at discharge (102 days). After the first hospitalization, the patient developed an amiodarone‐related thyroid disease and chronic kidney disease for which she was followed up by the respective specialists. She was put on beta‐blocker therapy with carvedilol and aldosterone antagonist. Her newly developed Stage IV chronic kidney disease with a glomerular filtration rate between 15 and 20 mL/min was treated with additional sodium therapy for persistent hyponatremia. Three years later, after being hospitalized owing to severe hyponatremia, aldosterone antagonist administration was suspended. For the subsequent 5 years, the patient was asymptomatic and was followed up with echocardiograms ( Video S1 , 0:15), ECGs, and blood and troponin tests every 6 months.
Figure 1 Pathological findings in endomyocardial biopsy (EMB) at first episode. (A) EMB specimen showing extensive myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
In January 2020, the patient presented several times to the ED complaining of atypical chest pain and fever. ECG was unchanged, and troponin values were repeatedly normal; the echocardiogram also remained consistent ( Video S1 , 0:30). In March, she was re‐admitted to secondary care ED for dyspnoea and palpitations. ECG showed diffuse ST elevation with tombstone morphology; troponin was also markedly increased (peak TnI 83 000 ng/L, normal range 0–34 ng/L) (Figure 2A ). Because she presented during the coronavirus disease 2019 (COVID‐19) outbreak, she underwent a nasopharyngeal swab test for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which resulted negative. A bedside echocardiogram showed severe LV dysfunction with healthy coronary arteries ( Video S1 , 0:40). She was then transferred to our institution. On arrival, she developed haemodynamic and electrical instability consisting of an arrhythmic storm and cardiac arrest, requiring emergent femoral–femoral V‐A ECMO. One hour later, following severe haemodynamic instability, we decided to unload the LV by placing an apical venting through the previous left mini‐thoracotomy in the fifth intercostal space; an EMB was again performed at the LV apex. A 4 L/min support was commenced; better organ perfusion was evidenced by lactate reduction and pH improvement. Complex incessant arrhythmias persisted despite i.v. amiodarone, lidocaine, and esmolol administration. The EMB showed a virus‐negative lymphocytic myocarditis (Figure 3A and 3B ). Immunosuppressive therapy with steroids (methylprednisolone, 1 g i.v. bolus OD for the first 3 days, then 100 mg i.v. OD for the first week followed by progressive tapering in the subsequent days) was then immediately started; azathioprine (50 mg per os b.i.d.) was also added. A progressive normalization of ECG and biventricular contractility was observed (Figure 2B ). In the following days, there was a rapid recovery of cardiac function with a decreasing need for mechanical support. VA‐ECMO was removed on the ninth post‐operative day. She was transferred from the ICU on the 13th post‐operative day. Echocardiography at discharge showed mild LV dysfunction (LVEF 48%) ( Video S1 , 1:00). She was discharged home on Day 32, with a maintenance immunosuppressive therapy of oral methylprednisolone and azathioprine. Methylprednisolone was then tapered the following days with a weekly 25% reduction and a target of chronic 5 mg per day. Additionally, she is currently on alternating doses of azathioprine (100 mg per os 1 day and 150 mg the next day). Four weeks after discharge, once the test was introduced in Italy, an immunological assay for SARS‐CoV‐2 IgM and IgG was performed showing a weak positivity for specific antibodies while immunosuppressed.
Figure 2 (A) ECG at hospital admission showing a wide QRS complex. (B) ECG at discharge showing a restoration of the sinus rhythm; QRS waves narrowing with diffuse negative T waves; low voltages on all the precordial leads.
Figure 3 Pathological findings in endomyocardial biopsy (EMB) at recurrent fulminant myocarditis (FM) episode. (A) EMB specimen showing persistent myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
Discussion
This is the first report to show that lymphocytic virus‐negative FM relapses can be observed in the same patient with a similar presentation severity. Regardless of the MCS used, prompt LV unloading is critical for myocardial recovery; in addition, timely integration of MCS with tailored EMB‐guided immunosuppression was of critical importance in the treatment of our patient. Outcome of lymphocytic FM compared with non‐fulminant disease is controversial, reported as excellent 1 or bad. 2 So far, it is unclear whether the fulminant modality has independent negative prognostic value per se regardless of other known negative predictors such as the histology, giant cell vs. lymphocytic, and the degree of biventricular dysfunction. 2
FM is rare, and fulminant episodes of recurrences have already been reported in literature. 4 , 5 On the basis of serological tests, the aetiology of recurrent myocarditis in cases discussed by Matsue and Yoshimizu et al. is to be considered viral related, missing any EMB in both. In our case, immunohistochemical results of EMBs performed during the acute phase pointed to lymphocytic myocarditis. All serological and molecular tests on the samples obtained were negative for viruses, hence our definition of virus‐negative immune‐mediated lymphocytic myocarditis.
Although this is the first report of recurrent immune‐mediated lymphocytic FM with a fulminant relapse, our specific case keeps in line with the relapsing–remitting course of other autoimmune diseases. 2 In the first episode of FM for our patient, immunosuppression was withheld because of concomitant pneumonia and, after pneumonia resolution, because of the sustained recovery of ventricular function. The long‐lasting asymptomatic state of the patient with preserved biventricular function in the following 5 years confirmed that the first episode was indeed cured. During the strict echocardiographic follow‐up in the time preceding the recurrence, no clinical or instrumental evidence ever suggested the presence of a subclinical myocarditis, justifying the absence of further invasive examinations. The second episode highlights the importance of a timely combined surgical and medical approach; initial high dose i.v. steroids were highly effective in suppressing a life‐threatening arrhythmic storm.
Another interesting feature of this case was the presence of pneumonia as a prodromal event in both FM episodes. We hypothesize that, in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune‐mediated hyper‐response. 2 The patient had a history of pneumonia in the first months of 2020 during the initial spread of the COVID‐19 pandemic in Northern Italy. In the absence of severe symptomatology and the still dormant SARS‐CoV‐2 outbreak, a CT scan was not performed; the patient was discharged home on antibiotic therapy with a community‐acquired pneumonia diagnosis after a chest X‐ray. Nasopharyngeal swabs tests performed during hospitalization were negative, as was EMB‐based analysis of viral activity. It cannot be excluded that an autoimmune inflammatory process was triggered by the pneumonia prodromal episode 2 months prior. Unfortunately, the late introduction (May 2020) of serological assays for SARS‐CoV‐2 in the Italian market delayed our ability to make fully informed decisions regarding the treatment of this patient, who was already undergoing a heavy immunosuppressive regimen with steroid and azathioprine as a relapse maintenance therapy. Regardless, pathology studies up to date have yet to specifically address the myocardium and the burden of myocarditis in COVID‐19 patients, which remain to be established. 6 , 7
Funding
Departmental Strategic Investment (SID) 2020, BIRD205838, University of Padua.
Supporting information
Video S1. Transthoracic‐Echocardiogram 3 days post BiVAD implantation (0:05); Transthoracic‐Echocardiogram at discharge (0:15); Transthoracic‐Echocardiogram 5 years after the first episode (0:30); Transthoracic‐Echocardiogram and Coronary Angiography at admission for recurrent FM (0:40); Transthoracic‐Echocardiogram at discharge (1:00).
Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33225579 | 19,625,863 | 2021-02 |
What was the dosage of drug 'AMIODARONE'? | Recurrent autoimmune myocarditis in a young woman during the coronavirus disease 2019 pandemic.
We report a unique case of a young woman with recurrent immune-mediated (virus-negative) lymphocytic fulminant myocarditis during the coronavirus disease 2019 pandemic. At the first endomyocardial biopsy (EMB)-proven episode, she had concomitant pneumonia, and a temporary biventricular assist device implant was followed by complete and long-lasting cardiac recovery. Five years later, she was re-admitted for relapsing cardiogenic shock with a recent history of pneumonia. She was treated with extracorporeal life support with apical venting for left ventricular unloading, and full recovery was achieved. Despite negative seriate nasopharyngeal swabs and EMB during hospitalization, an antibody positivity for severe acute respiratory syndrome coronavirus 2 was discovered after 4 weeks from discharge. This is the first report of an EMB-proven, immune-mediated (virus-negative) recurrence of fulminant myocarditis. We hypothesize that in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune-mediated hyper-response.
Introduction
Fulminant myocarditis (FM) is characterized by sudden onset with haemodynamic compromise requiring immediate inotropic therapy and/or mechanical circulatory support (MCS). 1 , 2 , 3 In FM, endomyocardial biopsy (EMB) is mandatory to achieve certainty in diagnosis and guide aetiology‐directed therapy. 2
Case report
In February 2015, a 40‐year‐old female and mother of two young children presented to the emergency department (ED) complaining of fatigue and chest pain without any relevant clinical history. She had no family history of cardiomyopathy or autoimmune disease. Computed tomography (CT) scan ruled out pulmonary embolism but showed right lung pneumonia. Severe left ventricular (LV) systolic dysfunction [LV ejection fraction (LVEF) < 20%] and unobstructed coronary arteries were detected ( Video S1 , 0:05). Despite inotropic support, the patient needed percutaneous veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) support. After 48 h with no clinical improvement, the patient was referred to our centre. Through a left mini‐thoracotomy in the fifth intercostal space, the cardiac apex was approached for inflow LV assist device (LVAD) implantation, and a myocardial sample was taken for histological analysis. With the use of a right mini‐thoracotomy in the second intercostal space, a vascular prosthesis was anastomosed to the aorta as outflow line. A right ventricular assist device (RVAD) was implanted using the left femoral vein and the pulmonary artery through a left mini‐thoracotomy in the second intercostal space. A diagnosis of virus‐negative lymphocytic myocarditis was made on the basis of EMB (Figure 1A and 1B ). Serum tested weakly positive for anti‐heart and anti‐intercalated disk autoantibodies. Although the diagnosis consisted of a lymphocytic immune‐mediated (virus‐negative) myocarditis with severe systolic dysfunction, the patient was not put on immunosuppression because of pneumonia. She was progressively weaned from RVAD, which was removed after 6 days. Twenty days later, the LVAD was also removed, as a complete LV recovery was achieved. The patient's stay in the intensive care unit (ICU) was prolonged (37 days) owing to nosocomial pneumonia, acute renal failure needing 14 days of continuous veno‐venous haemodialysis, positive blood cultures for Candida utilis and Enterococcus faecium, and presence of Enterovirus on sputum. LVEF was 50% at discharge (102 days). After the first hospitalization, the patient developed an amiodarone‐related thyroid disease and chronic kidney disease for which she was followed up by the respective specialists. She was put on beta‐blocker therapy with carvedilol and aldosterone antagonist. Her newly developed Stage IV chronic kidney disease with a glomerular filtration rate between 15 and 20 mL/min was treated with additional sodium therapy for persistent hyponatremia. Three years later, after being hospitalized owing to severe hyponatremia, aldosterone antagonist administration was suspended. For the subsequent 5 years, the patient was asymptomatic and was followed up with echocardiograms ( Video S1 , 0:15), ECGs, and blood and troponin tests every 6 months.
Figure 1 Pathological findings in endomyocardial biopsy (EMB) at first episode. (A) EMB specimen showing extensive myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
In January 2020, the patient presented several times to the ED complaining of atypical chest pain and fever. ECG was unchanged, and troponin values were repeatedly normal; the echocardiogram also remained consistent ( Video S1 , 0:30). In March, she was re‐admitted to secondary care ED for dyspnoea and palpitations. ECG showed diffuse ST elevation with tombstone morphology; troponin was also markedly increased (peak TnI 83 000 ng/L, normal range 0–34 ng/L) (Figure 2A ). Because she presented during the coronavirus disease 2019 (COVID‐19) outbreak, she underwent a nasopharyngeal swab test for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which resulted negative. A bedside echocardiogram showed severe LV dysfunction with healthy coronary arteries ( Video S1 , 0:40). She was then transferred to our institution. On arrival, she developed haemodynamic and electrical instability consisting of an arrhythmic storm and cardiac arrest, requiring emergent femoral–femoral V‐A ECMO. One hour later, following severe haemodynamic instability, we decided to unload the LV by placing an apical venting through the previous left mini‐thoracotomy in the fifth intercostal space; an EMB was again performed at the LV apex. A 4 L/min support was commenced; better organ perfusion was evidenced by lactate reduction and pH improvement. Complex incessant arrhythmias persisted despite i.v. amiodarone, lidocaine, and esmolol administration. The EMB showed a virus‐negative lymphocytic myocarditis (Figure 3A and 3B ). Immunosuppressive therapy with steroids (methylprednisolone, 1 g i.v. bolus OD for the first 3 days, then 100 mg i.v. OD for the first week followed by progressive tapering in the subsequent days) was then immediately started; azathioprine (50 mg per os b.i.d.) was also added. A progressive normalization of ECG and biventricular contractility was observed (Figure 2B ). In the following days, there was a rapid recovery of cardiac function with a decreasing need for mechanical support. VA‐ECMO was removed on the ninth post‐operative day. She was transferred from the ICU on the 13th post‐operative day. Echocardiography at discharge showed mild LV dysfunction (LVEF 48%) ( Video S1 , 1:00). She was discharged home on Day 32, with a maintenance immunosuppressive therapy of oral methylprednisolone and azathioprine. Methylprednisolone was then tapered the following days with a weekly 25% reduction and a target of chronic 5 mg per day. Additionally, she is currently on alternating doses of azathioprine (100 mg per os 1 day and 150 mg the next day). Four weeks after discharge, once the test was introduced in Italy, an immunological assay for SARS‐CoV‐2 IgM and IgG was performed showing a weak positivity for specific antibodies while immunosuppressed.
Figure 2 (A) ECG at hospital admission showing a wide QRS complex. (B) ECG at discharge showing a restoration of the sinus rhythm; QRS waves narrowing with diffuse negative T waves; low voltages on all the precordial leads.
Figure 3 Pathological findings in endomyocardial biopsy (EMB) at recurrent fulminant myocarditis (FM) episode. (A) EMB specimen showing persistent myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
Discussion
This is the first report to show that lymphocytic virus‐negative FM relapses can be observed in the same patient with a similar presentation severity. Regardless of the MCS used, prompt LV unloading is critical for myocardial recovery; in addition, timely integration of MCS with tailored EMB‐guided immunosuppression was of critical importance in the treatment of our patient. Outcome of lymphocytic FM compared with non‐fulminant disease is controversial, reported as excellent 1 or bad. 2 So far, it is unclear whether the fulminant modality has independent negative prognostic value per se regardless of other known negative predictors such as the histology, giant cell vs. lymphocytic, and the degree of biventricular dysfunction. 2
FM is rare, and fulminant episodes of recurrences have already been reported in literature. 4 , 5 On the basis of serological tests, the aetiology of recurrent myocarditis in cases discussed by Matsue and Yoshimizu et al. is to be considered viral related, missing any EMB in both. In our case, immunohistochemical results of EMBs performed during the acute phase pointed to lymphocytic myocarditis. All serological and molecular tests on the samples obtained were negative for viruses, hence our definition of virus‐negative immune‐mediated lymphocytic myocarditis.
Although this is the first report of recurrent immune‐mediated lymphocytic FM with a fulminant relapse, our specific case keeps in line with the relapsing–remitting course of other autoimmune diseases. 2 In the first episode of FM for our patient, immunosuppression was withheld because of concomitant pneumonia and, after pneumonia resolution, because of the sustained recovery of ventricular function. The long‐lasting asymptomatic state of the patient with preserved biventricular function in the following 5 years confirmed that the first episode was indeed cured. During the strict echocardiographic follow‐up in the time preceding the recurrence, no clinical or instrumental evidence ever suggested the presence of a subclinical myocarditis, justifying the absence of further invasive examinations. The second episode highlights the importance of a timely combined surgical and medical approach; initial high dose i.v. steroids were highly effective in suppressing a life‐threatening arrhythmic storm.
Another interesting feature of this case was the presence of pneumonia as a prodromal event in both FM episodes. We hypothesize that, in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune‐mediated hyper‐response. 2 The patient had a history of pneumonia in the first months of 2020 during the initial spread of the COVID‐19 pandemic in Northern Italy. In the absence of severe symptomatology and the still dormant SARS‐CoV‐2 outbreak, a CT scan was not performed; the patient was discharged home on antibiotic therapy with a community‐acquired pneumonia diagnosis after a chest X‐ray. Nasopharyngeal swabs tests performed during hospitalization were negative, as was EMB‐based analysis of viral activity. It cannot be excluded that an autoimmune inflammatory process was triggered by the pneumonia prodromal episode 2 months prior. Unfortunately, the late introduction (May 2020) of serological assays for SARS‐CoV‐2 in the Italian market delayed our ability to make fully informed decisions regarding the treatment of this patient, who was already undergoing a heavy immunosuppressive regimen with steroid and azathioprine as a relapse maintenance therapy. Regardless, pathology studies up to date have yet to specifically address the myocardium and the burden of myocarditis in COVID‐19 patients, which remain to be established. 6 , 7
Funding
Departmental Strategic Investment (SID) 2020, BIRD205838, University of Padua.
Supporting information
Video S1. Transthoracic‐Echocardiogram 3 days post BiVAD implantation (0:05); Transthoracic‐Echocardiogram at discharge (0:15); Transthoracic‐Echocardiogram 5 years after the first episode (0:30); Transthoracic‐Echocardiogram and Coronary Angiography at admission for recurrent FM (0:40); Transthoracic‐Echocardiogram at discharge (1:00).
Click here for additional data file. | UNKNOWN | DrugDosageText | CC BY-NC | 33225579 | 19,436,841 | 2021-02 |
What was the outcome of reaction 'Chronic kidney disease'? | Recurrent autoimmune myocarditis in a young woman during the coronavirus disease 2019 pandemic.
We report a unique case of a young woman with recurrent immune-mediated (virus-negative) lymphocytic fulminant myocarditis during the coronavirus disease 2019 pandemic. At the first endomyocardial biopsy (EMB)-proven episode, she had concomitant pneumonia, and a temporary biventricular assist device implant was followed by complete and long-lasting cardiac recovery. Five years later, she was re-admitted for relapsing cardiogenic shock with a recent history of pneumonia. She was treated with extracorporeal life support with apical venting for left ventricular unloading, and full recovery was achieved. Despite negative seriate nasopharyngeal swabs and EMB during hospitalization, an antibody positivity for severe acute respiratory syndrome coronavirus 2 was discovered after 4 weeks from discharge. This is the first report of an EMB-proven, immune-mediated (virus-negative) recurrence of fulminant myocarditis. We hypothesize that in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune-mediated hyper-response.
Introduction
Fulminant myocarditis (FM) is characterized by sudden onset with haemodynamic compromise requiring immediate inotropic therapy and/or mechanical circulatory support (MCS). 1 , 2 , 3 In FM, endomyocardial biopsy (EMB) is mandatory to achieve certainty in diagnosis and guide aetiology‐directed therapy. 2
Case report
In February 2015, a 40‐year‐old female and mother of two young children presented to the emergency department (ED) complaining of fatigue and chest pain without any relevant clinical history. She had no family history of cardiomyopathy or autoimmune disease. Computed tomography (CT) scan ruled out pulmonary embolism but showed right lung pneumonia. Severe left ventricular (LV) systolic dysfunction [LV ejection fraction (LVEF) < 20%] and unobstructed coronary arteries were detected ( Video S1 , 0:05). Despite inotropic support, the patient needed percutaneous veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) support. After 48 h with no clinical improvement, the patient was referred to our centre. Through a left mini‐thoracotomy in the fifth intercostal space, the cardiac apex was approached for inflow LV assist device (LVAD) implantation, and a myocardial sample was taken for histological analysis. With the use of a right mini‐thoracotomy in the second intercostal space, a vascular prosthesis was anastomosed to the aorta as outflow line. A right ventricular assist device (RVAD) was implanted using the left femoral vein and the pulmonary artery through a left mini‐thoracotomy in the second intercostal space. A diagnosis of virus‐negative lymphocytic myocarditis was made on the basis of EMB (Figure 1A and 1B ). Serum tested weakly positive for anti‐heart and anti‐intercalated disk autoantibodies. Although the diagnosis consisted of a lymphocytic immune‐mediated (virus‐negative) myocarditis with severe systolic dysfunction, the patient was not put on immunosuppression because of pneumonia. She was progressively weaned from RVAD, which was removed after 6 days. Twenty days later, the LVAD was also removed, as a complete LV recovery was achieved. The patient's stay in the intensive care unit (ICU) was prolonged (37 days) owing to nosocomial pneumonia, acute renal failure needing 14 days of continuous veno‐venous haemodialysis, positive blood cultures for Candida utilis and Enterococcus faecium, and presence of Enterovirus on sputum. LVEF was 50% at discharge (102 days). After the first hospitalization, the patient developed an amiodarone‐related thyroid disease and chronic kidney disease for which she was followed up by the respective specialists. She was put on beta‐blocker therapy with carvedilol and aldosterone antagonist. Her newly developed Stage IV chronic kidney disease with a glomerular filtration rate between 15 and 20 mL/min was treated with additional sodium therapy for persistent hyponatremia. Three years later, after being hospitalized owing to severe hyponatremia, aldosterone antagonist administration was suspended. For the subsequent 5 years, the patient was asymptomatic and was followed up with echocardiograms ( Video S1 , 0:15), ECGs, and blood and troponin tests every 6 months.
Figure 1 Pathological findings in endomyocardial biopsy (EMB) at first episode. (A) EMB specimen showing extensive myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
In January 2020, the patient presented several times to the ED complaining of atypical chest pain and fever. ECG was unchanged, and troponin values were repeatedly normal; the echocardiogram also remained consistent ( Video S1 , 0:30). In March, she was re‐admitted to secondary care ED for dyspnoea and palpitations. ECG showed diffuse ST elevation with tombstone morphology; troponin was also markedly increased (peak TnI 83 000 ng/L, normal range 0–34 ng/L) (Figure 2A ). Because she presented during the coronavirus disease 2019 (COVID‐19) outbreak, she underwent a nasopharyngeal swab test for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which resulted negative. A bedside echocardiogram showed severe LV dysfunction with healthy coronary arteries ( Video S1 , 0:40). She was then transferred to our institution. On arrival, she developed haemodynamic and electrical instability consisting of an arrhythmic storm and cardiac arrest, requiring emergent femoral–femoral V‐A ECMO. One hour later, following severe haemodynamic instability, we decided to unload the LV by placing an apical venting through the previous left mini‐thoracotomy in the fifth intercostal space; an EMB was again performed at the LV apex. A 4 L/min support was commenced; better organ perfusion was evidenced by lactate reduction and pH improvement. Complex incessant arrhythmias persisted despite i.v. amiodarone, lidocaine, and esmolol administration. The EMB showed a virus‐negative lymphocytic myocarditis (Figure 3A and 3B ). Immunosuppressive therapy with steroids (methylprednisolone, 1 g i.v. bolus OD for the first 3 days, then 100 mg i.v. OD for the first week followed by progressive tapering in the subsequent days) was then immediately started; azathioprine (50 mg per os b.i.d.) was also added. A progressive normalization of ECG and biventricular contractility was observed (Figure 2B ). In the following days, there was a rapid recovery of cardiac function with a decreasing need for mechanical support. VA‐ECMO was removed on the ninth post‐operative day. She was transferred from the ICU on the 13th post‐operative day. Echocardiography at discharge showed mild LV dysfunction (LVEF 48%) ( Video S1 , 1:00). She was discharged home on Day 32, with a maintenance immunosuppressive therapy of oral methylprednisolone and azathioprine. Methylprednisolone was then tapered the following days with a weekly 25% reduction and a target of chronic 5 mg per day. Additionally, she is currently on alternating doses of azathioprine (100 mg per os 1 day and 150 mg the next day). Four weeks after discharge, once the test was introduced in Italy, an immunological assay for SARS‐CoV‐2 IgM and IgG was performed showing a weak positivity for specific antibodies while immunosuppressed.
Figure 2 (A) ECG at hospital admission showing a wide QRS complex. (B) ECG at discharge showing a restoration of the sinus rhythm; QRS waves narrowing with diffuse negative T waves; low voltages on all the precordial leads.
Figure 3 Pathological findings in endomyocardial biopsy (EMB) at recurrent fulminant myocarditis (FM) episode. (A) EMB specimen showing persistent myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
Discussion
This is the first report to show that lymphocytic virus‐negative FM relapses can be observed in the same patient with a similar presentation severity. Regardless of the MCS used, prompt LV unloading is critical for myocardial recovery; in addition, timely integration of MCS with tailored EMB‐guided immunosuppression was of critical importance in the treatment of our patient. Outcome of lymphocytic FM compared with non‐fulminant disease is controversial, reported as excellent 1 or bad. 2 So far, it is unclear whether the fulminant modality has independent negative prognostic value per se regardless of other known negative predictors such as the histology, giant cell vs. lymphocytic, and the degree of biventricular dysfunction. 2
FM is rare, and fulminant episodes of recurrences have already been reported in literature. 4 , 5 On the basis of serological tests, the aetiology of recurrent myocarditis in cases discussed by Matsue and Yoshimizu et al. is to be considered viral related, missing any EMB in both. In our case, immunohistochemical results of EMBs performed during the acute phase pointed to lymphocytic myocarditis. All serological and molecular tests on the samples obtained were negative for viruses, hence our definition of virus‐negative immune‐mediated lymphocytic myocarditis.
Although this is the first report of recurrent immune‐mediated lymphocytic FM with a fulminant relapse, our specific case keeps in line with the relapsing–remitting course of other autoimmune diseases. 2 In the first episode of FM for our patient, immunosuppression was withheld because of concomitant pneumonia and, after pneumonia resolution, because of the sustained recovery of ventricular function. The long‐lasting asymptomatic state of the patient with preserved biventricular function in the following 5 years confirmed that the first episode was indeed cured. During the strict echocardiographic follow‐up in the time preceding the recurrence, no clinical or instrumental evidence ever suggested the presence of a subclinical myocarditis, justifying the absence of further invasive examinations. The second episode highlights the importance of a timely combined surgical and medical approach; initial high dose i.v. steroids were highly effective in suppressing a life‐threatening arrhythmic storm.
Another interesting feature of this case was the presence of pneumonia as a prodromal event in both FM episodes. We hypothesize that, in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune‐mediated hyper‐response. 2 The patient had a history of pneumonia in the first months of 2020 during the initial spread of the COVID‐19 pandemic in Northern Italy. In the absence of severe symptomatology and the still dormant SARS‐CoV‐2 outbreak, a CT scan was not performed; the patient was discharged home on antibiotic therapy with a community‐acquired pneumonia diagnosis after a chest X‐ray. Nasopharyngeal swabs tests performed during hospitalization were negative, as was EMB‐based analysis of viral activity. It cannot be excluded that an autoimmune inflammatory process was triggered by the pneumonia prodromal episode 2 months prior. Unfortunately, the late introduction (May 2020) of serological assays for SARS‐CoV‐2 in the Italian market delayed our ability to make fully informed decisions regarding the treatment of this patient, who was already undergoing a heavy immunosuppressive regimen with steroid and azathioprine as a relapse maintenance therapy. Regardless, pathology studies up to date have yet to specifically address the myocardium and the burden of myocarditis in COVID‐19 patients, which remain to be established. 6 , 7
Funding
Departmental Strategic Investment (SID) 2020, BIRD205838, University of Padua.
Supporting information
Video S1. Transthoracic‐Echocardiogram 3 days post BiVAD implantation (0:05); Transthoracic‐Echocardiogram at discharge (0:15); Transthoracic‐Echocardiogram 5 years after the first episode (0:30); Transthoracic‐Echocardiogram and Coronary Angiography at admission for recurrent FM (0:40); Transthoracic‐Echocardiogram at discharge (1:00).
Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33225579 | 19,625,863 | 2021-02 |
What was the outcome of reaction 'Hyponatraemia'? | Recurrent autoimmune myocarditis in a young woman during the coronavirus disease 2019 pandemic.
We report a unique case of a young woman with recurrent immune-mediated (virus-negative) lymphocytic fulminant myocarditis during the coronavirus disease 2019 pandemic. At the first endomyocardial biopsy (EMB)-proven episode, she had concomitant pneumonia, and a temporary biventricular assist device implant was followed by complete and long-lasting cardiac recovery. Five years later, she was re-admitted for relapsing cardiogenic shock with a recent history of pneumonia. She was treated with extracorporeal life support with apical venting for left ventricular unloading, and full recovery was achieved. Despite negative seriate nasopharyngeal swabs and EMB during hospitalization, an antibody positivity for severe acute respiratory syndrome coronavirus 2 was discovered after 4 weeks from discharge. This is the first report of an EMB-proven, immune-mediated (virus-negative) recurrence of fulminant myocarditis. We hypothesize that in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune-mediated hyper-response.
Introduction
Fulminant myocarditis (FM) is characterized by sudden onset with haemodynamic compromise requiring immediate inotropic therapy and/or mechanical circulatory support (MCS). 1 , 2 , 3 In FM, endomyocardial biopsy (EMB) is mandatory to achieve certainty in diagnosis and guide aetiology‐directed therapy. 2
Case report
In February 2015, a 40‐year‐old female and mother of two young children presented to the emergency department (ED) complaining of fatigue and chest pain without any relevant clinical history. She had no family history of cardiomyopathy or autoimmune disease. Computed tomography (CT) scan ruled out pulmonary embolism but showed right lung pneumonia. Severe left ventricular (LV) systolic dysfunction [LV ejection fraction (LVEF) < 20%] and unobstructed coronary arteries were detected ( Video S1 , 0:05). Despite inotropic support, the patient needed percutaneous veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) support. After 48 h with no clinical improvement, the patient was referred to our centre. Through a left mini‐thoracotomy in the fifth intercostal space, the cardiac apex was approached for inflow LV assist device (LVAD) implantation, and a myocardial sample was taken for histological analysis. With the use of a right mini‐thoracotomy in the second intercostal space, a vascular prosthesis was anastomosed to the aorta as outflow line. A right ventricular assist device (RVAD) was implanted using the left femoral vein and the pulmonary artery through a left mini‐thoracotomy in the second intercostal space. A diagnosis of virus‐negative lymphocytic myocarditis was made on the basis of EMB (Figure 1A and 1B ). Serum tested weakly positive for anti‐heart and anti‐intercalated disk autoantibodies. Although the diagnosis consisted of a lymphocytic immune‐mediated (virus‐negative) myocarditis with severe systolic dysfunction, the patient was not put on immunosuppression because of pneumonia. She was progressively weaned from RVAD, which was removed after 6 days. Twenty days later, the LVAD was also removed, as a complete LV recovery was achieved. The patient's stay in the intensive care unit (ICU) was prolonged (37 days) owing to nosocomial pneumonia, acute renal failure needing 14 days of continuous veno‐venous haemodialysis, positive blood cultures for Candida utilis and Enterococcus faecium, and presence of Enterovirus on sputum. LVEF was 50% at discharge (102 days). After the first hospitalization, the patient developed an amiodarone‐related thyroid disease and chronic kidney disease for which she was followed up by the respective specialists. She was put on beta‐blocker therapy with carvedilol and aldosterone antagonist. Her newly developed Stage IV chronic kidney disease with a glomerular filtration rate between 15 and 20 mL/min was treated with additional sodium therapy for persistent hyponatremia. Three years later, after being hospitalized owing to severe hyponatremia, aldosterone antagonist administration was suspended. For the subsequent 5 years, the patient was asymptomatic and was followed up with echocardiograms ( Video S1 , 0:15), ECGs, and blood and troponin tests every 6 months.
Figure 1 Pathological findings in endomyocardial biopsy (EMB) at first episode. (A) EMB specimen showing extensive myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
In January 2020, the patient presented several times to the ED complaining of atypical chest pain and fever. ECG was unchanged, and troponin values were repeatedly normal; the echocardiogram also remained consistent ( Video S1 , 0:30). In March, she was re‐admitted to secondary care ED for dyspnoea and palpitations. ECG showed diffuse ST elevation with tombstone morphology; troponin was also markedly increased (peak TnI 83 000 ng/L, normal range 0–34 ng/L) (Figure 2A ). Because she presented during the coronavirus disease 2019 (COVID‐19) outbreak, she underwent a nasopharyngeal swab test for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which resulted negative. A bedside echocardiogram showed severe LV dysfunction with healthy coronary arteries ( Video S1 , 0:40). She was then transferred to our institution. On arrival, she developed haemodynamic and electrical instability consisting of an arrhythmic storm and cardiac arrest, requiring emergent femoral–femoral V‐A ECMO. One hour later, following severe haemodynamic instability, we decided to unload the LV by placing an apical venting through the previous left mini‐thoracotomy in the fifth intercostal space; an EMB was again performed at the LV apex. A 4 L/min support was commenced; better organ perfusion was evidenced by lactate reduction and pH improvement. Complex incessant arrhythmias persisted despite i.v. amiodarone, lidocaine, and esmolol administration. The EMB showed a virus‐negative lymphocytic myocarditis (Figure 3A and 3B ). Immunosuppressive therapy with steroids (methylprednisolone, 1 g i.v. bolus OD for the first 3 days, then 100 mg i.v. OD for the first week followed by progressive tapering in the subsequent days) was then immediately started; azathioprine (50 mg per os b.i.d.) was also added. A progressive normalization of ECG and biventricular contractility was observed (Figure 2B ). In the following days, there was a rapid recovery of cardiac function with a decreasing need for mechanical support. VA‐ECMO was removed on the ninth post‐operative day. She was transferred from the ICU on the 13th post‐operative day. Echocardiography at discharge showed mild LV dysfunction (LVEF 48%) ( Video S1 , 1:00). She was discharged home on Day 32, with a maintenance immunosuppressive therapy of oral methylprednisolone and azathioprine. Methylprednisolone was then tapered the following days with a weekly 25% reduction and a target of chronic 5 mg per day. Additionally, she is currently on alternating doses of azathioprine (100 mg per os 1 day and 150 mg the next day). Four weeks after discharge, once the test was introduced in Italy, an immunological assay for SARS‐CoV‐2 IgM and IgG was performed showing a weak positivity for specific antibodies while immunosuppressed.
Figure 2 (A) ECG at hospital admission showing a wide QRS complex. (B) ECG at discharge showing a restoration of the sinus rhythm; QRS waves narrowing with diffuse negative T waves; low voltages on all the precordial leads.
Figure 3 Pathological findings in endomyocardial biopsy (EMB) at recurrent fulminant myocarditis (FM) episode. (A) EMB specimen showing persistent myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
Discussion
This is the first report to show that lymphocytic virus‐negative FM relapses can be observed in the same patient with a similar presentation severity. Regardless of the MCS used, prompt LV unloading is critical for myocardial recovery; in addition, timely integration of MCS with tailored EMB‐guided immunosuppression was of critical importance in the treatment of our patient. Outcome of lymphocytic FM compared with non‐fulminant disease is controversial, reported as excellent 1 or bad. 2 So far, it is unclear whether the fulminant modality has independent negative prognostic value per se regardless of other known negative predictors such as the histology, giant cell vs. lymphocytic, and the degree of biventricular dysfunction. 2
FM is rare, and fulminant episodes of recurrences have already been reported in literature. 4 , 5 On the basis of serological tests, the aetiology of recurrent myocarditis in cases discussed by Matsue and Yoshimizu et al. is to be considered viral related, missing any EMB in both. In our case, immunohistochemical results of EMBs performed during the acute phase pointed to lymphocytic myocarditis. All serological and molecular tests on the samples obtained were negative for viruses, hence our definition of virus‐negative immune‐mediated lymphocytic myocarditis.
Although this is the first report of recurrent immune‐mediated lymphocytic FM with a fulminant relapse, our specific case keeps in line with the relapsing–remitting course of other autoimmune diseases. 2 In the first episode of FM for our patient, immunosuppression was withheld because of concomitant pneumonia and, after pneumonia resolution, because of the sustained recovery of ventricular function. The long‐lasting asymptomatic state of the patient with preserved biventricular function in the following 5 years confirmed that the first episode was indeed cured. During the strict echocardiographic follow‐up in the time preceding the recurrence, no clinical or instrumental evidence ever suggested the presence of a subclinical myocarditis, justifying the absence of further invasive examinations. The second episode highlights the importance of a timely combined surgical and medical approach; initial high dose i.v. steroids were highly effective in suppressing a life‐threatening arrhythmic storm.
Another interesting feature of this case was the presence of pneumonia as a prodromal event in both FM episodes. We hypothesize that, in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune‐mediated hyper‐response. 2 The patient had a history of pneumonia in the first months of 2020 during the initial spread of the COVID‐19 pandemic in Northern Italy. In the absence of severe symptomatology and the still dormant SARS‐CoV‐2 outbreak, a CT scan was not performed; the patient was discharged home on antibiotic therapy with a community‐acquired pneumonia diagnosis after a chest X‐ray. Nasopharyngeal swabs tests performed during hospitalization were negative, as was EMB‐based analysis of viral activity. It cannot be excluded that an autoimmune inflammatory process was triggered by the pneumonia prodromal episode 2 months prior. Unfortunately, the late introduction (May 2020) of serological assays for SARS‐CoV‐2 in the Italian market delayed our ability to make fully informed decisions regarding the treatment of this patient, who was already undergoing a heavy immunosuppressive regimen with steroid and azathioprine as a relapse maintenance therapy. Regardless, pathology studies up to date have yet to specifically address the myocardium and the burden of myocarditis in COVID‐19 patients, which remain to be established. 6 , 7
Funding
Departmental Strategic Investment (SID) 2020, BIRD205838, University of Padua.
Supporting information
Video S1. Transthoracic‐Echocardiogram 3 days post BiVAD implantation (0:05); Transthoracic‐Echocardiogram at discharge (0:15); Transthoracic‐Echocardiogram 5 years after the first episode (0:30); Transthoracic‐Echocardiogram and Coronary Angiography at admission for recurrent FM (0:40); Transthoracic‐Echocardiogram at discharge (1:00).
Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33225579 | 19,625,863 | 2021-02 |
What was the outcome of reaction 'Thyroid disorder'? | Recurrent autoimmune myocarditis in a young woman during the coronavirus disease 2019 pandemic.
We report a unique case of a young woman with recurrent immune-mediated (virus-negative) lymphocytic fulminant myocarditis during the coronavirus disease 2019 pandemic. At the first endomyocardial biopsy (EMB)-proven episode, she had concomitant pneumonia, and a temporary biventricular assist device implant was followed by complete and long-lasting cardiac recovery. Five years later, she was re-admitted for relapsing cardiogenic shock with a recent history of pneumonia. She was treated with extracorporeal life support with apical venting for left ventricular unloading, and full recovery was achieved. Despite negative seriate nasopharyngeal swabs and EMB during hospitalization, an antibody positivity for severe acute respiratory syndrome coronavirus 2 was discovered after 4 weeks from discharge. This is the first report of an EMB-proven, immune-mediated (virus-negative) recurrence of fulminant myocarditis. We hypothesize that in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune-mediated hyper-response.
Introduction
Fulminant myocarditis (FM) is characterized by sudden onset with haemodynamic compromise requiring immediate inotropic therapy and/or mechanical circulatory support (MCS). 1 , 2 , 3 In FM, endomyocardial biopsy (EMB) is mandatory to achieve certainty in diagnosis and guide aetiology‐directed therapy. 2
Case report
In February 2015, a 40‐year‐old female and mother of two young children presented to the emergency department (ED) complaining of fatigue and chest pain without any relevant clinical history. She had no family history of cardiomyopathy or autoimmune disease. Computed tomography (CT) scan ruled out pulmonary embolism but showed right lung pneumonia. Severe left ventricular (LV) systolic dysfunction [LV ejection fraction (LVEF) < 20%] and unobstructed coronary arteries were detected ( Video S1 , 0:05). Despite inotropic support, the patient needed percutaneous veno‐arterial extracorporeal membrane oxygenation (V‐A ECMO) support. After 48 h with no clinical improvement, the patient was referred to our centre. Through a left mini‐thoracotomy in the fifth intercostal space, the cardiac apex was approached for inflow LV assist device (LVAD) implantation, and a myocardial sample was taken for histological analysis. With the use of a right mini‐thoracotomy in the second intercostal space, a vascular prosthesis was anastomosed to the aorta as outflow line. A right ventricular assist device (RVAD) was implanted using the left femoral vein and the pulmonary artery through a left mini‐thoracotomy in the second intercostal space. A diagnosis of virus‐negative lymphocytic myocarditis was made on the basis of EMB (Figure 1A and 1B ). Serum tested weakly positive for anti‐heart and anti‐intercalated disk autoantibodies. Although the diagnosis consisted of a lymphocytic immune‐mediated (virus‐negative) myocarditis with severe systolic dysfunction, the patient was not put on immunosuppression because of pneumonia. She was progressively weaned from RVAD, which was removed after 6 days. Twenty days later, the LVAD was also removed, as a complete LV recovery was achieved. The patient's stay in the intensive care unit (ICU) was prolonged (37 days) owing to nosocomial pneumonia, acute renal failure needing 14 days of continuous veno‐venous haemodialysis, positive blood cultures for Candida utilis and Enterococcus faecium, and presence of Enterovirus on sputum. LVEF was 50% at discharge (102 days). After the first hospitalization, the patient developed an amiodarone‐related thyroid disease and chronic kidney disease for which she was followed up by the respective specialists. She was put on beta‐blocker therapy with carvedilol and aldosterone antagonist. Her newly developed Stage IV chronic kidney disease with a glomerular filtration rate between 15 and 20 mL/min was treated with additional sodium therapy for persistent hyponatremia. Three years later, after being hospitalized owing to severe hyponatremia, aldosterone antagonist administration was suspended. For the subsequent 5 years, the patient was asymptomatic and was followed up with echocardiograms ( Video S1 , 0:15), ECGs, and blood and troponin tests every 6 months.
Figure 1 Pathological findings in endomyocardial biopsy (EMB) at first episode. (A) EMB specimen showing extensive myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
In January 2020, the patient presented several times to the ED complaining of atypical chest pain and fever. ECG was unchanged, and troponin values were repeatedly normal; the echocardiogram also remained consistent ( Video S1 , 0:30). In March, she was re‐admitted to secondary care ED for dyspnoea and palpitations. ECG showed diffuse ST elevation with tombstone morphology; troponin was also markedly increased (peak TnI 83 000 ng/L, normal range 0–34 ng/L) (Figure 2A ). Because she presented during the coronavirus disease 2019 (COVID‐19) outbreak, she underwent a nasopharyngeal swab test for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which resulted negative. A bedside echocardiogram showed severe LV dysfunction with healthy coronary arteries ( Video S1 , 0:40). She was then transferred to our institution. On arrival, she developed haemodynamic and electrical instability consisting of an arrhythmic storm and cardiac arrest, requiring emergent femoral–femoral V‐A ECMO. One hour later, following severe haemodynamic instability, we decided to unload the LV by placing an apical venting through the previous left mini‐thoracotomy in the fifth intercostal space; an EMB was again performed at the LV apex. A 4 L/min support was commenced; better organ perfusion was evidenced by lactate reduction and pH improvement. Complex incessant arrhythmias persisted despite i.v. amiodarone, lidocaine, and esmolol administration. The EMB showed a virus‐negative lymphocytic myocarditis (Figure 3A and 3B ). Immunosuppressive therapy with steroids (methylprednisolone, 1 g i.v. bolus OD for the first 3 days, then 100 mg i.v. OD for the first week followed by progressive tapering in the subsequent days) was then immediately started; azathioprine (50 mg per os b.i.d.) was also added. A progressive normalization of ECG and biventricular contractility was observed (Figure 2B ). In the following days, there was a rapid recovery of cardiac function with a decreasing need for mechanical support. VA‐ECMO was removed on the ninth post‐operative day. She was transferred from the ICU on the 13th post‐operative day. Echocardiography at discharge showed mild LV dysfunction (LVEF 48%) ( Video S1 , 1:00). She was discharged home on Day 32, with a maintenance immunosuppressive therapy of oral methylprednisolone and azathioprine. Methylprednisolone was then tapered the following days with a weekly 25% reduction and a target of chronic 5 mg per day. Additionally, she is currently on alternating doses of azathioprine (100 mg per os 1 day and 150 mg the next day). Four weeks after discharge, once the test was introduced in Italy, an immunological assay for SARS‐CoV‐2 IgM and IgG was performed showing a weak positivity for specific antibodies while immunosuppressed.
Figure 2 (A) ECG at hospital admission showing a wide QRS complex. (B) ECG at discharge showing a restoration of the sinus rhythm; QRS waves narrowing with diffuse negative T waves; low voltages on all the precordial leads.
Figure 3 Pathological findings in endomyocardial biopsy (EMB) at recurrent fulminant myocarditis (FM) episode. (A) EMB specimen showing persistent myocardial inflammation associated with diffuse myocytes necrosis [hematoxylin and eosin (H&E); scale bar 200 μm]. (B) Strong positivity of immunohistochemistry for T‐lymphocytes (immunostaining anti‐CD3; scale bar 200 μm).
Discussion
This is the first report to show that lymphocytic virus‐negative FM relapses can be observed in the same patient with a similar presentation severity. Regardless of the MCS used, prompt LV unloading is critical for myocardial recovery; in addition, timely integration of MCS with tailored EMB‐guided immunosuppression was of critical importance in the treatment of our patient. Outcome of lymphocytic FM compared with non‐fulminant disease is controversial, reported as excellent 1 or bad. 2 So far, it is unclear whether the fulminant modality has independent negative prognostic value per se regardless of other known negative predictors such as the histology, giant cell vs. lymphocytic, and the degree of biventricular dysfunction. 2
FM is rare, and fulminant episodes of recurrences have already been reported in literature. 4 , 5 On the basis of serological tests, the aetiology of recurrent myocarditis in cases discussed by Matsue and Yoshimizu et al. is to be considered viral related, missing any EMB in both. In our case, immunohistochemical results of EMBs performed during the acute phase pointed to lymphocytic myocarditis. All serological and molecular tests on the samples obtained were negative for viruses, hence our definition of virus‐negative immune‐mediated lymphocytic myocarditis.
Although this is the first report of recurrent immune‐mediated lymphocytic FM with a fulminant relapse, our specific case keeps in line with the relapsing–remitting course of other autoimmune diseases. 2 In the first episode of FM for our patient, immunosuppression was withheld because of concomitant pneumonia and, after pneumonia resolution, because of the sustained recovery of ventricular function. The long‐lasting asymptomatic state of the patient with preserved biventricular function in the following 5 years confirmed that the first episode was indeed cured. During the strict echocardiographic follow‐up in the time preceding the recurrence, no clinical or instrumental evidence ever suggested the presence of a subclinical myocarditis, justifying the absence of further invasive examinations. The second episode highlights the importance of a timely combined surgical and medical approach; initial high dose i.v. steroids were highly effective in suppressing a life‐threatening arrhythmic storm.
Another interesting feature of this case was the presence of pneumonia as a prodromal event in both FM episodes. We hypothesize that, in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune‐mediated hyper‐response. 2 The patient had a history of pneumonia in the first months of 2020 during the initial spread of the COVID‐19 pandemic in Northern Italy. In the absence of severe symptomatology and the still dormant SARS‐CoV‐2 outbreak, a CT scan was not performed; the patient was discharged home on antibiotic therapy with a community‐acquired pneumonia diagnosis after a chest X‐ray. Nasopharyngeal swabs tests performed during hospitalization were negative, as was EMB‐based analysis of viral activity. It cannot be excluded that an autoimmune inflammatory process was triggered by the pneumonia prodromal episode 2 months prior. Unfortunately, the late introduction (May 2020) of serological assays for SARS‐CoV‐2 in the Italian market delayed our ability to make fully informed decisions regarding the treatment of this patient, who was already undergoing a heavy immunosuppressive regimen with steroid and azathioprine as a relapse maintenance therapy. Regardless, pathology studies up to date have yet to specifically address the myocardium and the burden of myocarditis in COVID‐19 patients, which remain to be established. 6 , 7
Funding
Departmental Strategic Investment (SID) 2020, BIRD205838, University of Padua.
Supporting information
Video S1. Transthoracic‐Echocardiogram 3 days post BiVAD implantation (0:05); Transthoracic‐Echocardiogram at discharge (0:15); Transthoracic‐Echocardiogram 5 years after the first episode (0:30); Transthoracic‐Echocardiogram and Coronary Angiography at admission for recurrent FM (0:40); Transthoracic‐Echocardiogram at discharge (1:00).
Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33225579 | 19,625,863 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Novel 6-Month Treatment for Drug-Resistant Tuberculosis, United States.
The US Food and Drug Administration approved a 6-month regimen of pretomanid, bedaquiline, and linezolid for extensively drug-resistant or multidrug-intolerant tuberculosis after a trial in South Africa demonstrated 90% effectiveness 6 months posttreatment. We report on a patient who completed the regimen using a lower linezolid dose.
A woman from eastern Europe in her late 40s undergoing treatment for stage III cervical adenocarcinoma was found to have a right upper lobe pulmonary nodule. Pathology from tissue biopsy demonstrated necrotizing granulomas and numerous acid-fast bacilli (AFB); the sample was PCR positive for Mycobacterium tuberculosis. Adjuvant chemotherapy was held, and the patient was referred to the local public health department. The patient provided informed written consent for publication of her case study.
On evaluation, the patient was asymptomatic without physical findings and reported no previous diagnosis or treatment of tuberculosis (TB) disease or latent TB infection. Results of serologic testing for HIV and viral hepatitis B and C were negative. She had a mild chronic anemia and transient transaminitis during chemotherapy (peak alanine aminotransferase 215 IU/L; aspartate aminotransferase 185 IU/L). Three sputum samples were negative by AFB smear and culture; 1 was tested by PCR and was M. tuberculosis negative.
Treatment with rifampin, isoniazid, pyrazinamide, ethambutol and pyridoxine was initiated. Lung biopsy cultures grew M. tuberculosis, and GeneXpert MTB/RIF assay (Cepheid, https://www.cepheid.com) detected an rpoB mutation indicating likely rifampin resistance. Rapid molecular detection of drug resistance and growth-based drug susceptibility testing performed by the Centers for Disease Control and Prevention (CDC) and Florida Bureau of Public Health Laboratories yielded concordant results. We detected resistance to isoniazid, rifampin, the fluoroquinolones (levofloxacin and moxifloxacin), and an injectable (kanamycin), confirming a diagnosis of extensively drug-resistant TB (XDR TB). Resistance was also detected for pyrazinamide but not for ethambutol, bedaquiline, or linezolid. The patient and her medical providers, in consultation with a CDC-funded TB Center of Excellence (COE, https://www.cdc.gov/tb/education/tb_coe), determined that her best treatment option was a 6-month all-oral regimen of bedaquiline, pretomanid, and linezolid (BPaL).
BPaL was approved by the US Food and Drug Administration (FDA) on August 14, 2019, based in part on results from the Nix-TB trial in South Africa, which included patients with XDR TB or multidrug-resistant (MDR) TB who failed or were intolerant of prior therapy (1). Pretomanid, the novel agent in the regimen, is a nitroimidazooxazine that blocks cell-wall production in actively replicating MTB organisms and acts as a respiratory poison and protein synthesis inhibitor to kill nonreplicating persister organisms (2). Bedaquiline is a diarylquinoline that inhibits mycobacterial adenosine triphosphate synthase in replicating and persister organisms, and linezolid is an oxazolidinone that also inhibits protein synthesis (3,4). The combined activity of BPaL enables cure in a far shorter period compared with currently recommended 18- to 24-month MDR TB regimens (5). In the Nix-TB trial, BPaL produced favorable outcomes in 98/109 (90%) patients at 6 months posttreatment (1); in addition, little preexisting resistance to bedaquiline, pretomanid, or linezolid has been reported (4,6).
Because pretomanid was not yet commercially available in the United States, the TB Alliance required an FDA-approved single-patient investigational new drug application and provided 6 months of pretomanid acquired internationally. A bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol was initiated for 2 weeks, then was narrowed to BPaL when pretomanid arrived.
For this patient, we initiated linezolid at 600 mg/d, given the toxicity of the Nix-TB dose of 1,200 mg/d, the patient’s paucibacillary disease, and TB COE’s experience with linezolid dosing (1,4,7,8). Therapeutic drug monitoring performed at the University of Florida Infectious Diseases Pharmacokinetic Laboratory (https://idpl.pharmacy.ufl.edu) was used to maintain a linezolid peak of 12–26 µg/mL and trough <2 µg/mL to reduce drug-induced toxicity (4,9).
The patient received outpatient BPaL treatment 7 days a week by directly observed therapy. We assessed liver, renal, hematologic, and neurologic function plus QTc intervals at baseline and every 2–4 weeks during treatment (Table 1). A few weeks into therapy, the patient’s linezolid level 18 hours postdose was measured at 7.62 µg/mL (serum trough level at 24 hours was likely lower but was still higher than expected) (Table 2). To reduce the trough while maintaining a peak serum level 4–16 times over her M. tuberculosis isolate’s linezolid MIC of 0.12 μg/mL, we extended the linezolid dosing interval to 600 mg every Monday, Wednesday, and Friday. A subsequent linezolid trough at 48 hours was calculated at <2 µg/mL. The patient completed 182 doses of BPaL over 26 weeks without treatment interruptions. Other than mild nausea that responded to pantoprazole, she had no adverse events or notable changes in laboratory values or electrocardiographs. Nine months after completion, the patient remained well; the state health department expects to closely monitor her for recurrent TB for 24 months after BPaL completion.
Table 1 Molecular susceptibility sequencing results and therapeutic drug monitoring data from treatment of XDR TB, Florida, USA*
Drug (dose) Sequencing result Date drug level drawn Trough, µg/mL 2h postdose level, µg/mL 6h postdose level, µg/mL Typical peak serum concentration, µg/mL
Bedaquiline (200 mg MWF) No atpE (ORF) mutation detected; no Rv0678/mmpR (ORF) mutation detected 2019 Nov 13 0.51 (42.25 h postdose) 1.40 1.42 1.2–1.8
(5–6 h postdose, maintenance phase)
N-monodesmethyl bedaquiline (metabolite) NT 2019 Nov 13 0.22 (42.25 h postdose) 0.24 0.27 NT
Pretomanid (200 mg/d) NT 2019 Nov 13 2.07 (18.25 h postdose) 3.43 2.98 2.3–4.3
(5–6 h postdose, at steady state)
Linezolid (600 mg/d) No rplC (ORF aa 84–217) mutation detected; no rrl (nt 2191–2929) mutation detected 2019 Nov 13 7.62 (18.25 h postdose) 24.15 17.88 12–26
Linezolid (600 mg MWF) NT 2020 Mar 12 <2.00† 19.04 13.6 12–26
*MWF, Monday/Wednesday/Friday; NT, not tested; ORF, open reading frame; XDR, extensively drug-resistant tuberculosis.
†Trough sample was not collected; based on the apparent elimination half-life, the linezolid concentration at 48 h was calculated to be <2 µg/mL, a value associated with minimal toxicity.
Table 2 Laboratory, electrocardiographic and clinical monitoring data for patient treated for XDR TB, United States*
Date AST, IU/L ALT, IU/L ALP, IU/L Creatinine, mg/dL Magnesium, mg/dL Hgb, g/dL Leukocyte, × 109/L Plt, × 109/L QTc, msec Notes
Initial treatment with rifampin, isoniazid, pyrazinamide, and ethambutol
2019 Aug 2 67 86 221 0.66 NT 10.4 3.97 272 NT None
Bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol
2019 Oct 3 53 62 121 0.64 1.9 12.7 5.4 278 402 None
2019 Oct 15 73 70 147 NT NT 12.6 5.3 243 NT None
BPaL regimen
2019 Oct 21 57 71 135 0.94 1.9 12.9 3.9 257 413 None
2019 Nov 11 40 53 113 1.01 1.9 12.3 4.9 237 426 Pantoprazole started for brief nausea
2019 Dec 2 52 63 118 0.77 1.9 10.7 4.3 289 421 None
2019 Dec 16 NT NT NT NT NT 11.2 4.7 267 NT None
2020 Jan 6 58 74 107 0.80 2.0 12.5 5.1 271 422 None
2020 Feb 3 36 39 89 0.76 1.9 12.2 4.2 258 429 None
*Initial treatment period was August 5–September 9, 2019; bridging regimen period October 7–21, 2019; BPaL treatment period October 21, 2019–April 21, 2020. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BPaL, bedaquiline, pretomanid, and linezolid; Hgb, hemoglobin; leukocyte, leukocyte count; NT, not tested; Plt, platelet; QTc, corrected QT interval.
The patient, physicians, and public health staff involved reported high satisfaction with BPaL. Providers and TB programs in the United States considering this regimen for TB patients can seek guidance from CDC Division of Tuberculosis Elimination or their TB COE. Current trials using BPaL, such as ZeNix (https://www.tballiance.org/portfolio/trial/11883), are evaluating lower doses and shorter duration of linezolid compared with those of the Nix-TB trial. The 6-month, all oral, highly effective BPaL regimen is a notable advancement toward reducing global TB deaths (10).
Dr. Haley is a medical consultant for the Southeast National TB Center and an adjunct clinical professor in the Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida.
Suggested citation for this article: Haley CA, Macias P, Jasuja S, Jones BA, Rowlinson M-C, Jaimon R, et al. Novel 6-month treatment for drug-resistant tuberculosis, United States. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203766 | MOXIFLOXACIN | DrugsGivenReaction | CC BY | 33227229 | 18,924,181 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Novel 6-Month Treatment for Drug-Resistant Tuberculosis, United States.
The US Food and Drug Administration approved a 6-month regimen of pretomanid, bedaquiline, and linezolid for extensively drug-resistant or multidrug-intolerant tuberculosis after a trial in South Africa demonstrated 90% effectiveness 6 months posttreatment. We report on a patient who completed the regimen using a lower linezolid dose.
A woman from eastern Europe in her late 40s undergoing treatment for stage III cervical adenocarcinoma was found to have a right upper lobe pulmonary nodule. Pathology from tissue biopsy demonstrated necrotizing granulomas and numerous acid-fast bacilli (AFB); the sample was PCR positive for Mycobacterium tuberculosis. Adjuvant chemotherapy was held, and the patient was referred to the local public health department. The patient provided informed written consent for publication of her case study.
On evaluation, the patient was asymptomatic without physical findings and reported no previous diagnosis or treatment of tuberculosis (TB) disease or latent TB infection. Results of serologic testing for HIV and viral hepatitis B and C were negative. She had a mild chronic anemia and transient transaminitis during chemotherapy (peak alanine aminotransferase 215 IU/L; aspartate aminotransferase 185 IU/L). Three sputum samples were negative by AFB smear and culture; 1 was tested by PCR and was M. tuberculosis negative.
Treatment with rifampin, isoniazid, pyrazinamide, ethambutol and pyridoxine was initiated. Lung biopsy cultures grew M. tuberculosis, and GeneXpert MTB/RIF assay (Cepheid, https://www.cepheid.com) detected an rpoB mutation indicating likely rifampin resistance. Rapid molecular detection of drug resistance and growth-based drug susceptibility testing performed by the Centers for Disease Control and Prevention (CDC) and Florida Bureau of Public Health Laboratories yielded concordant results. We detected resistance to isoniazid, rifampin, the fluoroquinolones (levofloxacin and moxifloxacin), and an injectable (kanamycin), confirming a diagnosis of extensively drug-resistant TB (XDR TB). Resistance was also detected for pyrazinamide but not for ethambutol, bedaquiline, or linezolid. The patient and her medical providers, in consultation with a CDC-funded TB Center of Excellence (COE, https://www.cdc.gov/tb/education/tb_coe), determined that her best treatment option was a 6-month all-oral regimen of bedaquiline, pretomanid, and linezolid (BPaL).
BPaL was approved by the US Food and Drug Administration (FDA) on August 14, 2019, based in part on results from the Nix-TB trial in South Africa, which included patients with XDR TB or multidrug-resistant (MDR) TB who failed or were intolerant of prior therapy (1). Pretomanid, the novel agent in the regimen, is a nitroimidazooxazine that blocks cell-wall production in actively replicating MTB organisms and acts as a respiratory poison and protein synthesis inhibitor to kill nonreplicating persister organisms (2). Bedaquiline is a diarylquinoline that inhibits mycobacterial adenosine triphosphate synthase in replicating and persister organisms, and linezolid is an oxazolidinone that also inhibits protein synthesis (3,4). The combined activity of BPaL enables cure in a far shorter period compared with currently recommended 18- to 24-month MDR TB regimens (5). In the Nix-TB trial, BPaL produced favorable outcomes in 98/109 (90%) patients at 6 months posttreatment (1); in addition, little preexisting resistance to bedaquiline, pretomanid, or linezolid has been reported (4,6).
Because pretomanid was not yet commercially available in the United States, the TB Alliance required an FDA-approved single-patient investigational new drug application and provided 6 months of pretomanid acquired internationally. A bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol was initiated for 2 weeks, then was narrowed to BPaL when pretomanid arrived.
For this patient, we initiated linezolid at 600 mg/d, given the toxicity of the Nix-TB dose of 1,200 mg/d, the patient’s paucibacillary disease, and TB COE’s experience with linezolid dosing (1,4,7,8). Therapeutic drug monitoring performed at the University of Florida Infectious Diseases Pharmacokinetic Laboratory (https://idpl.pharmacy.ufl.edu) was used to maintain a linezolid peak of 12–26 µg/mL and trough <2 µg/mL to reduce drug-induced toxicity (4,9).
The patient received outpatient BPaL treatment 7 days a week by directly observed therapy. We assessed liver, renal, hematologic, and neurologic function plus QTc intervals at baseline and every 2–4 weeks during treatment (Table 1). A few weeks into therapy, the patient’s linezolid level 18 hours postdose was measured at 7.62 µg/mL (serum trough level at 24 hours was likely lower but was still higher than expected) (Table 2). To reduce the trough while maintaining a peak serum level 4–16 times over her M. tuberculosis isolate’s linezolid MIC of 0.12 μg/mL, we extended the linezolid dosing interval to 600 mg every Monday, Wednesday, and Friday. A subsequent linezolid trough at 48 hours was calculated at <2 µg/mL. The patient completed 182 doses of BPaL over 26 weeks without treatment interruptions. Other than mild nausea that responded to pantoprazole, she had no adverse events or notable changes in laboratory values or electrocardiographs. Nine months after completion, the patient remained well; the state health department expects to closely monitor her for recurrent TB for 24 months after BPaL completion.
Table 1 Molecular susceptibility sequencing results and therapeutic drug monitoring data from treatment of XDR TB, Florida, USA*
Drug (dose) Sequencing result Date drug level drawn Trough, µg/mL 2h postdose level, µg/mL 6h postdose level, µg/mL Typical peak serum concentration, µg/mL
Bedaquiline (200 mg MWF) No atpE (ORF) mutation detected; no Rv0678/mmpR (ORF) mutation detected 2019 Nov 13 0.51 (42.25 h postdose) 1.40 1.42 1.2–1.8
(5–6 h postdose, maintenance phase)
N-monodesmethyl bedaquiline (metabolite) NT 2019 Nov 13 0.22 (42.25 h postdose) 0.24 0.27 NT
Pretomanid (200 mg/d) NT 2019 Nov 13 2.07 (18.25 h postdose) 3.43 2.98 2.3–4.3
(5–6 h postdose, at steady state)
Linezolid (600 mg/d) No rplC (ORF aa 84–217) mutation detected; no rrl (nt 2191–2929) mutation detected 2019 Nov 13 7.62 (18.25 h postdose) 24.15 17.88 12–26
Linezolid (600 mg MWF) NT 2020 Mar 12 <2.00† 19.04 13.6 12–26
*MWF, Monday/Wednesday/Friday; NT, not tested; ORF, open reading frame; XDR, extensively drug-resistant tuberculosis.
†Trough sample was not collected; based on the apparent elimination half-life, the linezolid concentration at 48 h was calculated to be <2 µg/mL, a value associated with minimal toxicity.
Table 2 Laboratory, electrocardiographic and clinical monitoring data for patient treated for XDR TB, United States*
Date AST, IU/L ALT, IU/L ALP, IU/L Creatinine, mg/dL Magnesium, mg/dL Hgb, g/dL Leukocyte, × 109/L Plt, × 109/L QTc, msec Notes
Initial treatment with rifampin, isoniazid, pyrazinamide, and ethambutol
2019 Aug 2 67 86 221 0.66 NT 10.4 3.97 272 NT None
Bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol
2019 Oct 3 53 62 121 0.64 1.9 12.7 5.4 278 402 None
2019 Oct 15 73 70 147 NT NT 12.6 5.3 243 NT None
BPaL regimen
2019 Oct 21 57 71 135 0.94 1.9 12.9 3.9 257 413 None
2019 Nov 11 40 53 113 1.01 1.9 12.3 4.9 237 426 Pantoprazole started for brief nausea
2019 Dec 2 52 63 118 0.77 1.9 10.7 4.3 289 421 None
2019 Dec 16 NT NT NT NT NT 11.2 4.7 267 NT None
2020 Jan 6 58 74 107 0.80 2.0 12.5 5.1 271 422 None
2020 Feb 3 36 39 89 0.76 1.9 12.2 4.2 258 429 None
*Initial treatment period was August 5–September 9, 2019; bridging regimen period October 7–21, 2019; BPaL treatment period October 21, 2019–April 21, 2020. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BPaL, bedaquiline, pretomanid, and linezolid; Hgb, hemoglobin; leukocyte, leukocyte count; NT, not tested; Plt, platelet; QTc, corrected QT interval.
The patient, physicians, and public health staff involved reported high satisfaction with BPaL. Providers and TB programs in the United States considering this regimen for TB patients can seek guidance from CDC Division of Tuberculosis Elimination or their TB COE. Current trials using BPaL, such as ZeNix (https://www.tballiance.org/portfolio/trial/11883), are evaluating lower doses and shorter duration of linezolid compared with those of the Nix-TB trial. The 6-month, all oral, highly effective BPaL regimen is a notable advancement toward reducing global TB deaths (10).
Dr. Haley is a medical consultant for the Southeast National TB Center and an adjunct clinical professor in the Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida.
Suggested citation for this article: Haley CA, Macias P, Jasuja S, Jones BA, Rowlinson M-C, Jaimon R, et al. Novel 6-month treatment for drug-resistant tuberculosis, United States. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203766 | BEDAQUILINE FUMARATE, ISONIAZID, LINEZOLID, PRETOMANID, RIFAMPIN | DrugsGivenReaction | CC BY | 33227229 | 18,593,672 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Novel 6-Month Treatment for Drug-Resistant Tuberculosis, United States.
The US Food and Drug Administration approved a 6-month regimen of pretomanid, bedaquiline, and linezolid for extensively drug-resistant or multidrug-intolerant tuberculosis after a trial in South Africa demonstrated 90% effectiveness 6 months posttreatment. We report on a patient who completed the regimen using a lower linezolid dose.
A woman from eastern Europe in her late 40s undergoing treatment for stage III cervical adenocarcinoma was found to have a right upper lobe pulmonary nodule. Pathology from tissue biopsy demonstrated necrotizing granulomas and numerous acid-fast bacilli (AFB); the sample was PCR positive for Mycobacterium tuberculosis. Adjuvant chemotherapy was held, and the patient was referred to the local public health department. The patient provided informed written consent for publication of her case study.
On evaluation, the patient was asymptomatic without physical findings and reported no previous diagnosis or treatment of tuberculosis (TB) disease or latent TB infection. Results of serologic testing for HIV and viral hepatitis B and C were negative. She had a mild chronic anemia and transient transaminitis during chemotherapy (peak alanine aminotransferase 215 IU/L; aspartate aminotransferase 185 IU/L). Three sputum samples were negative by AFB smear and culture; 1 was tested by PCR and was M. tuberculosis negative.
Treatment with rifampin, isoniazid, pyrazinamide, ethambutol and pyridoxine was initiated. Lung biopsy cultures grew M. tuberculosis, and GeneXpert MTB/RIF assay (Cepheid, https://www.cepheid.com) detected an rpoB mutation indicating likely rifampin resistance. Rapid molecular detection of drug resistance and growth-based drug susceptibility testing performed by the Centers for Disease Control and Prevention (CDC) and Florida Bureau of Public Health Laboratories yielded concordant results. We detected resistance to isoniazid, rifampin, the fluoroquinolones (levofloxacin and moxifloxacin), and an injectable (kanamycin), confirming a diagnosis of extensively drug-resistant TB (XDR TB). Resistance was also detected for pyrazinamide but not for ethambutol, bedaquiline, or linezolid. The patient and her medical providers, in consultation with a CDC-funded TB Center of Excellence (COE, https://www.cdc.gov/tb/education/tb_coe), determined that her best treatment option was a 6-month all-oral regimen of bedaquiline, pretomanid, and linezolid (BPaL).
BPaL was approved by the US Food and Drug Administration (FDA) on August 14, 2019, based in part on results from the Nix-TB trial in South Africa, which included patients with XDR TB or multidrug-resistant (MDR) TB who failed or were intolerant of prior therapy (1). Pretomanid, the novel agent in the regimen, is a nitroimidazooxazine that blocks cell-wall production in actively replicating MTB organisms and acts as a respiratory poison and protein synthesis inhibitor to kill nonreplicating persister organisms (2). Bedaquiline is a diarylquinoline that inhibits mycobacterial adenosine triphosphate synthase in replicating and persister organisms, and linezolid is an oxazolidinone that also inhibits protein synthesis (3,4). The combined activity of BPaL enables cure in a far shorter period compared with currently recommended 18- to 24-month MDR TB regimens (5). In the Nix-TB trial, BPaL produced favorable outcomes in 98/109 (90%) patients at 6 months posttreatment (1); in addition, little preexisting resistance to bedaquiline, pretomanid, or linezolid has been reported (4,6).
Because pretomanid was not yet commercially available in the United States, the TB Alliance required an FDA-approved single-patient investigational new drug application and provided 6 months of pretomanid acquired internationally. A bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol was initiated for 2 weeks, then was narrowed to BPaL when pretomanid arrived.
For this patient, we initiated linezolid at 600 mg/d, given the toxicity of the Nix-TB dose of 1,200 mg/d, the patient’s paucibacillary disease, and TB COE’s experience with linezolid dosing (1,4,7,8). Therapeutic drug monitoring performed at the University of Florida Infectious Diseases Pharmacokinetic Laboratory (https://idpl.pharmacy.ufl.edu) was used to maintain a linezolid peak of 12–26 µg/mL and trough <2 µg/mL to reduce drug-induced toxicity (4,9).
The patient received outpatient BPaL treatment 7 days a week by directly observed therapy. We assessed liver, renal, hematologic, and neurologic function plus QTc intervals at baseline and every 2–4 weeks during treatment (Table 1). A few weeks into therapy, the patient’s linezolid level 18 hours postdose was measured at 7.62 µg/mL (serum trough level at 24 hours was likely lower but was still higher than expected) (Table 2). To reduce the trough while maintaining a peak serum level 4–16 times over her M. tuberculosis isolate’s linezolid MIC of 0.12 μg/mL, we extended the linezolid dosing interval to 600 mg every Monday, Wednesday, and Friday. A subsequent linezolid trough at 48 hours was calculated at <2 µg/mL. The patient completed 182 doses of BPaL over 26 weeks without treatment interruptions. Other than mild nausea that responded to pantoprazole, she had no adverse events or notable changes in laboratory values or electrocardiographs. Nine months after completion, the patient remained well; the state health department expects to closely monitor her for recurrent TB for 24 months after BPaL completion.
Table 1 Molecular susceptibility sequencing results and therapeutic drug monitoring data from treatment of XDR TB, Florida, USA*
Drug (dose) Sequencing result Date drug level drawn Trough, µg/mL 2h postdose level, µg/mL 6h postdose level, µg/mL Typical peak serum concentration, µg/mL
Bedaquiline (200 mg MWF) No atpE (ORF) mutation detected; no Rv0678/mmpR (ORF) mutation detected 2019 Nov 13 0.51 (42.25 h postdose) 1.40 1.42 1.2–1.8
(5–6 h postdose, maintenance phase)
N-monodesmethyl bedaquiline (metabolite) NT 2019 Nov 13 0.22 (42.25 h postdose) 0.24 0.27 NT
Pretomanid (200 mg/d) NT 2019 Nov 13 2.07 (18.25 h postdose) 3.43 2.98 2.3–4.3
(5–6 h postdose, at steady state)
Linezolid (600 mg/d) No rplC (ORF aa 84–217) mutation detected; no rrl (nt 2191–2929) mutation detected 2019 Nov 13 7.62 (18.25 h postdose) 24.15 17.88 12–26
Linezolid (600 mg MWF) NT 2020 Mar 12 <2.00† 19.04 13.6 12–26
*MWF, Monday/Wednesday/Friday; NT, not tested; ORF, open reading frame; XDR, extensively drug-resistant tuberculosis.
†Trough sample was not collected; based on the apparent elimination half-life, the linezolid concentration at 48 h was calculated to be <2 µg/mL, a value associated with minimal toxicity.
Table 2 Laboratory, electrocardiographic and clinical monitoring data for patient treated for XDR TB, United States*
Date AST, IU/L ALT, IU/L ALP, IU/L Creatinine, mg/dL Magnesium, mg/dL Hgb, g/dL Leukocyte, × 109/L Plt, × 109/L QTc, msec Notes
Initial treatment with rifampin, isoniazid, pyrazinamide, and ethambutol
2019 Aug 2 67 86 221 0.66 NT 10.4 3.97 272 NT None
Bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol
2019 Oct 3 53 62 121 0.64 1.9 12.7 5.4 278 402 None
2019 Oct 15 73 70 147 NT NT 12.6 5.3 243 NT None
BPaL regimen
2019 Oct 21 57 71 135 0.94 1.9 12.9 3.9 257 413 None
2019 Nov 11 40 53 113 1.01 1.9 12.3 4.9 237 426 Pantoprazole started for brief nausea
2019 Dec 2 52 63 118 0.77 1.9 10.7 4.3 289 421 None
2019 Dec 16 NT NT NT NT NT 11.2 4.7 267 NT None
2020 Jan 6 58 74 107 0.80 2.0 12.5 5.1 271 422 None
2020 Feb 3 36 39 89 0.76 1.9 12.2 4.2 258 429 None
*Initial treatment period was August 5–September 9, 2019; bridging regimen period October 7–21, 2019; BPaL treatment period October 21, 2019–April 21, 2020. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BPaL, bedaquiline, pretomanid, and linezolid; Hgb, hemoglobin; leukocyte, leukocyte count; NT, not tested; Plt, platelet; QTc, corrected QT interval.
The patient, physicians, and public health staff involved reported high satisfaction with BPaL. Providers and TB programs in the United States considering this regimen for TB patients can seek guidance from CDC Division of Tuberculosis Elimination or their TB COE. Current trials using BPaL, such as ZeNix (https://www.tballiance.org/portfolio/trial/11883), are evaluating lower doses and shorter duration of linezolid compared with those of the Nix-TB trial. The 6-month, all oral, highly effective BPaL regimen is a notable advancement toward reducing global TB deaths (10).
Dr. Haley is a medical consultant for the Southeast National TB Center and an adjunct clinical professor in the Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida.
Suggested citation for this article: Haley CA, Macias P, Jasuja S, Jones BA, Rowlinson M-C, Jaimon R, et al. Novel 6-month treatment for drug-resistant tuberculosis, United States. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203766 | MOXIFLOXACIN | DrugsGivenReaction | CC BY | 33227229 | 18,924,181 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Novel 6-Month Treatment for Drug-Resistant Tuberculosis, United States.
The US Food and Drug Administration approved a 6-month regimen of pretomanid, bedaquiline, and linezolid for extensively drug-resistant or multidrug-intolerant tuberculosis after a trial in South Africa demonstrated 90% effectiveness 6 months posttreatment. We report on a patient who completed the regimen using a lower linezolid dose.
A woman from eastern Europe in her late 40s undergoing treatment for stage III cervical adenocarcinoma was found to have a right upper lobe pulmonary nodule. Pathology from tissue biopsy demonstrated necrotizing granulomas and numerous acid-fast bacilli (AFB); the sample was PCR positive for Mycobacterium tuberculosis. Adjuvant chemotherapy was held, and the patient was referred to the local public health department. The patient provided informed written consent for publication of her case study.
On evaluation, the patient was asymptomatic without physical findings and reported no previous diagnosis or treatment of tuberculosis (TB) disease or latent TB infection. Results of serologic testing for HIV and viral hepatitis B and C were negative. She had a mild chronic anemia and transient transaminitis during chemotherapy (peak alanine aminotransferase 215 IU/L; aspartate aminotransferase 185 IU/L). Three sputum samples were negative by AFB smear and culture; 1 was tested by PCR and was M. tuberculosis negative.
Treatment with rifampin, isoniazid, pyrazinamide, ethambutol and pyridoxine was initiated. Lung biopsy cultures grew M. tuberculosis, and GeneXpert MTB/RIF assay (Cepheid, https://www.cepheid.com) detected an rpoB mutation indicating likely rifampin resistance. Rapid molecular detection of drug resistance and growth-based drug susceptibility testing performed by the Centers for Disease Control and Prevention (CDC) and Florida Bureau of Public Health Laboratories yielded concordant results. We detected resistance to isoniazid, rifampin, the fluoroquinolones (levofloxacin and moxifloxacin), and an injectable (kanamycin), confirming a diagnosis of extensively drug-resistant TB (XDR TB). Resistance was also detected for pyrazinamide but not for ethambutol, bedaquiline, or linezolid. The patient and her medical providers, in consultation with a CDC-funded TB Center of Excellence (COE, https://www.cdc.gov/tb/education/tb_coe), determined that her best treatment option was a 6-month all-oral regimen of bedaquiline, pretomanid, and linezolid (BPaL).
BPaL was approved by the US Food and Drug Administration (FDA) on August 14, 2019, based in part on results from the Nix-TB trial in South Africa, which included patients with XDR TB or multidrug-resistant (MDR) TB who failed or were intolerant of prior therapy (1). Pretomanid, the novel agent in the regimen, is a nitroimidazooxazine that blocks cell-wall production in actively replicating MTB organisms and acts as a respiratory poison and protein synthesis inhibitor to kill nonreplicating persister organisms (2). Bedaquiline is a diarylquinoline that inhibits mycobacterial adenosine triphosphate synthase in replicating and persister organisms, and linezolid is an oxazolidinone that also inhibits protein synthesis (3,4). The combined activity of BPaL enables cure in a far shorter period compared with currently recommended 18- to 24-month MDR TB regimens (5). In the Nix-TB trial, BPaL produced favorable outcomes in 98/109 (90%) patients at 6 months posttreatment (1); in addition, little preexisting resistance to bedaquiline, pretomanid, or linezolid has been reported (4,6).
Because pretomanid was not yet commercially available in the United States, the TB Alliance required an FDA-approved single-patient investigational new drug application and provided 6 months of pretomanid acquired internationally. A bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol was initiated for 2 weeks, then was narrowed to BPaL when pretomanid arrived.
For this patient, we initiated linezolid at 600 mg/d, given the toxicity of the Nix-TB dose of 1,200 mg/d, the patient’s paucibacillary disease, and TB COE’s experience with linezolid dosing (1,4,7,8). Therapeutic drug monitoring performed at the University of Florida Infectious Diseases Pharmacokinetic Laboratory (https://idpl.pharmacy.ufl.edu) was used to maintain a linezolid peak of 12–26 µg/mL and trough <2 µg/mL to reduce drug-induced toxicity (4,9).
The patient received outpatient BPaL treatment 7 days a week by directly observed therapy. We assessed liver, renal, hematologic, and neurologic function plus QTc intervals at baseline and every 2–4 weeks during treatment (Table 1). A few weeks into therapy, the patient’s linezolid level 18 hours postdose was measured at 7.62 µg/mL (serum trough level at 24 hours was likely lower but was still higher than expected) (Table 2). To reduce the trough while maintaining a peak serum level 4–16 times over her M. tuberculosis isolate’s linezolid MIC of 0.12 μg/mL, we extended the linezolid dosing interval to 600 mg every Monday, Wednesday, and Friday. A subsequent linezolid trough at 48 hours was calculated at <2 µg/mL. The patient completed 182 doses of BPaL over 26 weeks without treatment interruptions. Other than mild nausea that responded to pantoprazole, she had no adverse events or notable changes in laboratory values or electrocardiographs. Nine months after completion, the patient remained well; the state health department expects to closely monitor her for recurrent TB for 24 months after BPaL completion.
Table 1 Molecular susceptibility sequencing results and therapeutic drug monitoring data from treatment of XDR TB, Florida, USA*
Drug (dose) Sequencing result Date drug level drawn Trough, µg/mL 2h postdose level, µg/mL 6h postdose level, µg/mL Typical peak serum concentration, µg/mL
Bedaquiline (200 mg MWF) No atpE (ORF) mutation detected; no Rv0678/mmpR (ORF) mutation detected 2019 Nov 13 0.51 (42.25 h postdose) 1.40 1.42 1.2–1.8
(5–6 h postdose, maintenance phase)
N-monodesmethyl bedaquiline (metabolite) NT 2019 Nov 13 0.22 (42.25 h postdose) 0.24 0.27 NT
Pretomanid (200 mg/d) NT 2019 Nov 13 2.07 (18.25 h postdose) 3.43 2.98 2.3–4.3
(5–6 h postdose, at steady state)
Linezolid (600 mg/d) No rplC (ORF aa 84–217) mutation detected; no rrl (nt 2191–2929) mutation detected 2019 Nov 13 7.62 (18.25 h postdose) 24.15 17.88 12–26
Linezolid (600 mg MWF) NT 2020 Mar 12 <2.00† 19.04 13.6 12–26
*MWF, Monday/Wednesday/Friday; NT, not tested; ORF, open reading frame; XDR, extensively drug-resistant tuberculosis.
†Trough sample was not collected; based on the apparent elimination half-life, the linezolid concentration at 48 h was calculated to be <2 µg/mL, a value associated with minimal toxicity.
Table 2 Laboratory, electrocardiographic and clinical monitoring data for patient treated for XDR TB, United States*
Date AST, IU/L ALT, IU/L ALP, IU/L Creatinine, mg/dL Magnesium, mg/dL Hgb, g/dL Leukocyte, × 109/L Plt, × 109/L QTc, msec Notes
Initial treatment with rifampin, isoniazid, pyrazinamide, and ethambutol
2019 Aug 2 67 86 221 0.66 NT 10.4 3.97 272 NT None
Bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol
2019 Oct 3 53 62 121 0.64 1.9 12.7 5.4 278 402 None
2019 Oct 15 73 70 147 NT NT 12.6 5.3 243 NT None
BPaL regimen
2019 Oct 21 57 71 135 0.94 1.9 12.9 3.9 257 413 None
2019 Nov 11 40 53 113 1.01 1.9 12.3 4.9 237 426 Pantoprazole started for brief nausea
2019 Dec 2 52 63 118 0.77 1.9 10.7 4.3 289 421 None
2019 Dec 16 NT NT NT NT NT 11.2 4.7 267 NT None
2020 Jan 6 58 74 107 0.80 2.0 12.5 5.1 271 422 None
2020 Feb 3 36 39 89 0.76 1.9 12.2 4.2 258 429 None
*Initial treatment period was August 5–September 9, 2019; bridging regimen period October 7–21, 2019; BPaL treatment period October 21, 2019–April 21, 2020. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BPaL, bedaquiline, pretomanid, and linezolid; Hgb, hemoglobin; leukocyte, leukocyte count; NT, not tested; Plt, platelet; QTc, corrected QT interval.
The patient, physicians, and public health staff involved reported high satisfaction with BPaL. Providers and TB programs in the United States considering this regimen for TB patients can seek guidance from CDC Division of Tuberculosis Elimination or their TB COE. Current trials using BPaL, such as ZeNix (https://www.tballiance.org/portfolio/trial/11883), are evaluating lower doses and shorter duration of linezolid compared with those of the Nix-TB trial. The 6-month, all oral, highly effective BPaL regimen is a notable advancement toward reducing global TB deaths (10).
Dr. Haley is a medical consultant for the Southeast National TB Center and an adjunct clinical professor in the Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida.
Suggested citation for this article: Haley CA, Macias P, Jasuja S, Jones BA, Rowlinson M-C, Jaimon R, et al. Novel 6-month treatment for drug-resistant tuberculosis, United States. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203766 | MOXIFLOXACIN | DrugsGivenReaction | CC BY | 33227229 | 18,924,181 | 2021-01 |
What was the administration route of drug 'BEDAQUILINE FUMARATE'? | Novel 6-Month Treatment for Drug-Resistant Tuberculosis, United States.
The US Food and Drug Administration approved a 6-month regimen of pretomanid, bedaquiline, and linezolid for extensively drug-resistant or multidrug-intolerant tuberculosis after a trial in South Africa demonstrated 90% effectiveness 6 months posttreatment. We report on a patient who completed the regimen using a lower linezolid dose.
A woman from eastern Europe in her late 40s undergoing treatment for stage III cervical adenocarcinoma was found to have a right upper lobe pulmonary nodule. Pathology from tissue biopsy demonstrated necrotizing granulomas and numerous acid-fast bacilli (AFB); the sample was PCR positive for Mycobacterium tuberculosis. Adjuvant chemotherapy was held, and the patient was referred to the local public health department. The patient provided informed written consent for publication of her case study.
On evaluation, the patient was asymptomatic without physical findings and reported no previous diagnosis or treatment of tuberculosis (TB) disease or latent TB infection. Results of serologic testing for HIV and viral hepatitis B and C were negative. She had a mild chronic anemia and transient transaminitis during chemotherapy (peak alanine aminotransferase 215 IU/L; aspartate aminotransferase 185 IU/L). Three sputum samples were negative by AFB smear and culture; 1 was tested by PCR and was M. tuberculosis negative.
Treatment with rifampin, isoniazid, pyrazinamide, ethambutol and pyridoxine was initiated. Lung biopsy cultures grew M. tuberculosis, and GeneXpert MTB/RIF assay (Cepheid, https://www.cepheid.com) detected an rpoB mutation indicating likely rifampin resistance. Rapid molecular detection of drug resistance and growth-based drug susceptibility testing performed by the Centers for Disease Control and Prevention (CDC) and Florida Bureau of Public Health Laboratories yielded concordant results. We detected resistance to isoniazid, rifampin, the fluoroquinolones (levofloxacin and moxifloxacin), and an injectable (kanamycin), confirming a diagnosis of extensively drug-resistant TB (XDR TB). Resistance was also detected for pyrazinamide but not for ethambutol, bedaquiline, or linezolid. The patient and her medical providers, in consultation with a CDC-funded TB Center of Excellence (COE, https://www.cdc.gov/tb/education/tb_coe), determined that her best treatment option was a 6-month all-oral regimen of bedaquiline, pretomanid, and linezolid (BPaL).
BPaL was approved by the US Food and Drug Administration (FDA) on August 14, 2019, based in part on results from the Nix-TB trial in South Africa, which included patients with XDR TB or multidrug-resistant (MDR) TB who failed or were intolerant of prior therapy (1). Pretomanid, the novel agent in the regimen, is a nitroimidazooxazine that blocks cell-wall production in actively replicating MTB organisms and acts as a respiratory poison and protein synthesis inhibitor to kill nonreplicating persister organisms (2). Bedaquiline is a diarylquinoline that inhibits mycobacterial adenosine triphosphate synthase in replicating and persister organisms, and linezolid is an oxazolidinone that also inhibits protein synthesis (3,4). The combined activity of BPaL enables cure in a far shorter period compared with currently recommended 18- to 24-month MDR TB regimens (5). In the Nix-TB trial, BPaL produced favorable outcomes in 98/109 (90%) patients at 6 months posttreatment (1); in addition, little preexisting resistance to bedaquiline, pretomanid, or linezolid has been reported (4,6).
Because pretomanid was not yet commercially available in the United States, the TB Alliance required an FDA-approved single-patient investigational new drug application and provided 6 months of pretomanid acquired internationally. A bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol was initiated for 2 weeks, then was narrowed to BPaL when pretomanid arrived.
For this patient, we initiated linezolid at 600 mg/d, given the toxicity of the Nix-TB dose of 1,200 mg/d, the patient’s paucibacillary disease, and TB COE’s experience with linezolid dosing (1,4,7,8). Therapeutic drug monitoring performed at the University of Florida Infectious Diseases Pharmacokinetic Laboratory (https://idpl.pharmacy.ufl.edu) was used to maintain a linezolid peak of 12–26 µg/mL and trough <2 µg/mL to reduce drug-induced toxicity (4,9).
The patient received outpatient BPaL treatment 7 days a week by directly observed therapy. We assessed liver, renal, hematologic, and neurologic function plus QTc intervals at baseline and every 2–4 weeks during treatment (Table 1). A few weeks into therapy, the patient’s linezolid level 18 hours postdose was measured at 7.62 µg/mL (serum trough level at 24 hours was likely lower but was still higher than expected) (Table 2). To reduce the trough while maintaining a peak serum level 4–16 times over her M. tuberculosis isolate’s linezolid MIC of 0.12 μg/mL, we extended the linezolid dosing interval to 600 mg every Monday, Wednesday, and Friday. A subsequent linezolid trough at 48 hours was calculated at <2 µg/mL. The patient completed 182 doses of BPaL over 26 weeks without treatment interruptions. Other than mild nausea that responded to pantoprazole, she had no adverse events or notable changes in laboratory values or electrocardiographs. Nine months after completion, the patient remained well; the state health department expects to closely monitor her for recurrent TB for 24 months after BPaL completion.
Table 1 Molecular susceptibility sequencing results and therapeutic drug monitoring data from treatment of XDR TB, Florida, USA*
Drug (dose) Sequencing result Date drug level drawn Trough, µg/mL 2h postdose level, µg/mL 6h postdose level, µg/mL Typical peak serum concentration, µg/mL
Bedaquiline (200 mg MWF) No atpE (ORF) mutation detected; no Rv0678/mmpR (ORF) mutation detected 2019 Nov 13 0.51 (42.25 h postdose) 1.40 1.42 1.2–1.8
(5–6 h postdose, maintenance phase)
N-monodesmethyl bedaquiline (metabolite) NT 2019 Nov 13 0.22 (42.25 h postdose) 0.24 0.27 NT
Pretomanid (200 mg/d) NT 2019 Nov 13 2.07 (18.25 h postdose) 3.43 2.98 2.3–4.3
(5–6 h postdose, at steady state)
Linezolid (600 mg/d) No rplC (ORF aa 84–217) mutation detected; no rrl (nt 2191–2929) mutation detected 2019 Nov 13 7.62 (18.25 h postdose) 24.15 17.88 12–26
Linezolid (600 mg MWF) NT 2020 Mar 12 <2.00† 19.04 13.6 12–26
*MWF, Monday/Wednesday/Friday; NT, not tested; ORF, open reading frame; XDR, extensively drug-resistant tuberculosis.
†Trough sample was not collected; based on the apparent elimination half-life, the linezolid concentration at 48 h was calculated to be <2 µg/mL, a value associated with minimal toxicity.
Table 2 Laboratory, electrocardiographic and clinical monitoring data for patient treated for XDR TB, United States*
Date AST, IU/L ALT, IU/L ALP, IU/L Creatinine, mg/dL Magnesium, mg/dL Hgb, g/dL Leukocyte, × 109/L Plt, × 109/L QTc, msec Notes
Initial treatment with rifampin, isoniazid, pyrazinamide, and ethambutol
2019 Aug 2 67 86 221 0.66 NT 10.4 3.97 272 NT None
Bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol
2019 Oct 3 53 62 121 0.64 1.9 12.7 5.4 278 402 None
2019 Oct 15 73 70 147 NT NT 12.6 5.3 243 NT None
BPaL regimen
2019 Oct 21 57 71 135 0.94 1.9 12.9 3.9 257 413 None
2019 Nov 11 40 53 113 1.01 1.9 12.3 4.9 237 426 Pantoprazole started for brief nausea
2019 Dec 2 52 63 118 0.77 1.9 10.7 4.3 289 421 None
2019 Dec 16 NT NT NT NT NT 11.2 4.7 267 NT None
2020 Jan 6 58 74 107 0.80 2.0 12.5 5.1 271 422 None
2020 Feb 3 36 39 89 0.76 1.9 12.2 4.2 258 429 None
*Initial treatment period was August 5–September 9, 2019; bridging regimen period October 7–21, 2019; BPaL treatment period October 21, 2019–April 21, 2020. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BPaL, bedaquiline, pretomanid, and linezolid; Hgb, hemoglobin; leukocyte, leukocyte count; NT, not tested; Plt, platelet; QTc, corrected QT interval.
The patient, physicians, and public health staff involved reported high satisfaction with BPaL. Providers and TB programs in the United States considering this regimen for TB patients can seek guidance from CDC Division of Tuberculosis Elimination or their TB COE. Current trials using BPaL, such as ZeNix (https://www.tballiance.org/portfolio/trial/11883), are evaluating lower doses and shorter duration of linezolid compared with those of the Nix-TB trial. The 6-month, all oral, highly effective BPaL regimen is a notable advancement toward reducing global TB deaths (10).
Dr. Haley is a medical consultant for the Southeast National TB Center and an adjunct clinical professor in the Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida.
Suggested citation for this article: Haley CA, Macias P, Jasuja S, Jones BA, Rowlinson M-C, Jaimon R, et al. Novel 6-month treatment for drug-resistant tuberculosis, United States. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203766 | Oral | DrugAdministrationRoute | CC BY | 33227229 | 18,593,672 | 2021-01 |
What was the dosage of drug 'ISONIAZID'? | Novel 6-Month Treatment for Drug-Resistant Tuberculosis, United States.
The US Food and Drug Administration approved a 6-month regimen of pretomanid, bedaquiline, and linezolid for extensively drug-resistant or multidrug-intolerant tuberculosis after a trial in South Africa demonstrated 90% effectiveness 6 months posttreatment. We report on a patient who completed the regimen using a lower linezolid dose.
A woman from eastern Europe in her late 40s undergoing treatment for stage III cervical adenocarcinoma was found to have a right upper lobe pulmonary nodule. Pathology from tissue biopsy demonstrated necrotizing granulomas and numerous acid-fast bacilli (AFB); the sample was PCR positive for Mycobacterium tuberculosis. Adjuvant chemotherapy was held, and the patient was referred to the local public health department. The patient provided informed written consent for publication of her case study.
On evaluation, the patient was asymptomatic without physical findings and reported no previous diagnosis or treatment of tuberculosis (TB) disease or latent TB infection. Results of serologic testing for HIV and viral hepatitis B and C were negative. She had a mild chronic anemia and transient transaminitis during chemotherapy (peak alanine aminotransferase 215 IU/L; aspartate aminotransferase 185 IU/L). Three sputum samples were negative by AFB smear and culture; 1 was tested by PCR and was M. tuberculosis negative.
Treatment with rifampin, isoniazid, pyrazinamide, ethambutol and pyridoxine was initiated. Lung biopsy cultures grew M. tuberculosis, and GeneXpert MTB/RIF assay (Cepheid, https://www.cepheid.com) detected an rpoB mutation indicating likely rifampin resistance. Rapid molecular detection of drug resistance and growth-based drug susceptibility testing performed by the Centers for Disease Control and Prevention (CDC) and Florida Bureau of Public Health Laboratories yielded concordant results. We detected resistance to isoniazid, rifampin, the fluoroquinolones (levofloxacin and moxifloxacin), and an injectable (kanamycin), confirming a diagnosis of extensively drug-resistant TB (XDR TB). Resistance was also detected for pyrazinamide but not for ethambutol, bedaquiline, or linezolid. The patient and her medical providers, in consultation with a CDC-funded TB Center of Excellence (COE, https://www.cdc.gov/tb/education/tb_coe), determined that her best treatment option was a 6-month all-oral regimen of bedaquiline, pretomanid, and linezolid (BPaL).
BPaL was approved by the US Food and Drug Administration (FDA) on August 14, 2019, based in part on results from the Nix-TB trial in South Africa, which included patients with XDR TB or multidrug-resistant (MDR) TB who failed or were intolerant of prior therapy (1). Pretomanid, the novel agent in the regimen, is a nitroimidazooxazine that blocks cell-wall production in actively replicating MTB organisms and acts as a respiratory poison and protein synthesis inhibitor to kill nonreplicating persister organisms (2). Bedaquiline is a diarylquinoline that inhibits mycobacterial adenosine triphosphate synthase in replicating and persister organisms, and linezolid is an oxazolidinone that also inhibits protein synthesis (3,4). The combined activity of BPaL enables cure in a far shorter period compared with currently recommended 18- to 24-month MDR TB regimens (5). In the Nix-TB trial, BPaL produced favorable outcomes in 98/109 (90%) patients at 6 months posttreatment (1); in addition, little preexisting resistance to bedaquiline, pretomanid, or linezolid has been reported (4,6).
Because pretomanid was not yet commercially available in the United States, the TB Alliance required an FDA-approved single-patient investigational new drug application and provided 6 months of pretomanid acquired internationally. A bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol was initiated for 2 weeks, then was narrowed to BPaL when pretomanid arrived.
For this patient, we initiated linezolid at 600 mg/d, given the toxicity of the Nix-TB dose of 1,200 mg/d, the patient’s paucibacillary disease, and TB COE’s experience with linezolid dosing (1,4,7,8). Therapeutic drug monitoring performed at the University of Florida Infectious Diseases Pharmacokinetic Laboratory (https://idpl.pharmacy.ufl.edu) was used to maintain a linezolid peak of 12–26 µg/mL and trough <2 µg/mL to reduce drug-induced toxicity (4,9).
The patient received outpatient BPaL treatment 7 days a week by directly observed therapy. We assessed liver, renal, hematologic, and neurologic function plus QTc intervals at baseline and every 2–4 weeks during treatment (Table 1). A few weeks into therapy, the patient’s linezolid level 18 hours postdose was measured at 7.62 µg/mL (serum trough level at 24 hours was likely lower but was still higher than expected) (Table 2). To reduce the trough while maintaining a peak serum level 4–16 times over her M. tuberculosis isolate’s linezolid MIC of 0.12 μg/mL, we extended the linezolid dosing interval to 600 mg every Monday, Wednesday, and Friday. A subsequent linezolid trough at 48 hours was calculated at <2 µg/mL. The patient completed 182 doses of BPaL over 26 weeks without treatment interruptions. Other than mild nausea that responded to pantoprazole, she had no adverse events or notable changes in laboratory values or electrocardiographs. Nine months after completion, the patient remained well; the state health department expects to closely monitor her for recurrent TB for 24 months after BPaL completion.
Table 1 Molecular susceptibility sequencing results and therapeutic drug monitoring data from treatment of XDR TB, Florida, USA*
Drug (dose) Sequencing result Date drug level drawn Trough, µg/mL 2h postdose level, µg/mL 6h postdose level, µg/mL Typical peak serum concentration, µg/mL
Bedaquiline (200 mg MWF) No atpE (ORF) mutation detected; no Rv0678/mmpR (ORF) mutation detected 2019 Nov 13 0.51 (42.25 h postdose) 1.40 1.42 1.2–1.8
(5–6 h postdose, maintenance phase)
N-monodesmethyl bedaquiline (metabolite) NT 2019 Nov 13 0.22 (42.25 h postdose) 0.24 0.27 NT
Pretomanid (200 mg/d) NT 2019 Nov 13 2.07 (18.25 h postdose) 3.43 2.98 2.3–4.3
(5–6 h postdose, at steady state)
Linezolid (600 mg/d) No rplC (ORF aa 84–217) mutation detected; no rrl (nt 2191–2929) mutation detected 2019 Nov 13 7.62 (18.25 h postdose) 24.15 17.88 12–26
Linezolid (600 mg MWF) NT 2020 Mar 12 <2.00† 19.04 13.6 12–26
*MWF, Monday/Wednesday/Friday; NT, not tested; ORF, open reading frame; XDR, extensively drug-resistant tuberculosis.
†Trough sample was not collected; based on the apparent elimination half-life, the linezolid concentration at 48 h was calculated to be <2 µg/mL, a value associated with minimal toxicity.
Table 2 Laboratory, electrocardiographic and clinical monitoring data for patient treated for XDR TB, United States*
Date AST, IU/L ALT, IU/L ALP, IU/L Creatinine, mg/dL Magnesium, mg/dL Hgb, g/dL Leukocyte, × 109/L Plt, × 109/L QTc, msec Notes
Initial treatment with rifampin, isoniazid, pyrazinamide, and ethambutol
2019 Aug 2 67 86 221 0.66 NT 10.4 3.97 272 NT None
Bridging regimen of bedaquiline, linezolid, moxifloxacin, cycloserine, clofazimine, and ethambutol
2019 Oct 3 53 62 121 0.64 1.9 12.7 5.4 278 402 None
2019 Oct 15 73 70 147 NT NT 12.6 5.3 243 NT None
BPaL regimen
2019 Oct 21 57 71 135 0.94 1.9 12.9 3.9 257 413 None
2019 Nov 11 40 53 113 1.01 1.9 12.3 4.9 237 426 Pantoprazole started for brief nausea
2019 Dec 2 52 63 118 0.77 1.9 10.7 4.3 289 421 None
2019 Dec 16 NT NT NT NT NT 11.2 4.7 267 NT None
2020 Jan 6 58 74 107 0.80 2.0 12.5 5.1 271 422 None
2020 Feb 3 36 39 89 0.76 1.9 12.2 4.2 258 429 None
*Initial treatment period was August 5–September 9, 2019; bridging regimen period October 7–21, 2019; BPaL treatment period October 21, 2019–April 21, 2020. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BPaL, bedaquiline, pretomanid, and linezolid; Hgb, hemoglobin; leukocyte, leukocyte count; NT, not tested; Plt, platelet; QTc, corrected QT interval.
The patient, physicians, and public health staff involved reported high satisfaction with BPaL. Providers and TB programs in the United States considering this regimen for TB patients can seek guidance from CDC Division of Tuberculosis Elimination or their TB COE. Current trials using BPaL, such as ZeNix (https://www.tballiance.org/portfolio/trial/11883), are evaluating lower doses and shorter duration of linezolid compared with those of the Nix-TB trial. The 6-month, all oral, highly effective BPaL regimen is a notable advancement toward reducing global TB deaths (10).
Dr. Haley is a medical consultant for the Southeast National TB Center and an adjunct clinical professor in the Department of Medicine, Division of Infectious Diseases and Global Medicine, University of Florida.
Suggested citation for this article: Haley CA, Macias P, Jasuja S, Jones BA, Rowlinson M-C, Jaimon R, et al. Novel 6-month treatment for drug-resistant tuberculosis, United States. Emerg Infect Dis. 2021 Jan [date cited]. https://doi.org/10.3201/eid2701.203766 | 600 mg (milligrams). | DrugDosage | CC BY | 33227229 | 18,593,672 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to bone'. | Enhanced toxicity with CDK 4/6 inhibitors and palliative radiotherapy: Non-consecutive case series and review of the literature.
Current first-line systemic treatment in most patients with metastatic hormone receptor-positive, HER-2 negative breast cancer is an aromatase inhibitor in combination with a cyclin dependant kinase (CDK) 4/6 inhibitor. Frequently, these patients require palliative radiotherapy (RT) for symptomatic disease management. There is a paucity of data on the safety of combining a CDK 4/6 inhibitor with palliative RT, with conflicting case reports in the literature. We report on 5 cases at our institution where enhanced radiotherapy toxicity was observed when palliative doses of RT was delivered during or prior to treatment with a CDK 4/6 inhibitor. After review of pre-clinical and mechanistic data, we hypothesise that the effects of CDK4/6 inhibition on normal tissue and the tumour microenvironment may impede tissue recovery and exacerbate acute radiation and radiation recall toxicities. Further studies are required to clarify the potential toxicities of this combination. Clinicians should consider the potential risks when combining CDK 4/6 inhibitors with palliative RT and individualise patient management accordingly.
Introduction
The current standard of care for the first-line treatment of metastatic hormone receptor-positive, HER‐2 negative breast cancer is an aromatase inhibitor (AI) in combination with a cyclin dependant kinase (CDK) 4/6 inhibitor. This is based on three recently published randomised trials demonstrating a progression-free survival benefit in favour of this combination compared with AI monotherapy [1], [2], [3]. Palbociclib, ribociclib and abemaciclib are potent and specific inhibitors of CDK4 and CDK6 with a more favourable toxicity profile compared with non-selective CDK inhibitors. Myelosuppression is the most commonly reported toxicity seen in up to 80% of women on palbociclib or ribociclib and up to 50% on abemaciclib. Other common toxicities include fatigue, nausea, diarrhoea, increased liver enzymes and skin toxicities [1], [2], [3], [4].
Palliative radiotherapy (RT) is often indicated for symptomatic disease management in patients with metastatic breast cancer (mBC). There is limited and conflicting data on the potential synergistic toxicities of palliative radiotherapy and CDK 4/6 inhibitors. Some small case series indicate that the combination is safe [5], [6], [7], [8], whilst other investigators have reported enhanced toxicities with the combination [9, 10].
Here, we report five cases of augmented toxicities in patients who received palliative RT and a CDK4/6 inhibitor. We reviewed the current literature, preclinical data, and postulate potential synergistic mechanisms for the enhanced toxicity. These cases were identified by a retrospective chart review over a three-year period where CDK 4/6 inhibitors were prescribed at our institution. In total, 63 patients received a CDK 4/6 inhibitor, twenty-six (41%) received palliative radiotherapy either during or prior to commencement of a CDK 4/6 inhibitor.
Case series
Case 1
A 43-year‐old woman presented with localised hormone receptor positive breast cancer (BC), and was managed with breast conservation surgery, adjuvant chemotherapy, whole breast irradiation and adjuvant endocrine treatment (tamoxifen). She relapsed within the breast ten years later and was managed with a mastectomy and switched to an AI. Two years later, she developed mBC and was commenced on fulvestrant. At subsequent progression she was switched to everolimus in combination with exemestane. At further progression, she received multiple lines of chemotherapy including capecitabine, vinorelbine, nanoparticle albumin-bound paclitaxel, eribulin and liposomal doxorubicin.
Nine years after the first onset of mBC, she received palliative RT, 20 Gy in 5 fractions to symptomatic mediastinal nodal metastases causing a persistent cough, shortness of breast and occasional hemoptysis. A standard anterior and posterior radiotherapy beam arrangement was used. The mean lung dose to the right lung was higher than the left lung (Table 1), because of partial cardiac shielding, reducing the dose delivered to the left lung (Fig. 1a), which has been depicted in a dose volume histogram (DVH), Fig. 1b. She had symptomatic improvement in the weeks following her treatment with a reduction in her cough, shortness of breath and hemoptysis.Table 1 Summary of clinical cases and relationship between palbociclib dosing and radiation.
Table 1Case Age (yr) Radiation site and dose (Gy)/fraction Palbociclib dose Interval between CDK 4/6 and radiation Adverse event and grading Radiation dose to organs at risk
1 43 Chest, 20 Gy/5 fractions 125 mg daily 4 months after Grade 5 pneumonitis Lung V20 = 33%; MLD left lung = 10 Gy; MLD right lung = 13Gy
2 54 Right breast, 36 Gy/12 fractions 125 mg daily 1 day before Grade 3 dermatitis Breast PTV: max dose = 36.7Gy
3 44 T-spine, 30 Gy/10 fractions 125 mg daily None, (concurrent) Grade 3 oesophagitis Oesophagus: max dose = 27.8 Gy; mean dose = 26.0 Gy
4 51 T-spine, 20 Gy/5 fractions 125 mg daily 5 days prior, 2 weeks after Grade 2 dermatitis Skin: V10 = 2.5%, V20 = 1%
5 70 C-spine, T-spine 20 Gy/5 fractions 125 mg daily 1 week before Grade 3 oesophagitis Oral Cavity: mean dose = 3.9 Gy; max dose = 20.2Gy
Abbreviations: V20 – Volume of organ (%) receiving ≥ 20 Gy; V10 - Volume of organ (%) receiving ≥ 10 Gy; max = maximum; MLD = mean lung dose.
Fig. 1 a. Irradiated lung volume (dose cloud, representing 20 Gy), using an anterior posterior beam arrangement to a dose of 20 Gy in 5 fractions.
b. Dose volume histogram of left lung (labelled Lung_L1) and right lung (labelled Lung_R1)
c. Pneumonitis, shortly after commencing Palbociclib.
d. Correlation between pneumonitis and 20 Gy dose cloud.
Fig 1
Four months after radiotherapy, she commenced on self-funded palbociclib 125 mg/daily concomitant with letrozole, being aware of the paucity of data on CDK4/6 therapy in the late-line treatment setting. Within one week of palbociclib therapy, the patient developed rapidly progressive shortness of breath. CT imaging revealed right lung ground glass opacity prominently in the distribution of previous radiation field (Fig. 1c and d). Palbociclib was ceased promptly. Despite high dose antibiotics and steroids she became hypoxic. Bronchoscopy findings confirmed diffuse inflamed mucosa, on the right bronchial tree with frothy white secretions. She became oxygen-dependant and was transferred to hospice with significant respiratory failure and functional decline.
The cause of death was treatment-related Grade 5 pneumonitis, which we postulate was a radiation recall reaction secondary to palbociclib.
Case 2
A 54-year-old post-menopausal woman presented with de novo metastatic hormone receptor-positive HER-2 negative lobular BC involving the right axillary nodes, adrenal glands and skeleton. She received three cycles of first-line palliative chemotherapy, whilst overseas (docetaxel, adriamycin and cyclophosphamide). Following satisfactory chemotherapeutic response, she continued on AI (letrozole) and bisphosphonate therapy. At the onset of disease progression, palbociclib was commenced in combination with ongoing letrozole. Twelve months later a bone metastasis in the right femoral neck required prophylactic pinning and palliative RT, 20 Gy in 5 fractions. Palbociclib therapy was ceased one day before RT and was recommenced one week after the completion of RT. No immediate or late radiation toxicities were observed to the hip or overlying skin.
Four months later she developed further progression evidenced by multiple small, biopsy-proven cutaneous nodules over the right breast. She received palliative RT, 36 Gy in 12 fractions to the whole breast, using medial and lateral tangential fields, consisting of 6MV photon fields with a 25% contribution from an 18-MV field-in-field boost. Electrons were not used in the treatment plan. Bolus, with a thickness of 5 mm was placed over the breast for the entire treatment course. Palbociclib was withheld during and recommenced one week after radiotherapy. At the end of the treatment the skin overlying the breast was erythematous. Within five days of recommencing palbociclib (twelve days after radiotherapy), the patient developed severe cutaneous desquamation over the treated area. Palbociclib was ceased. The Grade 3 radiation skin toxicities settled 10 days later with antibiotics and wound dressings. Antibiotics were prescribed by the treating radiation oncologist given the severity of the skin reaction and concern about the possibility of a concomitant infection. At no time did the patient develop a fever or display signs of systemic infection. Bacterial cultures were not performed.
Case 3
A 44-year-old premenopausal woman with locally advanced hormone receptor-positive, HER-2 negative BC was treated with neoadjuvant chemotherapy (5-fluorouracil, epirubicin and cyclophosphamide), mastectomy with reconstruction followed by adjuvant RT and adjuvant endocrine therapy (AI) with ovarian suppression (a lutenising hormone-releasing hormone agonist, goserelin). Eight years later, she developed mBC. Biopsy-proven bony metastases of the same phenotype in the T5 vertebral body with left-sided soft tissue extension was visible on CT and FDG- PET imaging (Fig. 2a and b). She was commenced on first line letrozole in combination with palbociclib. She continued on palbociclib while receiving palliative RT, 30 Gy in 10 fractions – with dose to the oesophagus and lungs depicted in a DVH, Fig. 2c. Within six days of completing palliative RT, Palbociclib was ceased due to Grade 3 oesophagitis. Severe odynophagia, dysphagia and fatigue necessitated admission to hospital for supportive care. The patient made a complete recovery and was recommenced on palbociclib.Fig. 2 a: FDG-PET scan demonstrating uptake within the oesophagus, consistent with the esophagitis
b: The 30 Gy dose cloud, delivered with a single posterior beam
c: Dose Volume Histogram showing dose to left lung (Lung_L), right lung (Lung_R) and oesophagus.
Fig 2
Case 4
A 51-year-old perimenopausal woman was diagnosed with de novo mBC with widespread metastatic bone disease. A core biopsy of a left breast lesion confirmed a grade 2 strongly hormone receptor-positive and HER-2 negative carcinoma. She had symptomatic hypercalcaemia treated with bisphosphonate therapy. She received palliative RT, 20 Gy in 5 fractions to painful bony disease in the cervical and thoracic vertebrae (C1–3 and T3–5). Palbociclib was commenced (100 mg daily then 125 mg at cycle 2) in combination with letrozole and ovarian suppression (goserelin).
Twelve months later, a routine CT scans demonstrated isolated disease progression at the T8 vertebra. She received palliative RT, 20 Gy in 5 fractions to this new site. Palbociclib was withheld for five days prior to palliative RT. Four days after completing RT she developed Grade 2 skin reaction in a well-defined area of marked skin desquamation within the radiotherapy field characterised by marked skin desquamation (Fig. 3). She recommenced palbociclib at 125 mg after the resolution of skin toxicities with no further issues.Fig. 3 skin reaction, 4 days after completing a dose of 20 Gy in 5 fractions to the thoracic spine, using a single posterior field.
Fig 3
Case 5
A 70-year-old woman had a Grade 3 hormone receptor-positive and HER-2 negative early BC, treated with wide local excision, axillary clearance, adjuvant anthracycline-based chemotherapy, adjuvant RT and an AI for five years. Eleven years later, she developed widespread bone metastases, hilar and mediastinal lymphadenopathy confirmed on PET and CT imaging. Mediastinal lymph node biopsies confirmed GATA-3 positive, hormone receptor-positive and HER2-negative invasive carcinoma of same phenotype as the original BC.
She received palliative RT, 20 Gy in 5 fractions to painful metastases in the T12-L4 vertebrae and commenced on an AI (letrozole). Two months after radiotherapy, she commenced on palbociclib within a Phase 4 clinical trial. Five months later, she reported new back and neck pain requiring further palliative RT, 20 Gy in 5 fractions to new sites in C1–3 and T1–3 vertebrae. Palbociclib was ceased for 3 weeks during RT. However, on the final day of RT she developed Grade 3 oesophagitis. Severe oral mucositis and odynophagia necessitated parenteral opioids and other supportive measures, including intravenous-fluids during her nine-day hospital admission. While the dose to the oral cavity and superior pharynx was above mucosal tolerance (depicted in DVH, Fig. 4), the rapidity of onset and the severity of the toxicity appears to be in excess of what would be expected with this palliative regimen.Fig. 4 Dose Volume Histogram showing dose oral cavity.
Fig 4
Discussion
Whilst many systemic anti-cancer therapies are associated with enhanced radiation toxicity to normal tissues and also associated with radiation recall [11], there is limited experience and published data on the safety of concomitant radiation and CDK4/6 inhibitors. Herein, we provide five examples where exaggerated toxicity was observed with palliative-intent RT and palbociclib, including one case of fatal pulmonary toxicity. Additionally, we observed skin and mucosal toxicity in excess of our clinical expectations. All patients received concomitant AI therapy with or without goserelin. Of note, the timing of palbociclib administration and the dose and site of RT varied between the cases (Table 1). Rapid onset of severe pneumonitis occurred within one week of palbociclib initiation, four months after RT to the chest and mediastinum (20 Gy in 5 fractions) in Case 1. The authors acknowledge that this patient also received everolimus (known to be associated with pneumonitis), however the drug was received seven years prior to radiotherapy, thus making this less likely to be the causative factor. Although pneumonitis is rarely associated with palbociclib monotherapy, localization to the high dose region of the radiation field, together with the temporal relationship between its commencement and the rapid onset of the pneumonitis would suggest a radiation recall phenomenon. The unilateral nature of the pneumonitis is likely explained by the higher mean lung dose on the right side (Table 1) due to cardiac shielding of the left lung; the increased dose delivered to the right lung is also depicted in the DVH (Fig. 1b). The authors acknowledge that whilst there was previous radiotherapy to the breast, this was ten years earlier and although possible, was unlikely to be a contributing factor to the pneumonitis. In Case 3, palbociclib was given concurrently with RT (C-spine, 30 Gy in 10 fractions) with resultant grade 3 oesophagitis first noted six days following RT completion. Cases 2, 4 and 5 arose in patients on established palbociclib therapy whose treatments were withheld during RT. With the exception of case 1, all patients recovered from their acute radiation toxicities, and no late toxicities have been observed. Of note, in Case 2 no enhanced toxicity was reported when the patient received radiotherapy to the hip. This is possibly explained by the fact that palliative doses of radiotherapy to the bone is mostly well tolerated.
Messer et al. reported on a 62-year old patient who developed early onset RT-related oesophagitis and dermatitis following RT to supraclavicular nodal disease (60 Gy in 30 fractions) while receiving palbociclib (125 mg daily) and fulvestrant [9]. Grade 3 radiation-related enterocolitis was observed in a 58-year old patient with mBC following RT (30 Gy in 10 fractions) to the left iliac bone and upper sacrum and concurrent palbociclib (100 mg daily) and fulvestrant [10]. Conversely, a number of case series described combining RT with CDK 4/6 inhibitors as safe and well-tolerated [5], [6], [7], [8]. To our knowledge, this is the largest series of cases reporting enhanced toxicity when combining radiotherapy with a CDK 4/6 inhibitor.
The cyclin D1-CDK 4/6 complex is implicated in extracellular signalling pathways essential in cell cycle progression through the G1–S phase via the phosphorylation of retinoblastoma (Rb) proteins and the release of key transcription factors, such as E2F family proteins [12]. The deregulation of key components in these pathways including the functional loss of Rb is highly prevalent in breast cancer. Oestrogen signalling is known to upregulate cyclin D1 levels and mediates multiple mitogenic processes converging on the cyclin D1-CDK 4/6 axis, leading to the promotion of cell cycle progression, thus forming the rationale of targeting CDK 4/6 [13], [14], [15]. A main mechanism of action of CDK4 /6 inhibition is thought to be cell cycle arrest with resultant tumour cell quiescence or senescence. Aside from reinforcing cytostasticity, loss of CDK 4/6 activity may also have other cellular implications such as altered cellular metabolism, disruption of reactive oxidative species (ROS) clearance and initiation of apoptosis. Interestingly, a recent study demonstrated that CDK 4/6 inhibition affected the maturation processes of immune system sentinel cells (e.g. neutrophils and regulatory T-cells) [16].
Ionising radiation causes both direct deoxyribonucleic acid damage and indirect cellular damage by generation of ROS, and may lead to tumour cellular death by various means including apoptosis, necrosis, autophagic cell death and mitotic catastrophe [17], [18], [19]. The cellular effects of RT including bystander effects on normal tissues and the tumour microenvironment following tissue damage are highly dependant on tissue type and varies between individuals [20]. Early effects (during or within weeks of radiation) often involve pro-inflammatory pathway activation characterised by pro-fibrotic cytokines, vascular injury and the coagulation cascade with initiation of early healing processes. Late effects (months or even years after radiation) are characterised by delayed onset fibrosis, cellular death, atrophy and vascular damage, partly due to an adaptive response to acute tissue damage. These processes may be perpetuated by cell loss and dysregulated interactions between new repopulating cells and/or hypoxia. Both early and late radiation effects on normal tissue can lead to the creation of an inflammatory milieu within the tumour micro-environment with the attraction of pro-inflammatory immune cells [18].
We hypothesise that the effects of CDK 4/6 inhibition on normal tissue and the tumour microenvironment may impede tissue recovery and exacerbate acute radiation and radiation recall toxicities (Fig. 5). Mechanisms may include inappropriate cell cycle arrest during cellular repair, effects on cellular metabolism, and loss of cellular ROS scavenging and elimination abilities. These processes may even lead to late radiation-related tissue damage in otherwise normal tissue [21]. Moreover, within the tumour microenvironment, CDK 4/6 inhibition may further augment anti-tumour immunity via activation of sentinel innate immune cells, thereby inducing local tissue damage [22, 23]. Preclinical studies have reported on the radiosensitising effects of CDK 4/6 inhibition in glioblastoma patient-derived cell lines and prostate cancer cell lines, and survival was extended when the two treatments were combined in glioblastoma mice models [24, 25]. While one study demonstrated the protective role of CDK 4/6 inhibition against radiation-induced intestinal injury in mice, another found that palbociclib before a single dose of subtotal body irradiation was protective but palbociclib before and during five daily fractions of irradiation exacerbated gastrointestinal injury in mice [25, 26].Fig. 5 Proposed mechanisms of tissue damage when combining CDK 4/6 inhibitors with radiation.
Fig 5
The above five cases highlight the importance of clinical vigilance when administering palbociclib either concurrently or after radiation. Although the vignettes reported all pertain to palbociclib – (the first approved CDK 4/6 inhibitor) - it is foreseeable that other CDK 4/6 inhibitors, owing to similar mechanistic actions may be associated with analogous effects. CDK 4/6 inhibitors are now a mainstay of treatment in mBC and their role in the adjuvant setting, in second line and beyond and other tumour types are also being actively investigated, underscoring the importance of understanding their safety profile when used in conjunction with radiotherapy.
These five cases (19%) were identified from a total of twenty-six patients who received palliative RT either prior to, or concomitantly with treatment with a CDK 4/6 inhibitor. We acknowledge that this is a retrospective analysis but this represents a not insignificant rate of enhanced toxicity worthy of further study.
In particular, a few clinically pertinent questions warrant careful study. First, what is the optimal timing of CDK 4/6 inhibitor administration before, during and after RT? If concurrent use is to be avoided, what then is an appropriate washout period of the CDK 4/6 inhibitor, conceivably to allow bystander tissue damage recovery or reduction of reactive immune cells within the radiation field? As suggested in preclinical studies, fractionation and scheduling of radiation will likely also play a role and requires further evaluation. Second, it is plausible that certain tissues or organs may be more vulnerable to injury. Examples include tissues that are rapidly renewing or those with continuous exposure to pathogens and consequently higher levels of innate reactive immunologic activities such as lung, skin and the gastrointestinal tract. Specific attention to these areas may be relevant for radiation planning. Third, there may be a subset of patients who are at higher risk, such as those suffering from superimposed infection or those with comorbid pathology in the radiation field for whom treatment should be carefully considered and individualised. Therefore, highly conformal radiotherapy planning techniques should be considered even when prescribing palliative intent radiotherapy to mitigate the risks of enhanced toxicity to organs at risk.
Conclusion
This case series demonstrates the potential of enhanced RT toxicity when administering a CDK 4/6 inhibitor concurrently or soon after radiotherapy. Clinicians using this combination should consider this potential when prescribing RT. Additional studies on combined CDK 4/6 inhibition and RT are required to further clarify the potential for enhanced toxicity from this combination.
Declaration of Competing Interest
None.
Funding source
None.
Ethical approval
None. | CYCLOPHOSPHAMIDE, DOCETAXEL, DOXORUBICIN HYDROCHLORIDE, LETROZOLE, PALBOCICLIB, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY-NC-ND | 33227663 | 18,675,217 | 2021-01 |
What was the outcome of reaction 'Oesophagitis'? | Enhanced toxicity with CDK 4/6 inhibitors and palliative radiotherapy: Non-consecutive case series and review of the literature.
Current first-line systemic treatment in most patients with metastatic hormone receptor-positive, HER-2 negative breast cancer is an aromatase inhibitor in combination with a cyclin dependant kinase (CDK) 4/6 inhibitor. Frequently, these patients require palliative radiotherapy (RT) for symptomatic disease management. There is a paucity of data on the safety of combining a CDK 4/6 inhibitor with palliative RT, with conflicting case reports in the literature. We report on 5 cases at our institution where enhanced radiotherapy toxicity was observed when palliative doses of RT was delivered during or prior to treatment with a CDK 4/6 inhibitor. After review of pre-clinical and mechanistic data, we hypothesise that the effects of CDK4/6 inhibition on normal tissue and the tumour microenvironment may impede tissue recovery and exacerbate acute radiation and radiation recall toxicities. Further studies are required to clarify the potential toxicities of this combination. Clinicians should consider the potential risks when combining CDK 4/6 inhibitors with palliative RT and individualise patient management accordingly.
Introduction
The current standard of care for the first-line treatment of metastatic hormone receptor-positive, HER‐2 negative breast cancer is an aromatase inhibitor (AI) in combination with a cyclin dependant kinase (CDK) 4/6 inhibitor. This is based on three recently published randomised trials demonstrating a progression-free survival benefit in favour of this combination compared with AI monotherapy [1], [2], [3]. Palbociclib, ribociclib and abemaciclib are potent and specific inhibitors of CDK4 and CDK6 with a more favourable toxicity profile compared with non-selective CDK inhibitors. Myelosuppression is the most commonly reported toxicity seen in up to 80% of women on palbociclib or ribociclib and up to 50% on abemaciclib. Other common toxicities include fatigue, nausea, diarrhoea, increased liver enzymes and skin toxicities [1], [2], [3], [4].
Palliative radiotherapy (RT) is often indicated for symptomatic disease management in patients with metastatic breast cancer (mBC). There is limited and conflicting data on the potential synergistic toxicities of palliative radiotherapy and CDK 4/6 inhibitors. Some small case series indicate that the combination is safe [5], [6], [7], [8], whilst other investigators have reported enhanced toxicities with the combination [9, 10].
Here, we report five cases of augmented toxicities in patients who received palliative RT and a CDK4/6 inhibitor. We reviewed the current literature, preclinical data, and postulate potential synergistic mechanisms for the enhanced toxicity. These cases were identified by a retrospective chart review over a three-year period where CDK 4/6 inhibitors were prescribed at our institution. In total, 63 patients received a CDK 4/6 inhibitor, twenty-six (41%) received palliative radiotherapy either during or prior to commencement of a CDK 4/6 inhibitor.
Case series
Case 1
A 43-year‐old woman presented with localised hormone receptor positive breast cancer (BC), and was managed with breast conservation surgery, adjuvant chemotherapy, whole breast irradiation and adjuvant endocrine treatment (tamoxifen). She relapsed within the breast ten years later and was managed with a mastectomy and switched to an AI. Two years later, she developed mBC and was commenced on fulvestrant. At subsequent progression she was switched to everolimus in combination with exemestane. At further progression, she received multiple lines of chemotherapy including capecitabine, vinorelbine, nanoparticle albumin-bound paclitaxel, eribulin and liposomal doxorubicin.
Nine years after the first onset of mBC, she received palliative RT, 20 Gy in 5 fractions to symptomatic mediastinal nodal metastases causing a persistent cough, shortness of breast and occasional hemoptysis. A standard anterior and posterior radiotherapy beam arrangement was used. The mean lung dose to the right lung was higher than the left lung (Table 1), because of partial cardiac shielding, reducing the dose delivered to the left lung (Fig. 1a), which has been depicted in a dose volume histogram (DVH), Fig. 1b. She had symptomatic improvement in the weeks following her treatment with a reduction in her cough, shortness of breath and hemoptysis.Table 1 Summary of clinical cases and relationship between palbociclib dosing and radiation.
Table 1Case Age (yr) Radiation site and dose (Gy)/fraction Palbociclib dose Interval between CDK 4/6 and radiation Adverse event and grading Radiation dose to organs at risk
1 43 Chest, 20 Gy/5 fractions 125 mg daily 4 months after Grade 5 pneumonitis Lung V20 = 33%; MLD left lung = 10 Gy; MLD right lung = 13Gy
2 54 Right breast, 36 Gy/12 fractions 125 mg daily 1 day before Grade 3 dermatitis Breast PTV: max dose = 36.7Gy
3 44 T-spine, 30 Gy/10 fractions 125 mg daily None, (concurrent) Grade 3 oesophagitis Oesophagus: max dose = 27.8 Gy; mean dose = 26.0 Gy
4 51 T-spine, 20 Gy/5 fractions 125 mg daily 5 days prior, 2 weeks after Grade 2 dermatitis Skin: V10 = 2.5%, V20 = 1%
5 70 C-spine, T-spine 20 Gy/5 fractions 125 mg daily 1 week before Grade 3 oesophagitis Oral Cavity: mean dose = 3.9 Gy; max dose = 20.2Gy
Abbreviations: V20 – Volume of organ (%) receiving ≥ 20 Gy; V10 - Volume of organ (%) receiving ≥ 10 Gy; max = maximum; MLD = mean lung dose.
Fig. 1 a. Irradiated lung volume (dose cloud, representing 20 Gy), using an anterior posterior beam arrangement to a dose of 20 Gy in 5 fractions.
b. Dose volume histogram of left lung (labelled Lung_L1) and right lung (labelled Lung_R1)
c. Pneumonitis, shortly after commencing Palbociclib.
d. Correlation between pneumonitis and 20 Gy dose cloud.
Fig 1
Four months after radiotherapy, she commenced on self-funded palbociclib 125 mg/daily concomitant with letrozole, being aware of the paucity of data on CDK4/6 therapy in the late-line treatment setting. Within one week of palbociclib therapy, the patient developed rapidly progressive shortness of breath. CT imaging revealed right lung ground glass opacity prominently in the distribution of previous radiation field (Fig. 1c and d). Palbociclib was ceased promptly. Despite high dose antibiotics and steroids she became hypoxic. Bronchoscopy findings confirmed diffuse inflamed mucosa, on the right bronchial tree with frothy white secretions. She became oxygen-dependant and was transferred to hospice with significant respiratory failure and functional decline.
The cause of death was treatment-related Grade 5 pneumonitis, which we postulate was a radiation recall reaction secondary to palbociclib.
Case 2
A 54-year-old post-menopausal woman presented with de novo metastatic hormone receptor-positive HER-2 negative lobular BC involving the right axillary nodes, adrenal glands and skeleton. She received three cycles of first-line palliative chemotherapy, whilst overseas (docetaxel, adriamycin and cyclophosphamide). Following satisfactory chemotherapeutic response, she continued on AI (letrozole) and bisphosphonate therapy. At the onset of disease progression, palbociclib was commenced in combination with ongoing letrozole. Twelve months later a bone metastasis in the right femoral neck required prophylactic pinning and palliative RT, 20 Gy in 5 fractions. Palbociclib therapy was ceased one day before RT and was recommenced one week after the completion of RT. No immediate or late radiation toxicities were observed to the hip or overlying skin.
Four months later she developed further progression evidenced by multiple small, biopsy-proven cutaneous nodules over the right breast. She received palliative RT, 36 Gy in 12 fractions to the whole breast, using medial and lateral tangential fields, consisting of 6MV photon fields with a 25% contribution from an 18-MV field-in-field boost. Electrons were not used in the treatment plan. Bolus, with a thickness of 5 mm was placed over the breast for the entire treatment course. Palbociclib was withheld during and recommenced one week after radiotherapy. At the end of the treatment the skin overlying the breast was erythematous. Within five days of recommencing palbociclib (twelve days after radiotherapy), the patient developed severe cutaneous desquamation over the treated area. Palbociclib was ceased. The Grade 3 radiation skin toxicities settled 10 days later with antibiotics and wound dressings. Antibiotics were prescribed by the treating radiation oncologist given the severity of the skin reaction and concern about the possibility of a concomitant infection. At no time did the patient develop a fever or display signs of systemic infection. Bacterial cultures were not performed.
Case 3
A 44-year-old premenopausal woman with locally advanced hormone receptor-positive, HER-2 negative BC was treated with neoadjuvant chemotherapy (5-fluorouracil, epirubicin and cyclophosphamide), mastectomy with reconstruction followed by adjuvant RT and adjuvant endocrine therapy (AI) with ovarian suppression (a lutenising hormone-releasing hormone agonist, goserelin). Eight years later, she developed mBC. Biopsy-proven bony metastases of the same phenotype in the T5 vertebral body with left-sided soft tissue extension was visible on CT and FDG- PET imaging (Fig. 2a and b). She was commenced on first line letrozole in combination with palbociclib. She continued on palbociclib while receiving palliative RT, 30 Gy in 10 fractions – with dose to the oesophagus and lungs depicted in a DVH, Fig. 2c. Within six days of completing palliative RT, Palbociclib was ceased due to Grade 3 oesophagitis. Severe odynophagia, dysphagia and fatigue necessitated admission to hospital for supportive care. The patient made a complete recovery and was recommenced on palbociclib.Fig. 2 a: FDG-PET scan demonstrating uptake within the oesophagus, consistent with the esophagitis
b: The 30 Gy dose cloud, delivered with a single posterior beam
c: Dose Volume Histogram showing dose to left lung (Lung_L), right lung (Lung_R) and oesophagus.
Fig 2
Case 4
A 51-year-old perimenopausal woman was diagnosed with de novo mBC with widespread metastatic bone disease. A core biopsy of a left breast lesion confirmed a grade 2 strongly hormone receptor-positive and HER-2 negative carcinoma. She had symptomatic hypercalcaemia treated with bisphosphonate therapy. She received palliative RT, 20 Gy in 5 fractions to painful bony disease in the cervical and thoracic vertebrae (C1–3 and T3–5). Palbociclib was commenced (100 mg daily then 125 mg at cycle 2) in combination with letrozole and ovarian suppression (goserelin).
Twelve months later, a routine CT scans demonstrated isolated disease progression at the T8 vertebra. She received palliative RT, 20 Gy in 5 fractions to this new site. Palbociclib was withheld for five days prior to palliative RT. Four days after completing RT she developed Grade 2 skin reaction in a well-defined area of marked skin desquamation within the radiotherapy field characterised by marked skin desquamation (Fig. 3). She recommenced palbociclib at 125 mg after the resolution of skin toxicities with no further issues.Fig. 3 skin reaction, 4 days after completing a dose of 20 Gy in 5 fractions to the thoracic spine, using a single posterior field.
Fig 3
Case 5
A 70-year-old woman had a Grade 3 hormone receptor-positive and HER-2 negative early BC, treated with wide local excision, axillary clearance, adjuvant anthracycline-based chemotherapy, adjuvant RT and an AI for five years. Eleven years later, she developed widespread bone metastases, hilar and mediastinal lymphadenopathy confirmed on PET and CT imaging. Mediastinal lymph node biopsies confirmed GATA-3 positive, hormone receptor-positive and HER2-negative invasive carcinoma of same phenotype as the original BC.
She received palliative RT, 20 Gy in 5 fractions to painful metastases in the T12-L4 vertebrae and commenced on an AI (letrozole). Two months after radiotherapy, she commenced on palbociclib within a Phase 4 clinical trial. Five months later, she reported new back and neck pain requiring further palliative RT, 20 Gy in 5 fractions to new sites in C1–3 and T1–3 vertebrae. Palbociclib was ceased for 3 weeks during RT. However, on the final day of RT she developed Grade 3 oesophagitis. Severe oral mucositis and odynophagia necessitated parenteral opioids and other supportive measures, including intravenous-fluids during her nine-day hospital admission. While the dose to the oral cavity and superior pharynx was above mucosal tolerance (depicted in DVH, Fig. 4), the rapidity of onset and the severity of the toxicity appears to be in excess of what would be expected with this palliative regimen.Fig. 4 Dose Volume Histogram showing dose oral cavity.
Fig 4
Discussion
Whilst many systemic anti-cancer therapies are associated with enhanced radiation toxicity to normal tissues and also associated with radiation recall [11], there is limited experience and published data on the safety of concomitant radiation and CDK4/6 inhibitors. Herein, we provide five examples where exaggerated toxicity was observed with palliative-intent RT and palbociclib, including one case of fatal pulmonary toxicity. Additionally, we observed skin and mucosal toxicity in excess of our clinical expectations. All patients received concomitant AI therapy with or without goserelin. Of note, the timing of palbociclib administration and the dose and site of RT varied between the cases (Table 1). Rapid onset of severe pneumonitis occurred within one week of palbociclib initiation, four months after RT to the chest and mediastinum (20 Gy in 5 fractions) in Case 1. The authors acknowledge that this patient also received everolimus (known to be associated with pneumonitis), however the drug was received seven years prior to radiotherapy, thus making this less likely to be the causative factor. Although pneumonitis is rarely associated with palbociclib monotherapy, localization to the high dose region of the radiation field, together with the temporal relationship between its commencement and the rapid onset of the pneumonitis would suggest a radiation recall phenomenon. The unilateral nature of the pneumonitis is likely explained by the higher mean lung dose on the right side (Table 1) due to cardiac shielding of the left lung; the increased dose delivered to the right lung is also depicted in the DVH (Fig. 1b). The authors acknowledge that whilst there was previous radiotherapy to the breast, this was ten years earlier and although possible, was unlikely to be a contributing factor to the pneumonitis. In Case 3, palbociclib was given concurrently with RT (C-spine, 30 Gy in 10 fractions) with resultant grade 3 oesophagitis first noted six days following RT completion. Cases 2, 4 and 5 arose in patients on established palbociclib therapy whose treatments were withheld during RT. With the exception of case 1, all patients recovered from their acute radiation toxicities, and no late toxicities have been observed. Of note, in Case 2 no enhanced toxicity was reported when the patient received radiotherapy to the hip. This is possibly explained by the fact that palliative doses of radiotherapy to the bone is mostly well tolerated.
Messer et al. reported on a 62-year old patient who developed early onset RT-related oesophagitis and dermatitis following RT to supraclavicular nodal disease (60 Gy in 30 fractions) while receiving palbociclib (125 mg daily) and fulvestrant [9]. Grade 3 radiation-related enterocolitis was observed in a 58-year old patient with mBC following RT (30 Gy in 10 fractions) to the left iliac bone and upper sacrum and concurrent palbociclib (100 mg daily) and fulvestrant [10]. Conversely, a number of case series described combining RT with CDK 4/6 inhibitors as safe and well-tolerated [5], [6], [7], [8]. To our knowledge, this is the largest series of cases reporting enhanced toxicity when combining radiotherapy with a CDK 4/6 inhibitor.
The cyclin D1-CDK 4/6 complex is implicated in extracellular signalling pathways essential in cell cycle progression through the G1–S phase via the phosphorylation of retinoblastoma (Rb) proteins and the release of key transcription factors, such as E2F family proteins [12]. The deregulation of key components in these pathways including the functional loss of Rb is highly prevalent in breast cancer. Oestrogen signalling is known to upregulate cyclin D1 levels and mediates multiple mitogenic processes converging on the cyclin D1-CDK 4/6 axis, leading to the promotion of cell cycle progression, thus forming the rationale of targeting CDK 4/6 [13], [14], [15]. A main mechanism of action of CDK4 /6 inhibition is thought to be cell cycle arrest with resultant tumour cell quiescence or senescence. Aside from reinforcing cytostasticity, loss of CDK 4/6 activity may also have other cellular implications such as altered cellular metabolism, disruption of reactive oxidative species (ROS) clearance and initiation of apoptosis. Interestingly, a recent study demonstrated that CDK 4/6 inhibition affected the maturation processes of immune system sentinel cells (e.g. neutrophils and regulatory T-cells) [16].
Ionising radiation causes both direct deoxyribonucleic acid damage and indirect cellular damage by generation of ROS, and may lead to tumour cellular death by various means including apoptosis, necrosis, autophagic cell death and mitotic catastrophe [17], [18], [19]. The cellular effects of RT including bystander effects on normal tissues and the tumour microenvironment following tissue damage are highly dependant on tissue type and varies between individuals [20]. Early effects (during or within weeks of radiation) often involve pro-inflammatory pathway activation characterised by pro-fibrotic cytokines, vascular injury and the coagulation cascade with initiation of early healing processes. Late effects (months or even years after radiation) are characterised by delayed onset fibrosis, cellular death, atrophy and vascular damage, partly due to an adaptive response to acute tissue damage. These processes may be perpetuated by cell loss and dysregulated interactions between new repopulating cells and/or hypoxia. Both early and late radiation effects on normal tissue can lead to the creation of an inflammatory milieu within the tumour micro-environment with the attraction of pro-inflammatory immune cells [18].
We hypothesise that the effects of CDK 4/6 inhibition on normal tissue and the tumour microenvironment may impede tissue recovery and exacerbate acute radiation and radiation recall toxicities (Fig. 5). Mechanisms may include inappropriate cell cycle arrest during cellular repair, effects on cellular metabolism, and loss of cellular ROS scavenging and elimination abilities. These processes may even lead to late radiation-related tissue damage in otherwise normal tissue [21]. Moreover, within the tumour microenvironment, CDK 4/6 inhibition may further augment anti-tumour immunity via activation of sentinel innate immune cells, thereby inducing local tissue damage [22, 23]. Preclinical studies have reported on the radiosensitising effects of CDK 4/6 inhibition in glioblastoma patient-derived cell lines and prostate cancer cell lines, and survival was extended when the two treatments were combined in glioblastoma mice models [24, 25]. While one study demonstrated the protective role of CDK 4/6 inhibition against radiation-induced intestinal injury in mice, another found that palbociclib before a single dose of subtotal body irradiation was protective but palbociclib before and during five daily fractions of irradiation exacerbated gastrointestinal injury in mice [25, 26].Fig. 5 Proposed mechanisms of tissue damage when combining CDK 4/6 inhibitors with radiation.
Fig 5
The above five cases highlight the importance of clinical vigilance when administering palbociclib either concurrently or after radiation. Although the vignettes reported all pertain to palbociclib – (the first approved CDK 4/6 inhibitor) - it is foreseeable that other CDK 4/6 inhibitors, owing to similar mechanistic actions may be associated with analogous effects. CDK 4/6 inhibitors are now a mainstay of treatment in mBC and their role in the adjuvant setting, in second line and beyond and other tumour types are also being actively investigated, underscoring the importance of understanding their safety profile when used in conjunction with radiotherapy.
These five cases (19%) were identified from a total of twenty-six patients who received palliative RT either prior to, or concomitantly with treatment with a CDK 4/6 inhibitor. We acknowledge that this is a retrospective analysis but this represents a not insignificant rate of enhanced toxicity worthy of further study.
In particular, a few clinically pertinent questions warrant careful study. First, what is the optimal timing of CDK 4/6 inhibitor administration before, during and after RT? If concurrent use is to be avoided, what then is an appropriate washout period of the CDK 4/6 inhibitor, conceivably to allow bystander tissue damage recovery or reduction of reactive immune cells within the radiation field? As suggested in preclinical studies, fractionation and scheduling of radiation will likely also play a role and requires further evaluation. Second, it is plausible that certain tissues or organs may be more vulnerable to injury. Examples include tissues that are rapidly renewing or those with continuous exposure to pathogens and consequently higher levels of innate reactive immunologic activities such as lung, skin and the gastrointestinal tract. Specific attention to these areas may be relevant for radiation planning. Third, there may be a subset of patients who are at higher risk, such as those suffering from superimposed infection or those with comorbid pathology in the radiation field for whom treatment should be carefully considered and individualised. Therefore, highly conformal radiotherapy planning techniques should be considered even when prescribing palliative intent radiotherapy to mitigate the risks of enhanced toxicity to organs at risk.
Conclusion
This case series demonstrates the potential of enhanced RT toxicity when administering a CDK 4/6 inhibitor concurrently or soon after radiotherapy. Clinicians using this combination should consider this potential when prescribing RT. Additional studies on combined CDK 4/6 inhibition and RT are required to further clarify the potential for enhanced toxicity from this combination.
Declaration of Competing Interest
None.
Funding source
None.
Ethical approval
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33227663 | 19,614,450 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diabetic ketoacidosis'. | A Remarkable Elevation in the Procalcitonin Levels Due to Diabetic Ketoacidosis in a Hemodialysis Patient.
Procalcitonin (PCT), a marker of the inflammatory response during infections, can be elevated by diabetic ketoacidosis (DKA). A male patient in his 50s with diabetic nephropathy on hemodialysis presented with vomiting and a reduced level of consciousness and was diagnosed with DKA. His PCT level was markedly elevated, but bacterial cultures (blood, urine, and stool) were negative. The PCT level decreased after DKA improvement. In this patient, DKA probably enhanced the PCT levels. As DKA can increase the PCT levels, an elevation of the PCT levels in DKA patients may not be indicative of infectious diseases, and non-infectious causes of DKA should therefore be considered.
Introduction
Diabetic ketoacidosis (DKA) is one of the most serious complications of diabetes mellitus (DM). It often manifests in type 1 and type 2 DM. Infections are the most common triggers of DKA. Several studies have reported that DKA enhances cytokine production (1-3). The procalcitonin (PCT) levels increase in bacterial infections/sepsis and they are used as markers of bacterial infection (4). However, they can also increase in conditions that elevate the cytokine levels, such as burns, trauma, surgery, and pancreatitis (5). A few studies have reported that PCT can increase in DKA. However, the mechanism by which DKA leads to elevated PCT levels remains unknown. To the best of our knowledge, only one report has quantified the PCT levels in DKA (6). Understanding the transition in the PCT level is important for elucidating the relationship between PCT and DKA. In this case report, we measured the PCT levels twice (during and after DKA). Importantly, this is the first report on the relationship between PCT and DKA in patients on hemodialysis (HD). Specifically, we herein present the case of a patient on HD with DKA who had markedly elevated PCT levels, and we assessed the relationship between PCT and DKA.
Case Report
A male patient in his 50s presented to our hospital with vomiting, a reduced level of consciousness, and malaise that had developed 2 days prior to admission. He had been receiving treatment for type 1 DM for 34 years and HD for end-stage kidney disease due to diabetic nephropathy for 6 years. He had received online-hemodiafiltration (HDF) 2 days before admission. He was on insulin therapy (insulin glargine: 10 U at bedtime; insulin aspart: 6 U at breakfast, lunch, and dinner time), although he stopped the insulin therapy the day before admission. His regular medications were rabeprazole sodium, precipitated calcium carbonate, bixalomer, alfacalcidol, amitriptyline hydrochloride, and atorvastatin calcium hydrate. The initial physical examination showed a blood pressure of 100/51 mmHg, a heart rate of 80 beats/min, and an oxygen saturation of 99% (room air). His height, body weight, and body mass index were 163 cm, 57.6 kg, and 21.7 kg/m2, respectively. His respiratory sounds were clear, and no abnormal abdominal findings were noted. Blood investigations (Table 1) showed severe metabolic acidosis, hyperkalemia, hyponatremia, high PCT levels (62.84 ng/mL), hyperglycemia (767 mg/dL), and elevated 3-hydroxybutyric acid levels. Therefore, we diagnosed him with DKA, attributed to the cessation of insulin therapy. An electrocardiogram showed normal P and inverted T waves. Chest X-ray imaging (Fig. 1) showed no pneumonia, whereas chest computed tomography (CT) showed a very mild frosted glass image on the ventral side of the right lung (in S1). Therefore, we diagnosed him as having slight pneumonia.
Table 1. Laboratory Investigation.
Hematology Blood chemistry Blood gas (arterial blood)
WBC 14,530 /μL TP 6.8 g/dL Na 124 mmol/L pH 7.019
Neut 95.5 % Alb 3.6 g/dL K 7.8 mmol/L PCO2 26.4 mmHg
Lynph 0.5 % T-bil 0.1 mg/dL Cl 88 mmol/L PO2 82.1 mmHg
Mono 4 % AST 24 U/L Ca 8.9 mg/dL HCO3- 8.0 mmol/L
RBC 391 ×104/μL ALT 17 U/L P 6.2 mg/dL Lac 4.8 mEq/L
Hb 12.0 g/dL LDH 238 U/L CRP 6.38 mg/dL
Plt 10.5 ×104/μL γ-GTP 7 U/L PCT 62.84 ng/mL
Coagulation Alp 319 U/L PG 767 mg/dL
PT-INR 1.00 BUN 100.9 mg/dL 3-OHBA 4.3 mmol/L
APTT 29.4 s Crea 12.46 mg/dL CPR <0.01 ng/mL
Fib 646 mg/dL
D dimer 0.6 μg/mL
3-OHBA: 3-Hydroxybutyric acid, Alb: albumin, Alp: alkaline phosphatase, ALT: alanine aminotransferase, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, BUN: blood urea nitrogen, CPR: C-peptide immunoreactivity, Crea: creatinine, CRP: C-reactive protein, Fib: fibrinogen, Hb: hemoglobin, Lac: lactate, LDH: lactate dehydrogenase, Lymph: lymphocytes, Mono: monocytes, Neut: neutrophils, PCT: procalcitonin, PG: plasma glucose, Plt: platelet, PT-INR: prothrombin time international normalized ratio, RBC: red blood cells, T-bil: total-bilirubin, TP: total protein, WBC: white blood cells, γ-GTP: γ-glutamyl transpeptidase
Figure 1. Chest X-ray and computed tomography.
Calcium gluconate hydrate (1,700 mg) was injected intravenously, glucose insulin therapy was started, and emergency HD [polyethersulfone (PES) membrane; membrane surface area, 1.5 m2; blood flow, 150 mL/min; dialysis time, 4 h] was urgently performed to manage hyperkalemia. Maintenance hemodialysis (offline-HDF; PES membrane; membrane surface area, 2.1 m2; blood flow, 200 mL/min; dialysis time, 4 h) was started on the 2nd day. The continuous intravenous administration of insulin was initiated for managing DKA but was discontinued because of appetite improvement 3 days after admission. Subsequently, intensive insulin therapy was initiated.
A high inflammatory response [C-reactive protein (CRP) levels, 6.38 mg/dL; PCT levels, 62.84 ng/mL] was observed (Fig. 2). However, chest CT showed only a slight frosted glass image, and cultures for blood, urine, and stool were negative. We could not perform a sputum culture due to the absence of respiratory symptoms. The intravenous administration of tazobactam/piperacillin 4.5 g twice daily had been started at admission, but was discontinued on the 4th day; instead, oral sultamicillin 375mg once daily was initiated. CRP levels rapidly decreased, although his general condition improved. Therefore, we judged that the infection had resolved, and the antibiotics were discontinued on the 10th day. The PCT levels decreased to 29.6 ng/mL on the 8th day. The patient's blood glucose levels stabilized, and his general condition improved; therefore, he was discharged on the 12th day. After discharge, he did not develop any infectious disease and did not experience a recurrence of DKA.
Figure 2. Clinical course of the patient on HD admitted with DKA. CRP: C-reactive protein, CVII: continuous venous insulin infusion, DKA: diabetic ketoacidosis, HD: Hemodialysis, HDF: Hemodiafiltration, Neut: neutrophils, PCT: procalcitonin, SBTPC: sultamicillin, TAZ/PIPC: tazobactam/piperacillin, WBC: white blood cells
Discussion
PCT has higher sensitivity and specificity than CRP for distinguishing between infectious and non-infectious diseases. The PCT levels can help to differentiate between bacterial and viral infections with a high sensitivity (92%) (4). PCT is normally synthesized in thyroid C cells, as a precursor of calcitonin (7). However, in severe infections caused by bacteria, parasites, and fungi, inflammatory cytokines are produced by the action of bacterial cells and toxins. These cytokines act on organs, such as lungs, kidneys, liver, adipose tissue, and muscles, promoting PCT production (8).
However, serious trauma, surgical invasion, and severe burns, Plasmodium infection, acute respiratory distress syndrome (ARDS) can also lead to elevated PCT levels, and caution is required when interpreting PCT findings in such cases (5). Several studies have reported that DKA enhances cytokine production (1-3). Moreover, hyperglycemia also enhances cytokine production (9). Hence, DKA leads to the production of inflammatory cytokines and an increase in the PCT levels.
Ivaska et al. reported that when children with type 1 DM develop DKA, the PCT levels are high despite the absence of infection (10). Two studies have reported a PCT elevation after DKA in adults with type 1 DM (10, 11). Information regarding these eight previously reported cases is presented in Table 2. Except for our case, all cases of PCT elevation due to DKA were reported in women, and the median age of the patients was 34 years (range, 14-73 years), which was relatively low. This is likely because women have a stronger immune response than men do (12), and younger individuals in general show higher cytokine production. It is also widely considered that DKA is more likely to occur in young people (13).
Table 2. Comparison of the Present Case with Previously Reported DKA Patient with High PCT Level.
Sex Age
(year) Plasma glucose
(mg/dL) pH Lactate
(mEq/L) WBC
(/L) CRP
(mg/dL) PCT
(ng/mL) Reference
F 14 633 7.04 3.3 25,800 8.4 82.94 9
F 15 601 7.00 4.3 24,600 5.5 13.13 9
F N/A 522 N/A N/A N/A N/A 1.72 10
F 34 539 6.91 2.1 21,800 0.06 12.4 11
F 42 1,177 6.94 4.6 19,910 0.31 30.47 11
F 32 623 6.80 1.6 26,510 0.25 8.81 11
F 73 1,044 7.06 2.8 18,900 2.08 6.87 11
M 59 767 7.019 4.8 14,530 6.38 62.84 The present case
CRP: C-reactive protein, DKA: diabetic ketoacidosis, PCT: procalcitonin, WBC: white blood cells
The CRP levels were slightly elevated at 3.28±3.17 mg/dL, but the PCT levels were very high at 26.29±26.57 ng/mL. However, the level of inflammatory cytokines has not been examined in any previous studies, and it was not possible to prove that DKA enhances PCT production via inflammatory cytokines. Moreover, the number of reported cases is small, and many more cases should be examined and analyzed to elucidate the relationship between inflammatory cytokines and DKA.
In addition, the standard threshold for PCT is slightly higher in patients undergoing HD. Kubo et al. reported that the median PCT level before dialysis in such patients was 0.23 ng/mL, which was higher than that in healthy participants (14). Trimarchi et al. reported that the 95th percentile of PCT levels in 45 uninfected patients on HD was 0.8 ng/mL, which is the upper limit of the reference value (15). While the PCT level in such patients can be slightly higher than that in healthy individuals, the PCT levels in our case were markedly high at 62.84 ng/mL, and no serious bacterial infection was observed. Although candidiasis and aspergillosis antigen tests were not performed, the two conditions were deemed unlikely because the clinical course and findings were not in accordance with either of the two conditions. Moreover, β-D-glucan was negative (5.2 pg/mL), and there were no characteristic findings on CT. Since the patient did not have respiratory distress, and pulmonary edema was not detected on chest CT, ARDS was excluded. With no history of overseas travel, Plasmodium infection was unlikely. Although non-severe pneumonia may raise the PCT levels, DKA was strongly suspected to be the main cause of the PCT elevation. In addition, it has been reported that PCT decreases with an improvement in acute hyperglycemia (16); however, the transition trajectory of the PCT levels among DKA patients has not been clarified. In our case, the improvement of DKA was also associated with a reduction in the PCT levels to 29.6 ng/mL, further supporting their DKA-dependent increase. In contrast, Cipriano et al. reported that “PCT returned to normal values (＜0.5 ng/mL) after 3 days of hospitalization, thus reflecting the half-life of the protein.” (6). The decline in the PCT level was slow in our case. Meisner et al. suggested that plasma clearance of PCT may be delayed in patients with renal dysfunction (17). While HD will gradually eliminate PCT, our patient could not attain the urinary excretion of procalcitonin because he was anuric. It was suggested that the rate of PCT elimination was slow by HD and offline-HDF alone.
The PCT removal rate was found to be 53.7% in a single HD using PES membrane (14). Nevertheless, there are no reports of PCT removal rates of HDF. The molecular weight of PCT is approximal 13 kDa, which is similar to that of β2 microglobulin. Online HDF can achieve a 46% higher β2-microglobulin removal rate when compared with HD (18) suggesting that the first has a better PCT removal rate than the latter. However, he received offline-HDF, and the PCT removal rate was not as high as that of the online-HDF, indicating that the decline in the PCT level was slow. One limitation associated with this report was that the cause of PCT elevation was not only DKA, but pneumonia was also slightly involved.
Conclusion
Bacterial infections often cause DKA which may elevate the PCT levels. However, DKA in the absence of bacterial infection can also increase the PCT levels. Therefore, in DKA, it is necessary to carefully determine whether PCT is elevated because of bacterial infection or due to DKA itself. In patients on HD, the rate of PCT decline is slower. Further studies are thus needed to determine the transition of PCT in DKA patients on HD.
The authors state that they have no Conflict of Interest (COI). | ALFACALCIDOL, AMITRIPTYLINE HYDROCHLORIDE, ATORVASTATIN CALCIUM, BIXALOMER, CALCIUM CARBONATE, INSULIN ASPART, INSULIN GLARGINE, RABEPRAZOLE SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33229806 | 19,958,472 | 2021-04-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product dose omission issue'. | A Remarkable Elevation in the Procalcitonin Levels Due to Diabetic Ketoacidosis in a Hemodialysis Patient.
Procalcitonin (PCT), a marker of the inflammatory response during infections, can be elevated by diabetic ketoacidosis (DKA). A male patient in his 50s with diabetic nephropathy on hemodialysis presented with vomiting and a reduced level of consciousness and was diagnosed with DKA. His PCT level was markedly elevated, but bacterial cultures (blood, urine, and stool) were negative. The PCT level decreased after DKA improvement. In this patient, DKA probably enhanced the PCT levels. As DKA can increase the PCT levels, an elevation of the PCT levels in DKA patients may not be indicative of infectious diseases, and non-infectious causes of DKA should therefore be considered.
Introduction
Diabetic ketoacidosis (DKA) is one of the most serious complications of diabetes mellitus (DM). It often manifests in type 1 and type 2 DM. Infections are the most common triggers of DKA. Several studies have reported that DKA enhances cytokine production (1-3). The procalcitonin (PCT) levels increase in bacterial infections/sepsis and they are used as markers of bacterial infection (4). However, they can also increase in conditions that elevate the cytokine levels, such as burns, trauma, surgery, and pancreatitis (5). A few studies have reported that PCT can increase in DKA. However, the mechanism by which DKA leads to elevated PCT levels remains unknown. To the best of our knowledge, only one report has quantified the PCT levels in DKA (6). Understanding the transition in the PCT level is important for elucidating the relationship between PCT and DKA. In this case report, we measured the PCT levels twice (during and after DKA). Importantly, this is the first report on the relationship between PCT and DKA in patients on hemodialysis (HD). Specifically, we herein present the case of a patient on HD with DKA who had markedly elevated PCT levels, and we assessed the relationship between PCT and DKA.
Case Report
A male patient in his 50s presented to our hospital with vomiting, a reduced level of consciousness, and malaise that had developed 2 days prior to admission. He had been receiving treatment for type 1 DM for 34 years and HD for end-stage kidney disease due to diabetic nephropathy for 6 years. He had received online-hemodiafiltration (HDF) 2 days before admission. He was on insulin therapy (insulin glargine: 10 U at bedtime; insulin aspart: 6 U at breakfast, lunch, and dinner time), although he stopped the insulin therapy the day before admission. His regular medications were rabeprazole sodium, precipitated calcium carbonate, bixalomer, alfacalcidol, amitriptyline hydrochloride, and atorvastatin calcium hydrate. The initial physical examination showed a blood pressure of 100/51 mmHg, a heart rate of 80 beats/min, and an oxygen saturation of 99% (room air). His height, body weight, and body mass index were 163 cm, 57.6 kg, and 21.7 kg/m2, respectively. His respiratory sounds were clear, and no abnormal abdominal findings were noted. Blood investigations (Table 1) showed severe metabolic acidosis, hyperkalemia, hyponatremia, high PCT levels (62.84 ng/mL), hyperglycemia (767 mg/dL), and elevated 3-hydroxybutyric acid levels. Therefore, we diagnosed him with DKA, attributed to the cessation of insulin therapy. An electrocardiogram showed normal P and inverted T waves. Chest X-ray imaging (Fig. 1) showed no pneumonia, whereas chest computed tomography (CT) showed a very mild frosted glass image on the ventral side of the right lung (in S1). Therefore, we diagnosed him as having slight pneumonia.
Table 1. Laboratory Investigation.
Hematology Blood chemistry Blood gas (arterial blood)
WBC 14,530 /μL TP 6.8 g/dL Na 124 mmol/L pH 7.019
Neut 95.5 % Alb 3.6 g/dL K 7.8 mmol/L PCO2 26.4 mmHg
Lynph 0.5 % T-bil 0.1 mg/dL Cl 88 mmol/L PO2 82.1 mmHg
Mono 4 % AST 24 U/L Ca 8.9 mg/dL HCO3- 8.0 mmol/L
RBC 391 ×104/μL ALT 17 U/L P 6.2 mg/dL Lac 4.8 mEq/L
Hb 12.0 g/dL LDH 238 U/L CRP 6.38 mg/dL
Plt 10.5 ×104/μL γ-GTP 7 U/L PCT 62.84 ng/mL
Coagulation Alp 319 U/L PG 767 mg/dL
PT-INR 1.00 BUN 100.9 mg/dL 3-OHBA 4.3 mmol/L
APTT 29.4 s Crea 12.46 mg/dL CPR <0.01 ng/mL
Fib 646 mg/dL
D dimer 0.6 μg/mL
3-OHBA: 3-Hydroxybutyric acid, Alb: albumin, Alp: alkaline phosphatase, ALT: alanine aminotransferase, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, BUN: blood urea nitrogen, CPR: C-peptide immunoreactivity, Crea: creatinine, CRP: C-reactive protein, Fib: fibrinogen, Hb: hemoglobin, Lac: lactate, LDH: lactate dehydrogenase, Lymph: lymphocytes, Mono: monocytes, Neut: neutrophils, PCT: procalcitonin, PG: plasma glucose, Plt: platelet, PT-INR: prothrombin time international normalized ratio, RBC: red blood cells, T-bil: total-bilirubin, TP: total protein, WBC: white blood cells, γ-GTP: γ-glutamyl transpeptidase
Figure 1. Chest X-ray and computed tomography.
Calcium gluconate hydrate (1,700 mg) was injected intravenously, glucose insulin therapy was started, and emergency HD [polyethersulfone (PES) membrane; membrane surface area, 1.5 m2; blood flow, 150 mL/min; dialysis time, 4 h] was urgently performed to manage hyperkalemia. Maintenance hemodialysis (offline-HDF; PES membrane; membrane surface area, 2.1 m2; blood flow, 200 mL/min; dialysis time, 4 h) was started on the 2nd day. The continuous intravenous administration of insulin was initiated for managing DKA but was discontinued because of appetite improvement 3 days after admission. Subsequently, intensive insulin therapy was initiated.
A high inflammatory response [C-reactive protein (CRP) levels, 6.38 mg/dL; PCT levels, 62.84 ng/mL] was observed (Fig. 2). However, chest CT showed only a slight frosted glass image, and cultures for blood, urine, and stool were negative. We could not perform a sputum culture due to the absence of respiratory symptoms. The intravenous administration of tazobactam/piperacillin 4.5 g twice daily had been started at admission, but was discontinued on the 4th day; instead, oral sultamicillin 375mg once daily was initiated. CRP levels rapidly decreased, although his general condition improved. Therefore, we judged that the infection had resolved, and the antibiotics were discontinued on the 10th day. The PCT levels decreased to 29.6 ng/mL on the 8th day. The patient's blood glucose levels stabilized, and his general condition improved; therefore, he was discharged on the 12th day. After discharge, he did not develop any infectious disease and did not experience a recurrence of DKA.
Figure 2. Clinical course of the patient on HD admitted with DKA. CRP: C-reactive protein, CVII: continuous venous insulin infusion, DKA: diabetic ketoacidosis, HD: Hemodialysis, HDF: Hemodiafiltration, Neut: neutrophils, PCT: procalcitonin, SBTPC: sultamicillin, TAZ/PIPC: tazobactam/piperacillin, WBC: white blood cells
Discussion
PCT has higher sensitivity and specificity than CRP for distinguishing between infectious and non-infectious diseases. The PCT levels can help to differentiate between bacterial and viral infections with a high sensitivity (92%) (4). PCT is normally synthesized in thyroid C cells, as a precursor of calcitonin (7). However, in severe infections caused by bacteria, parasites, and fungi, inflammatory cytokines are produced by the action of bacterial cells and toxins. These cytokines act on organs, such as lungs, kidneys, liver, adipose tissue, and muscles, promoting PCT production (8).
However, serious trauma, surgical invasion, and severe burns, Plasmodium infection, acute respiratory distress syndrome (ARDS) can also lead to elevated PCT levels, and caution is required when interpreting PCT findings in such cases (5). Several studies have reported that DKA enhances cytokine production (1-3). Moreover, hyperglycemia also enhances cytokine production (9). Hence, DKA leads to the production of inflammatory cytokines and an increase in the PCT levels.
Ivaska et al. reported that when children with type 1 DM develop DKA, the PCT levels are high despite the absence of infection (10). Two studies have reported a PCT elevation after DKA in adults with type 1 DM (10, 11). Information regarding these eight previously reported cases is presented in Table 2. Except for our case, all cases of PCT elevation due to DKA were reported in women, and the median age of the patients was 34 years (range, 14-73 years), which was relatively low. This is likely because women have a stronger immune response than men do (12), and younger individuals in general show higher cytokine production. It is also widely considered that DKA is more likely to occur in young people (13).
Table 2. Comparison of the Present Case with Previously Reported DKA Patient with High PCT Level.
Sex Age
(year) Plasma glucose
(mg/dL) pH Lactate
(mEq/L) WBC
(/L) CRP
(mg/dL) PCT
(ng/mL) Reference
F 14 633 7.04 3.3 25,800 8.4 82.94 9
F 15 601 7.00 4.3 24,600 5.5 13.13 9
F N/A 522 N/A N/A N/A N/A 1.72 10
F 34 539 6.91 2.1 21,800 0.06 12.4 11
F 42 1,177 6.94 4.6 19,910 0.31 30.47 11
F 32 623 6.80 1.6 26,510 0.25 8.81 11
F 73 1,044 7.06 2.8 18,900 2.08 6.87 11
M 59 767 7.019 4.8 14,530 6.38 62.84 The present case
CRP: C-reactive protein, DKA: diabetic ketoacidosis, PCT: procalcitonin, WBC: white blood cells
The CRP levels were slightly elevated at 3.28±3.17 mg/dL, but the PCT levels were very high at 26.29±26.57 ng/mL. However, the level of inflammatory cytokines has not been examined in any previous studies, and it was not possible to prove that DKA enhances PCT production via inflammatory cytokines. Moreover, the number of reported cases is small, and many more cases should be examined and analyzed to elucidate the relationship between inflammatory cytokines and DKA.
In addition, the standard threshold for PCT is slightly higher in patients undergoing HD. Kubo et al. reported that the median PCT level before dialysis in such patients was 0.23 ng/mL, which was higher than that in healthy participants (14). Trimarchi et al. reported that the 95th percentile of PCT levels in 45 uninfected patients on HD was 0.8 ng/mL, which is the upper limit of the reference value (15). While the PCT level in such patients can be slightly higher than that in healthy individuals, the PCT levels in our case were markedly high at 62.84 ng/mL, and no serious bacterial infection was observed. Although candidiasis and aspergillosis antigen tests were not performed, the two conditions were deemed unlikely because the clinical course and findings were not in accordance with either of the two conditions. Moreover, β-D-glucan was negative (5.2 pg/mL), and there were no characteristic findings on CT. Since the patient did not have respiratory distress, and pulmonary edema was not detected on chest CT, ARDS was excluded. With no history of overseas travel, Plasmodium infection was unlikely. Although non-severe pneumonia may raise the PCT levels, DKA was strongly suspected to be the main cause of the PCT elevation. In addition, it has been reported that PCT decreases with an improvement in acute hyperglycemia (16); however, the transition trajectory of the PCT levels among DKA patients has not been clarified. In our case, the improvement of DKA was also associated with a reduction in the PCT levels to 29.6 ng/mL, further supporting their DKA-dependent increase. In contrast, Cipriano et al. reported that “PCT returned to normal values (＜0.5 ng/mL) after 3 days of hospitalization, thus reflecting the half-life of the protein.” (6). The decline in the PCT level was slow in our case. Meisner et al. suggested that plasma clearance of PCT may be delayed in patients with renal dysfunction (17). While HD will gradually eliminate PCT, our patient could not attain the urinary excretion of procalcitonin because he was anuric. It was suggested that the rate of PCT elimination was slow by HD and offline-HDF alone.
The PCT removal rate was found to be 53.7% in a single HD using PES membrane (14). Nevertheless, there are no reports of PCT removal rates of HDF. The molecular weight of PCT is approximal 13 kDa, which is similar to that of β2 microglobulin. Online HDF can achieve a 46% higher β2-microglobulin removal rate when compared with HD (18) suggesting that the first has a better PCT removal rate than the latter. However, he received offline-HDF, and the PCT removal rate was not as high as that of the online-HDF, indicating that the decline in the PCT level was slow. One limitation associated with this report was that the cause of PCT elevation was not only DKA, but pneumonia was also slightly involved.
Conclusion
Bacterial infections often cause DKA which may elevate the PCT levels. However, DKA in the absence of bacterial infection can also increase the PCT levels. Therefore, in DKA, it is necessary to carefully determine whether PCT is elevated because of bacterial infection or due to DKA itself. In patients on HD, the rate of PCT decline is slower. Further studies are thus needed to determine the transition of PCT in DKA patients on HD.
The authors state that they have no Conflict of Interest (COI). | ALFACALCIDOL, AMITRIPTYLINE HYDROCHLORIDE, ATORVASTATIN CALCIUM, BIXALOMER, CALCIUM CARBONATE, INSULIN ASPART, INSULIN GLARGINE, RABEPRAZOLE SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33229806 | 19,958,472 | 2021-04-15 |
What is the weight of the patient? | A Remarkable Elevation in the Procalcitonin Levels Due to Diabetic Ketoacidosis in a Hemodialysis Patient.
Procalcitonin (PCT), a marker of the inflammatory response during infections, can be elevated by diabetic ketoacidosis (DKA). A male patient in his 50s with diabetic nephropathy on hemodialysis presented with vomiting and a reduced level of consciousness and was diagnosed with DKA. His PCT level was markedly elevated, but bacterial cultures (blood, urine, and stool) were negative. The PCT level decreased after DKA improvement. In this patient, DKA probably enhanced the PCT levels. As DKA can increase the PCT levels, an elevation of the PCT levels in DKA patients may not be indicative of infectious diseases, and non-infectious causes of DKA should therefore be considered.
Introduction
Diabetic ketoacidosis (DKA) is one of the most serious complications of diabetes mellitus (DM). It often manifests in type 1 and type 2 DM. Infections are the most common triggers of DKA. Several studies have reported that DKA enhances cytokine production (1-3). The procalcitonin (PCT) levels increase in bacterial infections/sepsis and they are used as markers of bacterial infection (4). However, they can also increase in conditions that elevate the cytokine levels, such as burns, trauma, surgery, and pancreatitis (5). A few studies have reported that PCT can increase in DKA. However, the mechanism by which DKA leads to elevated PCT levels remains unknown. To the best of our knowledge, only one report has quantified the PCT levels in DKA (6). Understanding the transition in the PCT level is important for elucidating the relationship between PCT and DKA. In this case report, we measured the PCT levels twice (during and after DKA). Importantly, this is the first report on the relationship between PCT and DKA in patients on hemodialysis (HD). Specifically, we herein present the case of a patient on HD with DKA who had markedly elevated PCT levels, and we assessed the relationship between PCT and DKA.
Case Report
A male patient in his 50s presented to our hospital with vomiting, a reduced level of consciousness, and malaise that had developed 2 days prior to admission. He had been receiving treatment for type 1 DM for 34 years and HD for end-stage kidney disease due to diabetic nephropathy for 6 years. He had received online-hemodiafiltration (HDF) 2 days before admission. He was on insulin therapy (insulin glargine: 10 U at bedtime; insulin aspart: 6 U at breakfast, lunch, and dinner time), although he stopped the insulin therapy the day before admission. His regular medications were rabeprazole sodium, precipitated calcium carbonate, bixalomer, alfacalcidol, amitriptyline hydrochloride, and atorvastatin calcium hydrate. The initial physical examination showed a blood pressure of 100/51 mmHg, a heart rate of 80 beats/min, and an oxygen saturation of 99% (room air). His height, body weight, and body mass index were 163 cm, 57.6 kg, and 21.7 kg/m2, respectively. His respiratory sounds were clear, and no abnormal abdominal findings were noted. Blood investigations (Table 1) showed severe metabolic acidosis, hyperkalemia, hyponatremia, high PCT levels (62.84 ng/mL), hyperglycemia (767 mg/dL), and elevated 3-hydroxybutyric acid levels. Therefore, we diagnosed him with DKA, attributed to the cessation of insulin therapy. An electrocardiogram showed normal P and inverted T waves. Chest X-ray imaging (Fig. 1) showed no pneumonia, whereas chest computed tomography (CT) showed a very mild frosted glass image on the ventral side of the right lung (in S1). Therefore, we diagnosed him as having slight pneumonia.
Table 1. Laboratory Investigation.
Hematology Blood chemistry Blood gas (arterial blood)
WBC 14,530 /μL TP 6.8 g/dL Na 124 mmol/L pH 7.019
Neut 95.5 % Alb 3.6 g/dL K 7.8 mmol/L PCO2 26.4 mmHg
Lynph 0.5 % T-bil 0.1 mg/dL Cl 88 mmol/L PO2 82.1 mmHg
Mono 4 % AST 24 U/L Ca 8.9 mg/dL HCO3- 8.0 mmol/L
RBC 391 ×104/μL ALT 17 U/L P 6.2 mg/dL Lac 4.8 mEq/L
Hb 12.0 g/dL LDH 238 U/L CRP 6.38 mg/dL
Plt 10.5 ×104/μL γ-GTP 7 U/L PCT 62.84 ng/mL
Coagulation Alp 319 U/L PG 767 mg/dL
PT-INR 1.00 BUN 100.9 mg/dL 3-OHBA 4.3 mmol/L
APTT 29.4 s Crea 12.46 mg/dL CPR <0.01 ng/mL
Fib 646 mg/dL
D dimer 0.6 μg/mL
3-OHBA: 3-Hydroxybutyric acid, Alb: albumin, Alp: alkaline phosphatase, ALT: alanine aminotransferase, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, BUN: blood urea nitrogen, CPR: C-peptide immunoreactivity, Crea: creatinine, CRP: C-reactive protein, Fib: fibrinogen, Hb: hemoglobin, Lac: lactate, LDH: lactate dehydrogenase, Lymph: lymphocytes, Mono: monocytes, Neut: neutrophils, PCT: procalcitonin, PG: plasma glucose, Plt: platelet, PT-INR: prothrombin time international normalized ratio, RBC: red blood cells, T-bil: total-bilirubin, TP: total protein, WBC: white blood cells, γ-GTP: γ-glutamyl transpeptidase
Figure 1. Chest X-ray and computed tomography.
Calcium gluconate hydrate (1,700 mg) was injected intravenously, glucose insulin therapy was started, and emergency HD [polyethersulfone (PES) membrane; membrane surface area, 1.5 m2; blood flow, 150 mL/min; dialysis time, 4 h] was urgently performed to manage hyperkalemia. Maintenance hemodialysis (offline-HDF; PES membrane; membrane surface area, 2.1 m2; blood flow, 200 mL/min; dialysis time, 4 h) was started on the 2nd day. The continuous intravenous administration of insulin was initiated for managing DKA but was discontinued because of appetite improvement 3 days after admission. Subsequently, intensive insulin therapy was initiated.
A high inflammatory response [C-reactive protein (CRP) levels, 6.38 mg/dL; PCT levels, 62.84 ng/mL] was observed (Fig. 2). However, chest CT showed only a slight frosted glass image, and cultures for blood, urine, and stool were negative. We could not perform a sputum culture due to the absence of respiratory symptoms. The intravenous administration of tazobactam/piperacillin 4.5 g twice daily had been started at admission, but was discontinued on the 4th day; instead, oral sultamicillin 375mg once daily was initiated. CRP levels rapidly decreased, although his general condition improved. Therefore, we judged that the infection had resolved, and the antibiotics were discontinued on the 10th day. The PCT levels decreased to 29.6 ng/mL on the 8th day. The patient's blood glucose levels stabilized, and his general condition improved; therefore, he was discharged on the 12th day. After discharge, he did not develop any infectious disease and did not experience a recurrence of DKA.
Figure 2. Clinical course of the patient on HD admitted with DKA. CRP: C-reactive protein, CVII: continuous venous insulin infusion, DKA: diabetic ketoacidosis, HD: Hemodialysis, HDF: Hemodiafiltration, Neut: neutrophils, PCT: procalcitonin, SBTPC: sultamicillin, TAZ/PIPC: tazobactam/piperacillin, WBC: white blood cells
Discussion
PCT has higher sensitivity and specificity than CRP for distinguishing between infectious and non-infectious diseases. The PCT levels can help to differentiate between bacterial and viral infections with a high sensitivity (92%) (4). PCT is normally synthesized in thyroid C cells, as a precursor of calcitonin (7). However, in severe infections caused by bacteria, parasites, and fungi, inflammatory cytokines are produced by the action of bacterial cells and toxins. These cytokines act on organs, such as lungs, kidneys, liver, adipose tissue, and muscles, promoting PCT production (8).
However, serious trauma, surgical invasion, and severe burns, Plasmodium infection, acute respiratory distress syndrome (ARDS) can also lead to elevated PCT levels, and caution is required when interpreting PCT findings in such cases (5). Several studies have reported that DKA enhances cytokine production (1-3). Moreover, hyperglycemia also enhances cytokine production (9). Hence, DKA leads to the production of inflammatory cytokines and an increase in the PCT levels.
Ivaska et al. reported that when children with type 1 DM develop DKA, the PCT levels are high despite the absence of infection (10). Two studies have reported a PCT elevation after DKA in adults with type 1 DM (10, 11). Information regarding these eight previously reported cases is presented in Table 2. Except for our case, all cases of PCT elevation due to DKA were reported in women, and the median age of the patients was 34 years (range, 14-73 years), which was relatively low. This is likely because women have a stronger immune response than men do (12), and younger individuals in general show higher cytokine production. It is also widely considered that DKA is more likely to occur in young people (13).
Table 2. Comparison of the Present Case with Previously Reported DKA Patient with High PCT Level.
Sex Age
(year) Plasma glucose
(mg/dL) pH Lactate
(mEq/L) WBC
(/L) CRP
(mg/dL) PCT
(ng/mL) Reference
F 14 633 7.04 3.3 25,800 8.4 82.94 9
F 15 601 7.00 4.3 24,600 5.5 13.13 9
F N/A 522 N/A N/A N/A N/A 1.72 10
F 34 539 6.91 2.1 21,800 0.06 12.4 11
F 42 1,177 6.94 4.6 19,910 0.31 30.47 11
F 32 623 6.80 1.6 26,510 0.25 8.81 11
F 73 1,044 7.06 2.8 18,900 2.08 6.87 11
M 59 767 7.019 4.8 14,530 6.38 62.84 The present case
CRP: C-reactive protein, DKA: diabetic ketoacidosis, PCT: procalcitonin, WBC: white blood cells
The CRP levels were slightly elevated at 3.28±3.17 mg/dL, but the PCT levels were very high at 26.29±26.57 ng/mL. However, the level of inflammatory cytokines has not been examined in any previous studies, and it was not possible to prove that DKA enhances PCT production via inflammatory cytokines. Moreover, the number of reported cases is small, and many more cases should be examined and analyzed to elucidate the relationship between inflammatory cytokines and DKA.
In addition, the standard threshold for PCT is slightly higher in patients undergoing HD. Kubo et al. reported that the median PCT level before dialysis in such patients was 0.23 ng/mL, which was higher than that in healthy participants (14). Trimarchi et al. reported that the 95th percentile of PCT levels in 45 uninfected patients on HD was 0.8 ng/mL, which is the upper limit of the reference value (15). While the PCT level in such patients can be slightly higher than that in healthy individuals, the PCT levels in our case were markedly high at 62.84 ng/mL, and no serious bacterial infection was observed. Although candidiasis and aspergillosis antigen tests were not performed, the two conditions were deemed unlikely because the clinical course and findings were not in accordance with either of the two conditions. Moreover, β-D-glucan was negative (5.2 pg/mL), and there were no characteristic findings on CT. Since the patient did not have respiratory distress, and pulmonary edema was not detected on chest CT, ARDS was excluded. With no history of overseas travel, Plasmodium infection was unlikely. Although non-severe pneumonia may raise the PCT levels, DKA was strongly suspected to be the main cause of the PCT elevation. In addition, it has been reported that PCT decreases with an improvement in acute hyperglycemia (16); however, the transition trajectory of the PCT levels among DKA patients has not been clarified. In our case, the improvement of DKA was also associated with a reduction in the PCT levels to 29.6 ng/mL, further supporting their DKA-dependent increase. In contrast, Cipriano et al. reported that “PCT returned to normal values (＜0.5 ng/mL) after 3 days of hospitalization, thus reflecting the half-life of the protein.” (6). The decline in the PCT level was slow in our case. Meisner et al. suggested that plasma clearance of PCT may be delayed in patients with renal dysfunction (17). While HD will gradually eliminate PCT, our patient could not attain the urinary excretion of procalcitonin because he was anuric. It was suggested that the rate of PCT elimination was slow by HD and offline-HDF alone.
The PCT removal rate was found to be 53.7% in a single HD using PES membrane (14). Nevertheless, there are no reports of PCT removal rates of HDF. The molecular weight of PCT is approximal 13 kDa, which is similar to that of β2 microglobulin. Online HDF can achieve a 46% higher β2-microglobulin removal rate when compared with HD (18) suggesting that the first has a better PCT removal rate than the latter. However, he received offline-HDF, and the PCT removal rate was not as high as that of the online-HDF, indicating that the decline in the PCT level was slow. One limitation associated with this report was that the cause of PCT elevation was not only DKA, but pneumonia was also slightly involved.
Conclusion
Bacterial infections often cause DKA which may elevate the PCT levels. However, DKA in the absence of bacterial infection can also increase the PCT levels. Therefore, in DKA, it is necessary to carefully determine whether PCT is elevated because of bacterial infection or due to DKA itself. In patients on HD, the rate of PCT decline is slower. Further studies are thus needed to determine the transition of PCT in DKA patients on HD.
The authors state that they have no Conflict of Interest (COI). | 57.6 kg. | Weight | CC BY-NC-ND | 33229806 | 19,958,472 | 2021-04-15 |
What was the dosage of drug 'INSULIN ASPART'? | A Remarkable Elevation in the Procalcitonin Levels Due to Diabetic Ketoacidosis in a Hemodialysis Patient.
Procalcitonin (PCT), a marker of the inflammatory response during infections, can be elevated by diabetic ketoacidosis (DKA). A male patient in his 50s with diabetic nephropathy on hemodialysis presented with vomiting and a reduced level of consciousness and was diagnosed with DKA. His PCT level was markedly elevated, but bacterial cultures (blood, urine, and stool) were negative. The PCT level decreased after DKA improvement. In this patient, DKA probably enhanced the PCT levels. As DKA can increase the PCT levels, an elevation of the PCT levels in DKA patients may not be indicative of infectious diseases, and non-infectious causes of DKA should therefore be considered.
Introduction
Diabetic ketoacidosis (DKA) is one of the most serious complications of diabetes mellitus (DM). It often manifests in type 1 and type 2 DM. Infections are the most common triggers of DKA. Several studies have reported that DKA enhances cytokine production (1-3). The procalcitonin (PCT) levels increase in bacterial infections/sepsis and they are used as markers of bacterial infection (4). However, they can also increase in conditions that elevate the cytokine levels, such as burns, trauma, surgery, and pancreatitis (5). A few studies have reported that PCT can increase in DKA. However, the mechanism by which DKA leads to elevated PCT levels remains unknown. To the best of our knowledge, only one report has quantified the PCT levels in DKA (6). Understanding the transition in the PCT level is important for elucidating the relationship between PCT and DKA. In this case report, we measured the PCT levels twice (during and after DKA). Importantly, this is the first report on the relationship between PCT and DKA in patients on hemodialysis (HD). Specifically, we herein present the case of a patient on HD with DKA who had markedly elevated PCT levels, and we assessed the relationship between PCT and DKA.
Case Report
A male patient in his 50s presented to our hospital with vomiting, a reduced level of consciousness, and malaise that had developed 2 days prior to admission. He had been receiving treatment for type 1 DM for 34 years and HD for end-stage kidney disease due to diabetic nephropathy for 6 years. He had received online-hemodiafiltration (HDF) 2 days before admission. He was on insulin therapy (insulin glargine: 10 U at bedtime; insulin aspart: 6 U at breakfast, lunch, and dinner time), although he stopped the insulin therapy the day before admission. His regular medications were rabeprazole sodium, precipitated calcium carbonate, bixalomer, alfacalcidol, amitriptyline hydrochloride, and atorvastatin calcium hydrate. The initial physical examination showed a blood pressure of 100/51 mmHg, a heart rate of 80 beats/min, and an oxygen saturation of 99% (room air). His height, body weight, and body mass index were 163 cm, 57.6 kg, and 21.7 kg/m2, respectively. His respiratory sounds were clear, and no abnormal abdominal findings were noted. Blood investigations (Table 1) showed severe metabolic acidosis, hyperkalemia, hyponatremia, high PCT levels (62.84 ng/mL), hyperglycemia (767 mg/dL), and elevated 3-hydroxybutyric acid levels. Therefore, we diagnosed him with DKA, attributed to the cessation of insulin therapy. An electrocardiogram showed normal P and inverted T waves. Chest X-ray imaging (Fig. 1) showed no pneumonia, whereas chest computed tomography (CT) showed a very mild frosted glass image on the ventral side of the right lung (in S1). Therefore, we diagnosed him as having slight pneumonia.
Table 1. Laboratory Investigation.
Hematology Blood chemistry Blood gas (arterial blood)
WBC 14,530 /μL TP 6.8 g/dL Na 124 mmol/L pH 7.019
Neut 95.5 % Alb 3.6 g/dL K 7.8 mmol/L PCO2 26.4 mmHg
Lynph 0.5 % T-bil 0.1 mg/dL Cl 88 mmol/L PO2 82.1 mmHg
Mono 4 % AST 24 U/L Ca 8.9 mg/dL HCO3- 8.0 mmol/L
RBC 391 ×104/μL ALT 17 U/L P 6.2 mg/dL Lac 4.8 mEq/L
Hb 12.0 g/dL LDH 238 U/L CRP 6.38 mg/dL
Plt 10.5 ×104/μL γ-GTP 7 U/L PCT 62.84 ng/mL
Coagulation Alp 319 U/L PG 767 mg/dL
PT-INR 1.00 BUN 100.9 mg/dL 3-OHBA 4.3 mmol/L
APTT 29.4 s Crea 12.46 mg/dL CPR <0.01 ng/mL
Fib 646 mg/dL
D dimer 0.6 μg/mL
3-OHBA: 3-Hydroxybutyric acid, Alb: albumin, Alp: alkaline phosphatase, ALT: alanine aminotransferase, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, BUN: blood urea nitrogen, CPR: C-peptide immunoreactivity, Crea: creatinine, CRP: C-reactive protein, Fib: fibrinogen, Hb: hemoglobin, Lac: lactate, LDH: lactate dehydrogenase, Lymph: lymphocytes, Mono: monocytes, Neut: neutrophils, PCT: procalcitonin, PG: plasma glucose, Plt: platelet, PT-INR: prothrombin time international normalized ratio, RBC: red blood cells, T-bil: total-bilirubin, TP: total protein, WBC: white blood cells, γ-GTP: γ-glutamyl transpeptidase
Figure 1. Chest X-ray and computed tomography.
Calcium gluconate hydrate (1,700 mg) was injected intravenously, glucose insulin therapy was started, and emergency HD [polyethersulfone (PES) membrane; membrane surface area, 1.5 m2; blood flow, 150 mL/min; dialysis time, 4 h] was urgently performed to manage hyperkalemia. Maintenance hemodialysis (offline-HDF; PES membrane; membrane surface area, 2.1 m2; blood flow, 200 mL/min; dialysis time, 4 h) was started on the 2nd day. The continuous intravenous administration of insulin was initiated for managing DKA but was discontinued because of appetite improvement 3 days after admission. Subsequently, intensive insulin therapy was initiated.
A high inflammatory response [C-reactive protein (CRP) levels, 6.38 mg/dL; PCT levels, 62.84 ng/mL] was observed (Fig. 2). However, chest CT showed only a slight frosted glass image, and cultures for blood, urine, and stool were negative. We could not perform a sputum culture due to the absence of respiratory symptoms. The intravenous administration of tazobactam/piperacillin 4.5 g twice daily had been started at admission, but was discontinued on the 4th day; instead, oral sultamicillin 375mg once daily was initiated. CRP levels rapidly decreased, although his general condition improved. Therefore, we judged that the infection had resolved, and the antibiotics were discontinued on the 10th day. The PCT levels decreased to 29.6 ng/mL on the 8th day. The patient's blood glucose levels stabilized, and his general condition improved; therefore, he was discharged on the 12th day. After discharge, he did not develop any infectious disease and did not experience a recurrence of DKA.
Figure 2. Clinical course of the patient on HD admitted with DKA. CRP: C-reactive protein, CVII: continuous venous insulin infusion, DKA: diabetic ketoacidosis, HD: Hemodialysis, HDF: Hemodiafiltration, Neut: neutrophils, PCT: procalcitonin, SBTPC: sultamicillin, TAZ/PIPC: tazobactam/piperacillin, WBC: white blood cells
Discussion
PCT has higher sensitivity and specificity than CRP for distinguishing between infectious and non-infectious diseases. The PCT levels can help to differentiate between bacterial and viral infections with a high sensitivity (92%) (4). PCT is normally synthesized in thyroid C cells, as a precursor of calcitonin (7). However, in severe infections caused by bacteria, parasites, and fungi, inflammatory cytokines are produced by the action of bacterial cells and toxins. These cytokines act on organs, such as lungs, kidneys, liver, adipose tissue, and muscles, promoting PCT production (8).
However, serious trauma, surgical invasion, and severe burns, Plasmodium infection, acute respiratory distress syndrome (ARDS) can also lead to elevated PCT levels, and caution is required when interpreting PCT findings in such cases (5). Several studies have reported that DKA enhances cytokine production (1-3). Moreover, hyperglycemia also enhances cytokine production (9). Hence, DKA leads to the production of inflammatory cytokines and an increase in the PCT levels.
Ivaska et al. reported that when children with type 1 DM develop DKA, the PCT levels are high despite the absence of infection (10). Two studies have reported a PCT elevation after DKA in adults with type 1 DM (10, 11). Information regarding these eight previously reported cases is presented in Table 2. Except for our case, all cases of PCT elevation due to DKA were reported in women, and the median age of the patients was 34 years (range, 14-73 years), which was relatively low. This is likely because women have a stronger immune response than men do (12), and younger individuals in general show higher cytokine production. It is also widely considered that DKA is more likely to occur in young people (13).
Table 2. Comparison of the Present Case with Previously Reported DKA Patient with High PCT Level.
Sex Age
(year) Plasma glucose
(mg/dL) pH Lactate
(mEq/L) WBC
(/L) CRP
(mg/dL) PCT
(ng/mL) Reference
F 14 633 7.04 3.3 25,800 8.4 82.94 9
F 15 601 7.00 4.3 24,600 5.5 13.13 9
F N/A 522 N/A N/A N/A N/A 1.72 10
F 34 539 6.91 2.1 21,800 0.06 12.4 11
F 42 1,177 6.94 4.6 19,910 0.31 30.47 11
F 32 623 6.80 1.6 26,510 0.25 8.81 11
F 73 1,044 7.06 2.8 18,900 2.08 6.87 11
M 59 767 7.019 4.8 14,530 6.38 62.84 The present case
CRP: C-reactive protein, DKA: diabetic ketoacidosis, PCT: procalcitonin, WBC: white blood cells
The CRP levels were slightly elevated at 3.28±3.17 mg/dL, but the PCT levels were very high at 26.29±26.57 ng/mL. However, the level of inflammatory cytokines has not been examined in any previous studies, and it was not possible to prove that DKA enhances PCT production via inflammatory cytokines. Moreover, the number of reported cases is small, and many more cases should be examined and analyzed to elucidate the relationship between inflammatory cytokines and DKA.
In addition, the standard threshold for PCT is slightly higher in patients undergoing HD. Kubo et al. reported that the median PCT level before dialysis in such patients was 0.23 ng/mL, which was higher than that in healthy participants (14). Trimarchi et al. reported that the 95th percentile of PCT levels in 45 uninfected patients on HD was 0.8 ng/mL, which is the upper limit of the reference value (15). While the PCT level in such patients can be slightly higher than that in healthy individuals, the PCT levels in our case were markedly high at 62.84 ng/mL, and no serious bacterial infection was observed. Although candidiasis and aspergillosis antigen tests were not performed, the two conditions were deemed unlikely because the clinical course and findings were not in accordance with either of the two conditions. Moreover, β-D-glucan was negative (5.2 pg/mL), and there were no characteristic findings on CT. Since the patient did not have respiratory distress, and pulmonary edema was not detected on chest CT, ARDS was excluded. With no history of overseas travel, Plasmodium infection was unlikely. Although non-severe pneumonia may raise the PCT levels, DKA was strongly suspected to be the main cause of the PCT elevation. In addition, it has been reported that PCT decreases with an improvement in acute hyperglycemia (16); however, the transition trajectory of the PCT levels among DKA patients has not been clarified. In our case, the improvement of DKA was also associated with a reduction in the PCT levels to 29.6 ng/mL, further supporting their DKA-dependent increase. In contrast, Cipriano et al. reported that “PCT returned to normal values (＜0.5 ng/mL) after 3 days of hospitalization, thus reflecting the half-life of the protein.” (6). The decline in the PCT level was slow in our case. Meisner et al. suggested that plasma clearance of PCT may be delayed in patients with renal dysfunction (17). While HD will gradually eliminate PCT, our patient could not attain the urinary excretion of procalcitonin because he was anuric. It was suggested that the rate of PCT elimination was slow by HD and offline-HDF alone.
The PCT removal rate was found to be 53.7% in a single HD using PES membrane (14). Nevertheless, there are no reports of PCT removal rates of HDF. The molecular weight of PCT is approximal 13 kDa, which is similar to that of β2 microglobulin. Online HDF can achieve a 46% higher β2-microglobulin removal rate when compared with HD (18) suggesting that the first has a better PCT removal rate than the latter. However, he received offline-HDF, and the PCT removal rate was not as high as that of the online-HDF, indicating that the decline in the PCT level was slow. One limitation associated with this report was that the cause of PCT elevation was not only DKA, but pneumonia was also slightly involved.
Conclusion
Bacterial infections often cause DKA which may elevate the PCT levels. However, DKA in the absence of bacterial infection can also increase the PCT levels. Therefore, in DKA, it is necessary to carefully determine whether PCT is elevated because of bacterial infection or due to DKA itself. In patients on HD, the rate of PCT decline is slower. Further studies are thus needed to determine the transition of PCT in DKA patients on HD.
The authors state that they have no Conflict of Interest (COI). | 6 IU, TID (BREAKFAST, LUNCH, DINNER) | DrugDosageText | CC BY-NC-ND | 33229806 | 19,958,472 | 2021-04-15 |
What was the dosage of drug 'INSULIN GLARGINE'? | A Remarkable Elevation in the Procalcitonin Levels Due to Diabetic Ketoacidosis in a Hemodialysis Patient.
Procalcitonin (PCT), a marker of the inflammatory response during infections, can be elevated by diabetic ketoacidosis (DKA). A male patient in his 50s with diabetic nephropathy on hemodialysis presented with vomiting and a reduced level of consciousness and was diagnosed with DKA. His PCT level was markedly elevated, but bacterial cultures (blood, urine, and stool) were negative. The PCT level decreased after DKA improvement. In this patient, DKA probably enhanced the PCT levels. As DKA can increase the PCT levels, an elevation of the PCT levels in DKA patients may not be indicative of infectious diseases, and non-infectious causes of DKA should therefore be considered.
Introduction
Diabetic ketoacidosis (DKA) is one of the most serious complications of diabetes mellitus (DM). It often manifests in type 1 and type 2 DM. Infections are the most common triggers of DKA. Several studies have reported that DKA enhances cytokine production (1-3). The procalcitonin (PCT) levels increase in bacterial infections/sepsis and they are used as markers of bacterial infection (4). However, they can also increase in conditions that elevate the cytokine levels, such as burns, trauma, surgery, and pancreatitis (5). A few studies have reported that PCT can increase in DKA. However, the mechanism by which DKA leads to elevated PCT levels remains unknown. To the best of our knowledge, only one report has quantified the PCT levels in DKA (6). Understanding the transition in the PCT level is important for elucidating the relationship between PCT and DKA. In this case report, we measured the PCT levels twice (during and after DKA). Importantly, this is the first report on the relationship between PCT and DKA in patients on hemodialysis (HD). Specifically, we herein present the case of a patient on HD with DKA who had markedly elevated PCT levels, and we assessed the relationship between PCT and DKA.
Case Report
A male patient in his 50s presented to our hospital with vomiting, a reduced level of consciousness, and malaise that had developed 2 days prior to admission. He had been receiving treatment for type 1 DM for 34 years and HD for end-stage kidney disease due to diabetic nephropathy for 6 years. He had received online-hemodiafiltration (HDF) 2 days before admission. He was on insulin therapy (insulin glargine: 10 U at bedtime; insulin aspart: 6 U at breakfast, lunch, and dinner time), although he stopped the insulin therapy the day before admission. His regular medications were rabeprazole sodium, precipitated calcium carbonate, bixalomer, alfacalcidol, amitriptyline hydrochloride, and atorvastatin calcium hydrate. The initial physical examination showed a blood pressure of 100/51 mmHg, a heart rate of 80 beats/min, and an oxygen saturation of 99% (room air). His height, body weight, and body mass index were 163 cm, 57.6 kg, and 21.7 kg/m2, respectively. His respiratory sounds were clear, and no abnormal abdominal findings were noted. Blood investigations (Table 1) showed severe metabolic acidosis, hyperkalemia, hyponatremia, high PCT levels (62.84 ng/mL), hyperglycemia (767 mg/dL), and elevated 3-hydroxybutyric acid levels. Therefore, we diagnosed him with DKA, attributed to the cessation of insulin therapy. An electrocardiogram showed normal P and inverted T waves. Chest X-ray imaging (Fig. 1) showed no pneumonia, whereas chest computed tomography (CT) showed a very mild frosted glass image on the ventral side of the right lung (in S1). Therefore, we diagnosed him as having slight pneumonia.
Table 1. Laboratory Investigation.
Hematology Blood chemistry Blood gas (arterial blood)
WBC 14,530 /μL TP 6.8 g/dL Na 124 mmol/L pH 7.019
Neut 95.5 % Alb 3.6 g/dL K 7.8 mmol/L PCO2 26.4 mmHg
Lynph 0.5 % T-bil 0.1 mg/dL Cl 88 mmol/L PO2 82.1 mmHg
Mono 4 % AST 24 U/L Ca 8.9 mg/dL HCO3- 8.0 mmol/L
RBC 391 ×104/μL ALT 17 U/L P 6.2 mg/dL Lac 4.8 mEq/L
Hb 12.0 g/dL LDH 238 U/L CRP 6.38 mg/dL
Plt 10.5 ×104/μL γ-GTP 7 U/L PCT 62.84 ng/mL
Coagulation Alp 319 U/L PG 767 mg/dL
PT-INR 1.00 BUN 100.9 mg/dL 3-OHBA 4.3 mmol/L
APTT 29.4 s Crea 12.46 mg/dL CPR <0.01 ng/mL
Fib 646 mg/dL
D dimer 0.6 μg/mL
3-OHBA: 3-Hydroxybutyric acid, Alb: albumin, Alp: alkaline phosphatase, ALT: alanine aminotransferase, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, BUN: blood urea nitrogen, CPR: C-peptide immunoreactivity, Crea: creatinine, CRP: C-reactive protein, Fib: fibrinogen, Hb: hemoglobin, Lac: lactate, LDH: lactate dehydrogenase, Lymph: lymphocytes, Mono: monocytes, Neut: neutrophils, PCT: procalcitonin, PG: plasma glucose, Plt: platelet, PT-INR: prothrombin time international normalized ratio, RBC: red blood cells, T-bil: total-bilirubin, TP: total protein, WBC: white blood cells, γ-GTP: γ-glutamyl transpeptidase
Figure 1. Chest X-ray and computed tomography.
Calcium gluconate hydrate (1,700 mg) was injected intravenously, glucose insulin therapy was started, and emergency HD [polyethersulfone (PES) membrane; membrane surface area, 1.5 m2; blood flow, 150 mL/min; dialysis time, 4 h] was urgently performed to manage hyperkalemia. Maintenance hemodialysis (offline-HDF; PES membrane; membrane surface area, 2.1 m2; blood flow, 200 mL/min; dialysis time, 4 h) was started on the 2nd day. The continuous intravenous administration of insulin was initiated for managing DKA but was discontinued because of appetite improvement 3 days after admission. Subsequently, intensive insulin therapy was initiated.
A high inflammatory response [C-reactive protein (CRP) levels, 6.38 mg/dL; PCT levels, 62.84 ng/mL] was observed (Fig. 2). However, chest CT showed only a slight frosted glass image, and cultures for blood, urine, and stool were negative. We could not perform a sputum culture due to the absence of respiratory symptoms. The intravenous administration of tazobactam/piperacillin 4.5 g twice daily had been started at admission, but was discontinued on the 4th day; instead, oral sultamicillin 375mg once daily was initiated. CRP levels rapidly decreased, although his general condition improved. Therefore, we judged that the infection had resolved, and the antibiotics were discontinued on the 10th day. The PCT levels decreased to 29.6 ng/mL on the 8th day. The patient's blood glucose levels stabilized, and his general condition improved; therefore, he was discharged on the 12th day. After discharge, he did not develop any infectious disease and did not experience a recurrence of DKA.
Figure 2. Clinical course of the patient on HD admitted with DKA. CRP: C-reactive protein, CVII: continuous venous insulin infusion, DKA: diabetic ketoacidosis, HD: Hemodialysis, HDF: Hemodiafiltration, Neut: neutrophils, PCT: procalcitonin, SBTPC: sultamicillin, TAZ/PIPC: tazobactam/piperacillin, WBC: white blood cells
Discussion
PCT has higher sensitivity and specificity than CRP for distinguishing between infectious and non-infectious diseases. The PCT levels can help to differentiate between bacterial and viral infections with a high sensitivity (92%) (4). PCT is normally synthesized in thyroid C cells, as a precursor of calcitonin (7). However, in severe infections caused by bacteria, parasites, and fungi, inflammatory cytokines are produced by the action of bacterial cells and toxins. These cytokines act on organs, such as lungs, kidneys, liver, adipose tissue, and muscles, promoting PCT production (8).
However, serious trauma, surgical invasion, and severe burns, Plasmodium infection, acute respiratory distress syndrome (ARDS) can also lead to elevated PCT levels, and caution is required when interpreting PCT findings in such cases (5). Several studies have reported that DKA enhances cytokine production (1-3). Moreover, hyperglycemia also enhances cytokine production (9). Hence, DKA leads to the production of inflammatory cytokines and an increase in the PCT levels.
Ivaska et al. reported that when children with type 1 DM develop DKA, the PCT levels are high despite the absence of infection (10). Two studies have reported a PCT elevation after DKA in adults with type 1 DM (10, 11). Information regarding these eight previously reported cases is presented in Table 2. Except for our case, all cases of PCT elevation due to DKA were reported in women, and the median age of the patients was 34 years (range, 14-73 years), which was relatively low. This is likely because women have a stronger immune response than men do (12), and younger individuals in general show higher cytokine production. It is also widely considered that DKA is more likely to occur in young people (13).
Table 2. Comparison of the Present Case with Previously Reported DKA Patient with High PCT Level.
Sex Age
(year) Plasma glucose
(mg/dL) pH Lactate
(mEq/L) WBC
(/L) CRP
(mg/dL) PCT
(ng/mL) Reference
F 14 633 7.04 3.3 25,800 8.4 82.94 9
F 15 601 7.00 4.3 24,600 5.5 13.13 9
F N/A 522 N/A N/A N/A N/A 1.72 10
F 34 539 6.91 2.1 21,800 0.06 12.4 11
F 42 1,177 6.94 4.6 19,910 0.31 30.47 11
F 32 623 6.80 1.6 26,510 0.25 8.81 11
F 73 1,044 7.06 2.8 18,900 2.08 6.87 11
M 59 767 7.019 4.8 14,530 6.38 62.84 The present case
CRP: C-reactive protein, DKA: diabetic ketoacidosis, PCT: procalcitonin, WBC: white blood cells
The CRP levels were slightly elevated at 3.28±3.17 mg/dL, but the PCT levels were very high at 26.29±26.57 ng/mL. However, the level of inflammatory cytokines has not been examined in any previous studies, and it was not possible to prove that DKA enhances PCT production via inflammatory cytokines. Moreover, the number of reported cases is small, and many more cases should be examined and analyzed to elucidate the relationship between inflammatory cytokines and DKA.
In addition, the standard threshold for PCT is slightly higher in patients undergoing HD. Kubo et al. reported that the median PCT level before dialysis in such patients was 0.23 ng/mL, which was higher than that in healthy participants (14). Trimarchi et al. reported that the 95th percentile of PCT levels in 45 uninfected patients on HD was 0.8 ng/mL, which is the upper limit of the reference value (15). While the PCT level in such patients can be slightly higher than that in healthy individuals, the PCT levels in our case were markedly high at 62.84 ng/mL, and no serious bacterial infection was observed. Although candidiasis and aspergillosis antigen tests were not performed, the two conditions were deemed unlikely because the clinical course and findings were not in accordance with either of the two conditions. Moreover, β-D-glucan was negative (5.2 pg/mL), and there were no characteristic findings on CT. Since the patient did not have respiratory distress, and pulmonary edema was not detected on chest CT, ARDS was excluded. With no history of overseas travel, Plasmodium infection was unlikely. Although non-severe pneumonia may raise the PCT levels, DKA was strongly suspected to be the main cause of the PCT elevation. In addition, it has been reported that PCT decreases with an improvement in acute hyperglycemia (16); however, the transition trajectory of the PCT levels among DKA patients has not been clarified. In our case, the improvement of DKA was also associated with a reduction in the PCT levels to 29.6 ng/mL, further supporting their DKA-dependent increase. In contrast, Cipriano et al. reported that “PCT returned to normal values (＜0.5 ng/mL) after 3 days of hospitalization, thus reflecting the half-life of the protein.” (6). The decline in the PCT level was slow in our case. Meisner et al. suggested that plasma clearance of PCT may be delayed in patients with renal dysfunction (17). While HD will gradually eliminate PCT, our patient could not attain the urinary excretion of procalcitonin because he was anuric. It was suggested that the rate of PCT elimination was slow by HD and offline-HDF alone.
The PCT removal rate was found to be 53.7% in a single HD using PES membrane (14). Nevertheless, there are no reports of PCT removal rates of HDF. The molecular weight of PCT is approximal 13 kDa, which is similar to that of β2 microglobulin. Online HDF can achieve a 46% higher β2-microglobulin removal rate when compared with HD (18) suggesting that the first has a better PCT removal rate than the latter. However, he received offline-HDF, and the PCT removal rate was not as high as that of the online-HDF, indicating that the decline in the PCT level was slow. One limitation associated with this report was that the cause of PCT elevation was not only DKA, but pneumonia was also slightly involved.
Conclusion
Bacterial infections often cause DKA which may elevate the PCT levels. However, DKA in the absence of bacterial infection can also increase the PCT levels. Therefore, in DKA, it is necessary to carefully determine whether PCT is elevated because of bacterial infection or due to DKA itself. In patients on HD, the rate of PCT decline is slower. Further studies are thus needed to determine the transition of PCT in DKA patients on HD.
The authors state that they have no Conflict of Interest (COI). | 10 IU, QD (BEDTIME) | DrugDosageText | CC BY-NC-ND | 33229806 | 19,958,472 | 2021-04-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | Real-world bone turnover marker use: impact on treatment decisions and fracture.
The use of bone turnover marker (BTM) testing for patients with osteoporosis in the USA has not been well characterized. This retrospective US-based real-world data study found BTM testing has some association with treatment decision-making and lower fracture risk in patients with presumed osteoporosis, supporting its use in clinical practice.
BACKGROUND
The purpose of this study was to characterize bone turnover marker (BTM) testing patterns and estimate their clinical utility in treatment decision-making and fragility fracture risk in patients with osteoporosis using a retrospective claims database.
METHODS
Data from patients aged ≥ 50 years with newly diagnosed osteoporosis enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases from January 2008 to June 2018 were included. Osteoporosis was ascertained by explicit claims, fragility fracture events associated with osteoporosis, or prescribed anti-resorptive or anabolic therapy. BTM-tested patients were 1:1 propensity score matched to those untested following diagnosis. Generalized estimating equation models were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for testing versus no testing on both treatment decision-making and fragility fracture.
RESULTS
Of the 457,829 patients with osteoporosis, 6075 were identified with ≥ 1 BTM test following diagnosis; of these patients, 1345 had a unique treatment decision made ≤ 30 days from BTM testing. The percentage of patients receiving BTM tests increased significantly each year (average annual % change: + 8.1%; 95% CI: 5.6-9.0; p = 0.01). Patients tested were significantly more likely to have a treatment decision (OR: 1.14; 95% CI: 1.13-1.15), and testing was associated with lower odds of fracture versus those untested (OR: 0.87; 95% CI: 0.85-0.88).
CONCLUSIONS
In this large, heterogeneous population of patients with presumed osteoporosis, BTM testing was associated with treatment decision-making, likely leading to fragility fracture reduction following use.
Introduction
Osteoporosis, which is characterized by reduced bone mass and micro-architectural deterioration leading to increased bone fragility [1, 2], affects approximately 200 million people worldwide [3]. In 2020, the National Osteoporosis Foundation reported that approximately 54 million Americans, of all ages, are living with osteoporosis or low bone mass [4].
Bone turnover markers (BTMs) can be measured in serum, plasma, and urine [5], with bone formation and bone resorption marker levels relating to osteoblast and osteoclast activity, respectively. Bone formation markers include proteins such as osteocalcin or procollagen type I N propeptide (PINP), and the bone isoform of alkaline phosphatase (bone ALP). Bone resorption markers include fragments released from the telopeptide end region of type I collagen following its enzymatic degradation, such as the N-telopeptide of type I collagen (NTX), carboxy-terminal crosslinking telopeptide of type I collagen (CTX), deoxypyridinoline (DPD), and the enzyme tartrate-resistant acid phosphatase [6].
The International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine (IOF-IFCC) Bone Markers Working Group has identified CTX and PINP as promising markers for providing clinically useful information for monitoring osteoporosis treatment [7], and recommends that CTX and serum PINP, measured by standardized assays, be used as reference markers in observational and interventional studies [2]. American Association of Clinical Endocrinologists/American College of Endocrinology guideline recommendations for BTMs also advise use of CTX and PINP as monitoring tests for osteoporosis treatment [8], as do National Osteoporosis Foundation (NOF) guidelines [9]. An IOF and European Calcified Tissue Society taskforce has also suggested that PINP and CTX screening may be used to detect lack of adherence to oral bisphosphonates therapy [10].
In addition to monitoring osteoporosis treatment [11], and patients during treatment holiday [12, 13], a meta-analysis of published studies has shown that low levels of BTMs are modestly associated with reduced fracture risk [5]. A few studies have measured BTMs prior to hip fracture events [5, 14], and found conflicting reports with both positive [15] and negative [16] associations of BTM levels and the risk of osteoporosis-related hip fracture. In clinical practice, the use of BTM levels in predicting fracture outcomes is further complicated by significant within-patient variability of BTM levels due to patient age [17], comorbid conditions such as diabetes and chronic kidney disease [11], or ethnicity [18]. Sources of variability in BTM levels should be considered when interpreting test results. Particular attention should be paid to the appropriate use of reference intervals for determination of abnormal results, specifically related to the age and sex of the patient [19].
The majority of reports on the use of BTMs in clinical practice have tended to be single-site or small number multi-site studies [20] whose results may not be broadly applicable to the medically insured patients with osteoporosis in the USA. To help address this gap, we conducted an investigation using real-world data from a large patient population with osteoporosis in the USA. Our aims were threefold: (1) to assess trends in BTM test utilization; (2) to characterize the patterns of BTM testing and baseline characteristics of a heterogeneous population of patients in clinical practice; and (3) to estimate the potential clinical utility of BTM for treatment decision-making and association with fragility fracture.
Methods
Study design and data source
We undertook a population-based retrospective cohort analysis of patients enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases. These databases consist of the outpatient, inpatient, and pharmaceutical claims of approximately 50 million privately insured individuals and their dependents receiving care annually in the USA. Claims originated from more than 150 large employer-sponsored health insurance plans with patient coverage in all 50 states. The Medicare Supplemental and Co-ordination of Benefits databases represent commercially insured individuals, who have both Medicare coverage and supplemental employer-sponsored coverage, for Medicare-eligible active and retired employees and their Medicare-eligible dependents from employer-sponsored Medicare Supplemental plans. All data were anonymized to comply with the Health Insurance Portability and Accountability Act (HIPAA) and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required and formal informed consent was not obtained.
Study design and patient selection
Osteoporosis was defined at baseline in adult patients aged ≥ 50 years who were enrolled in a health plan with pharmaceutical coverage from January 1st 2008 to June 30th 2018. Osteoporosis was defined based on first recorded event according to (1) ≥ 1 inpatient or 2 outpatient claims (≥ 30 to ≤ 360 days apart) for osteoporosis, as defined under the International Classification of Diseases, Ninth (ICD-9-CM) or Tenth Revision (ICD-10-CM); (2) ≥ 1 claim for US Food and Drug Administration (FDA)-approved osteoporosis treatment (National Drug Code [NDC], Healthcare Common Procedure Coding System J- or C-codes); or (3) a fragility fracture considered to be associated with osteoporosis [6, 21, 22] (Online Resource Table 2). For hip fracture claims, ≥ 1 inpatient claim was required, and for other fracture types, ≥ 1 inpatient claim or ≥ 2 outpatient claims, ≥ 30 to ≤ 360 days apart (ICD-9-CM, ICD-10-CM codes, or Common Procedural Terminology [CPT] codes) were required. Patients were excluded if a claim of malignant neoplasm (excluding non-melanoma skin cancers), Paget’s disease of bone, or chronic kidney or end-stage renal disease was made at any time during the study period, to avoid misidentification of patients treated with medications as osteoporotic and inclusion of patients with malignancy-related fractures (Online Resource Table 3).
The index date was defined differently between BTM-tested and untested patients. In both cases, patients were required a minimum continuous enrollment ≥ 360 days prior to defined baseline (or washout period) and ≥ 360 days follow-up (Fig. 1) with allowable gap in coverage equivalent to ≤ 30 days. For those tested, the index date was defined as the date of the first BTM claim following osteoporosis diagnosis based on corresponding CPT codes for BTMs: osteocalcin (83937), bone-specific ALP (84080), and collagen cross-links (any method, 82523). PINP was not included in the present study as no unique CPT code (83519) is available to accurately classify receipt of this test. Untested patients were randomly assigned an index date based on a uniform distribution and the following criteria: to ensure adequate follow-up, the index date was required to fall before the final 360 days of data capture for the patient, and to ensure sufficient baseline washout period, the index date was required to fall after the first 360 days of data capture. Each patient was followed prospectively until an observed outcome, the end of continuous enrollment, reported death, or study end, whichever occurred first.Fig. 1 Study design schema of patients with osteoporosis aged ≥ 50 years enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Defining study outcomes
Study outcomes were compared between BTM-tested and untested groups in the follow-up period. Further details on how study outcomes were defined are provided in the Online Resource Methods section.
Outcome 1: Treatment decision-making
Osteoporosis treatments approved by the FDA during the study period were explored according to therapeutic mode of action: anti-resorptive (bisphosphonates, estrogen/progesterone, selective estrogen receptor modulators [SERMs], calcitonin, denosumab), or anabolic (teriparatide). Both injectable and oral routes were considered along with respective days of expected coverage or supply (i.e., 90/180/360 day intervals with allowable coverage gap of ≤ 30 days). Patients were classified according to the next observed treatment decision following a BTM test according to the days of coverage or supply: no treatment prescribed, treatment initiated, continue on the same treatment, restart following a treatment gap of > 30 days, between-class switch, or treatment discontinuation.
Outcome 2: Fragility fracture
Occurrence of a fragility fracture following index was assumed to be associated with osteoporosis and was classified according to methods reported by Song et al. [23]. Incident claims were captured by the presence of a qualified diagnosis of closed fractures of sites that may be associated with an increased risk of fracture, predominantly spine, hip, pelvis, and upper leg fractures [24]. Fractures were defined as those with ≥ 1 inpatient claims (primary or secondary discharge diagnosis) for hip fractures, and ≥ 1 inpatient (primary or secondary discharge diagnosis) or ≥ 2 outpatient claims (30–180 days apart) for all other sites. Fractures that were most likely the result of serious trauma were excluded, including compound or open fractures, multiple fractures within 7 days of a single claim, and vertebral fractures with concurrent spinal cord injury. Analyses were based on determination of the first claim for an osteoporotic fracture following index and any subsequent BTM event thereafter.
Statistical analysis
Descriptive statistics were used to characterize baseline socio-demographic and clinical characteristics of the osteoporotic patient cohort, summarizing continuous variables with means (standard deviation [SD]) or medians (interquartile range [IQR]) and categorical variables with counts and proportions (percentages). To explore trends in testing over calendar time [25], the annual period prevalence and associated 95% confidence intervals (CIs) were estimated among tested patients from 2008 forward. To evaluate longitudinal trends, the Cochran-Armitage test for trend and average annual percentage change (AAPC) were reported [26]. To account for variable enrollment in the MarketScan databases over time, the numerator was defined as the number of patients with one or more BTM tests and the denominator as total enrollment in a calendar year.
To examine the association between index testing on treatment decisions and fragility fracture, a multivariate logistic propensity score model conditioned on values at index (age, sex, year, region of care, insurance type, provider type [for treatment decision outcome model only]) and baseline (Charlson Comorbidity Index [CCI], score 1, 2, 3, or 6, where a higher score indicates a greater risk of 1-year mortality associated with more severe and/or greater co-morbidity burden) was fit [27]. The propensity score was used to match tested and untested patients using a fixed 1:1 ratio and nearest neighbor without replacement [25]. Propensity scores represent the conditional probability of assignment to the tested group and may be used to control for multiple observed covariates that are associated with the exposure and outcome [28]. That is, patients are assumed to have or not have been tested by chance and propensity score matching represents a non-parametric way to control for selection bias. Adequacy of matching in terms of patients’ baseline characteristics was evaluated using standardized differences; a value of < 0.1 was assumed to indicate a negligible difference in the characteristics between tested and untested patients [29]. A doubly robust method [30] was used where, in addition to the propensity score matching, generalized estimating equation (GEE) models were fit to estimate comparisons of odds and 95% CIs assessing the association between testing on treatment decision-making and fragility fracture. A binomial distribution and logistic link function were specified for both models fit with unstructured correlation structures, selected based on quasi-likelihood information criteria [31]. Additional covariates were not included in models as groups were well-balanced on baseline characteristics.
All statistical tests were two-sided and significance was determined using ɑ = 0.05. Analyses were conducted in SAS version 9.4 (SAS Institute, Inc., Cary, NC).
Results
Patient cohort
From 2008 to 2018, 457,829 individuals were classified as presumed osteoporotic (Fig. 2). Following application of inclusion criteria, 6075 patients (1.3%) were identified with one or more BTM test claims on or following diagnosis. Among all patients with osteoporosis, cohort entry declined over calendar time (Table 1), reflective of the annual decline in patients enrolled in Truven MarketScan, year-over-year. At the time of diagnosis, median age was 62 years (IQR: 57–74), with the majority of patients classified as female (79.6%), and 19.2% of patients having high CCI scores ≥ 2 (Table 1). Claims were most frequent from the South (33.7%) or North Central (29.9%) USA, while preferred provider organization (PPO) insurance coverage was common (49.7%). Compared with those untested, patients at osteoporosis diagnosis with BTM claims during follow-up were slightly younger; had lower CCI scores; were more likely to have PPO insurance coverage; and had higher proportions of diagnoses made at endocrinologists, rheumatologists, or primary care providers. Similarly, they were more likely to have an explicit osteoporosis diagnosis claim, not be covered via Medicare, have at least one bone mineral density (BMD) test during baseline, and have longer follow-up.Fig. 2 Cohort attrition of patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018, and 1:1 propensity score matched between those with tested and untested for bone turnover markers. BTM, bone turnover marker
Table 1 Characteristics at index or baseline of patients with presumed osteoporosis diagnosis and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018 (matched and all patients)
All patients with presumed osteoporosis (n = 457,829) Matched cohort
BTM tested (n = 6075) BTM untested, matched (n = 6075) Standard diffa (vs. tested)
Matched variables, n (%)
Cohort entry, calendar year
2008 61,642 (13.5) 1139 (18.8) 1134 (18.7) 0.9
2009 71,508 (15.6) 1064 (17.5) 1068 (17.6)
2010 62,365 (13.6) 859 (14.1) 858 (14.1)
2011 52,854 (11.5) 724 (11.9) 726 (12.0)
2012 49,357 (10.8) 575 (9.5) 576 (9.5)
2013 37,153 (8.1) 445 (7.3) 445 (7.3)
2014 38,941 (8.5) 444 (7.3) 447 (7.4)
2015 29,278 (6.4) 295 (4.9) 291 (4.8)
2016 24,639 (5.4) 235 (3.9) 234 (3.9)
2017 20,725 (4.5) 225 (3.7) 225 (3.7)
2018 9367 (2.1) 70 (1.2) 71 (1.2)
Median age, years (IQR) 62.0 (57.0–74.0) 59.0 (55.0–63.0) 59.0 (54.0–63.0) 1.3
Female sex 364,315 (79.6) 5511 (90.7) 5509 (90.7) 0.8
CCIb
0 263,726 (57.6) 3920 (64.5) 3918 (64.5) 0.2
1 106,551 (23.3) 1263 (20.8) 1261 (20.8)
≥ 2 87,552 (19.1) 892 (14.7) 896 (14.7)
Provider typec
Endocrinologist 3317 (0.7) 241 (4.0) 240 (4.0) 1.6
Rheumatologist 6118 (1.3) 212 (3.5) 212 (3.5)
Primary care provider 94,811 (20.7) 1465 (24.1) 1466 (24.1)
Acute, ambulatory, or urgent care 117,096 (25.6) 1362 (22.4) 1360 (22.4)
Other 131,331 (28.7) 1631 (26.9) 1632 (26.9)
Unknown 105,156 (23.0) 1164 (19.2) 1165 (19.2)
Other variables, n (%)
Claim at cohort entry
Osteoporosis therapy 159,032 (34.7) 4550 (74.9)
Anabolicd 7394 (1.6) 19 (0.3)
Anti-resorptivee 77,980 (17.0) 601 (9.9)
Fragility fracture 213,423 (46.6) 905 (14.9)
Database, n (%)
CCAE 276,970 (60.5) 4862 (80.0)
Medicare supplemental and CoB 180,859 (39.5) 1213 (20.0)
Bone mineral density claimb, n (%) 109,746 (24.0) 2952 (48.6)
Mortalityf, n (%) 734 (0.2) 13 (0.2)
Median follow-up time, years (IQR) 2.0 (1.1–3.6) 2.6 (1.1–3.6)
aStandard difference, p value < 0.01: values < 0.1 assumed to indicate negligible statistical difference between matched groups; bcharacteristics observed during the baseline period; cMatching on provider type only conducted for model 2 (impact of BTM on treatment decision-making). MarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care provider included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories; danabolic therapy (parathyroid hormone, dual-action bone agent, prostaglandin group E); eanti-resorptive therapy (bisphosphonate, estrogen, SERMs, calcitonin, denosumab); fin MarketScan databases, only inpatient mortality is captured. Therefore, mortality events outside of this setting are not captured in patient claims
BTM, bone turnover marker; CCI, Charlson Comorbidity Index; CCAE, Commercial Claims and Encounters; CoB, Co-ordination of Benefits; IQR, interquartile range
Following application of the propensity score model, 6075 BTM-tested patients were matched to 6075 untested patients (Table 1). Matched tested and untested patients were well-balanced on their baseline characteristics with none exhibiting a standard difference of > 0.1.
Real-world bone turnover marker test patterns
Among the 6075 tested patients, 8828 unique claims were made during the study period, with the majority being markers of resorption (76.6%; Table 2). In total, 14.4% (n = 875) of patients had concurrent claims for both resorption and formation markers. The annualized period prevalence of testing per 100 persons ranged from 0.23 (95% CI: 0.19–0.28) in 2008 to 0.47 (95% CI: 0.45–0.50) in 2018 (Fig. 3). During the study period, patients tested increased year-over-year (Cochran-Armitage test for trend, p = 0.03), with most of the increase occurring in the latter half of the study period (2015 onwards) and with an AAPC of 8.1% (95% CI: 5.6–9.0; p = 0.01). The AAPC prevalence for resorption markers was 4.2% (95% CI: 3.7–3.9; p = 0.04) and for formation markers, it was 6.9% (95% CI: 5.9–7.2; p = 0.02). No substantial difference in annual testing trends was observed when the analysis was repeated by age group deciles and sex (data not shown).Table 2 Characteristics of osteoporotic patients tested with bone turnover marker and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Patients tested (n = 6075) BTM tests (n = 8828)
Frequency (%) Frequency (%)
Year of BTM testa
2008 627 (10.3) 745 (8.4)
2009 868 (14.3) 994 (11.3)
2010 880 (14.5) 1015 (11.5)
2011 990 (16.3) 1122 (12.7)
2012 970 (16.0) 1092 (12.4)
2013 814 (13.4) 925 (10.5)
2014 698 (11.5) 803 (9.1)
2015 542 (8.9) 619 (7.0)
2016 539 (8.9) 615 (7.0)
2017 444 (7.3) 500 (5.7)
2018 341 (5.6) 398 (4.5)
Mode of action
Formation 2299 (37.8) 3100 (35.1)
Resorption 4622 (76.1) 6765 (76.6)
Place of BTM testb
Acute, ambulatory, or urgent care 8 (0.1) 11 (0.1)
Outpatient clinic/hospital 2094 (34.5) 2951 (33.4)
Inpatient clinic/hospital 16 (0.3) 24 (0.3)
Other 3958 (65.2) 5682 (64.4)
Unknown 122 (2.0) 160 (1.8)
Number of BTM tests per patient
Mean (SD) 2.2 (2.0)
Median (IQR) 1.0 (1.0–3.0)
1 test 4545 (74.8)
2 tests 937 (15.4)
≥ 3 tests 593 (9.8)
Median inter-test intervals, days (IQR)
Diagnosis to 1st test 160 (37–471)
1st to 2nd test 221 (125–384)
2nd to 3rd test 223 (134–377)
aCalendar year of first test claim (patient-level) or year of test claim (test-level); bMarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care providers included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories
BTM, bone turnover marker; IQR, interquartile range; SD, standard deviation
Fig. 3 Annual period prevalence (per 100 persons) of bone turnover marker testing and average testing per patient among patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
On average, patients had 2.2 test claims (SD 2.0) during the study period (Table 2), which remained stable irrespective of year of diagnosis (data not shown). Median claims suggest a non-normal distribution (1.0 IQR: 1.0–3.0) with only 593 patients (9.8%) reporting ≥ 3 BTM claims during follow-up. Follow-up BTM and dual-energy X-ray absorptiometry testing after osteoporosis diagnosis are recommended by clinical guidelines [8]; therefore, patterns of repeat testing were examined for those with > 1 test following index. Median time from osteoporosis diagnosis to first BTM claim was 160 days (IQR: 37–471), and for those with two or more claims the median inter-test interval was approximately 220 days between claimed tests. Approximately 30% of all tests were ordered by endocrinologists, rheumatologists, and primary care providers, with the majority of claims in the non-ambulatory or hospital or clinical setting.
Impact of bone turnover markers on treatment decision-making and fragility fracture
In total, 1345 patients (22%) had a unique treatment decision within 30 days of BTM testing. Treatment decisions were most common with anti-resorptives (89.1%) followed by anabolic (5.6%) and combination therapies (6.3%). This included treatment initiated (4.9%), continuation on the same treatment (8.4%), re-starting the same treatment following a gap of > 30 days (0.6%), and treatment discontinuation (8.2%). No observations for treatment switching were observed for tested patients. From the GEE propensity score model predicting treatment decision-making, tested patients were significantly more likely to have a treatment decision within 30 days compared to those untested (OR 1.14; 95% CI: 1.13–1.15). To further understand this observed effect, we conducted a post-hoc analysis of treatment decision-making by category of decision (new treatment, continuation, treatment restart, treatment switch, discontinuation). Assessment of BTMs was significantly associated with the decision to re-start treatment within 30 days of testing (OR 2.67; 95% CI: 2.51–2.93) and continue treatment (OR 1.03; 95% CI: 1.03–1.04), and treatment discontinuation (OR 1.03; 95% CI: 1.02–1.04). While no statistically significant association was observed for decision to initiate treatment (OR 1.01; 95% CI: 1.00–1.01) or switching treatment following testing (OR 1.02; 95% CI: 1.00–1.04), point observations suggest potential weak clinical significance.
The impact of testing on fracture events was also explored. A total of 1409 tested patients (23.2%) had a fragility fracture assumed to be due to osteoporosis following index, and this was linked to 3236 unique fracture events during the study period. The most common fracture type was wrist/forearm (562 events, 17.4%), followed by hip (440, 13.6%), vertebra (429, 13.2%), and femoral (381, 11.8%). In the model predicting fragility fracture following a BTM test, results suggest that testing was associated with lower odds of fracture compared to those patients untested (OR 0.87; 95% CI: 0.85–0.88).
Discussion
To our knowledge, this study represents the first known US nationwide epidemiological study of BTM testing among patients with presumed osteoporosis. We analyzed data from persons with a presumed osteoporosis diagnosis in the USA from 2008 to 2018 and observed that the annual proportion tested using BTMs rose from 0.23 tests per 100 patients in 2008 to 0.47 in 2018, with most of the increase occurring in the latter half of the study period. The observed rise in testing is encouraging, yet tested patients still remain below international guidelines for screening response to therapy. Among various BTMs, serum CTX-I and serum PINP are recently recommended as monitoring tests for osteoporosis treatment by several osteoporosis guidelines, including the NOF, the Japanese Osteoporosis Society, and the IOF [2, 9, 32].
BTMs may be employed as clinical tools for treatment decision-making at several important junctures of osteoporosis treatment. For example, baseline measurements of resorption and formation markers before commencement of anti-resorptive and anti-formation therapies, respectively, are of utility in monitoring treatment response and adherence. BTMs are also of potential clinical value in deciding whether patients should resume therapy following treatment holidays, and for monitoring patients during these periods [33]. Our results suggest that assessing BTM was significantly associated with the decision to re-start treatment for osteoporosis within 30 days of testing, to continue treatment, or to discontinue treatment. Published literature substantiates BTMs as having considerable utility in treatment decision-making in patients with osteoporosis [11]. In particular, measurement of BTMs can reflect response to therapies earlier than that of BMD, and can be used to monitor treatment compliance [6, 34]. PINP or CTX may be used to identify treatment responders and non-responders, and as a marker of poor patient adherence to common osteoporosis treatments [35, 36].
Our analysis showed that BTM testing was associated with lower odds of fracture compared to not testing patients with osteoporosis. This association could potentially be due to turnover data leading to change in pharmacotherapies reducing fracture risk. Supporting this, it has previously been reported that high levels of the BTMs NTX, DPD, and CTX are predictive of subsequent risk of hip fracture in women aged ≥ 75 years, independently of hip BMD [14]. High levels of NTX, DPD, CTX, and serum bone ALP have also been shown to be associated with increased risk of osteoporotic fracture in post-menopausal women, independently of BMD [37, 38]. BTM testing offers potential advantages versus traditional BMD testing, as the latter does not completely capture the risk of osteoporotic fracture, and the use of serial BMD measurements as a tool for treatment response requires an interval of more than a year. Bone turnover, by contrast, changes early and can be assessed within 3 months of starting treatment [34]. BTM measurements are also repeatable, relatively inexpensive, and non-invasive [39], potentially lowering the cost of care [40] and decreasing patient inconvenience as opposed to BMD testing. However, unlike BMD, BTM measurements are subject to a number of pre-analytical variations, including seasonal and diurnal variations [41].
As with all observational studies, and especially with studies using commercial insurance claims databases where changes in enrollment (including left censoring) and loss to follow-up (≥ 20%) [42] reduce the sample size of longitudinal studies, the results of the present study should be interpreted with caution. Firstly, the study provided an overall picture of BTM testing and it was not the intention of the claims data mining to determine which BTMs were being tested. It is, therefore, not possible to specify which BTMs are associated with an impact on treatment or predict fragility fracture risk. As previously mentioned, there is no unique CPT code (83519) available to accurately classify the receipt of PINP. Serum osteocalcin was included in this analysis and has been shown to correspond well with levels of PINP [33]. Secondly, outpatient claims may be recorded by a variety of staff with limited clinical training; therefore, misclassification is possible. In this study, the inclusion criterion for incident presumed osteoporosis diagnosis was based on > 1 claim, which may minimize the risk of misclassification bias. Finally, administrative claims do not provide insight into individual test results, which may be drivers of the observed association, or potential confounders not captured in the present database that may have biased the observations. The strengths of our study include the use of a large, longitudinal claims database from which we were able to analyze a heterogeneous, real-life population of patients in terms of decisions made about their treatment and incident fracture outcomes. MarketScan is a large, nationally representative database of individuals receiving employer-sponsored healthcare insurance, and the coding of inpatient claims in the USA is typically performed reliably by professional coders.
Conclusions
In this large, heterogeneous sample of US-based patients with presumed osteoporosis, we determined that BTM testing was associated with both treatment decision-making and a reduction of fragility fracture following use, conclusions which are consistent with published literature. While further investigation to validate the findings and understand the drivers is warranted, the evidence presented in this work provides further evidence of the value of monitoring osteoporotic patients with in vitro BTM monitoring diagnostic solutions.
Supplementary Information
ESM 1 (DOCX 25 kb)
The authors wish to acknowledge Dr. Andy Surinach of Genesis Research and Jaya Madala of Roche Diagnostics for their assistance in cohort development and code review.
Funding
This study was funded by Roche Diagnostics International Ltd. and Roche Diagnostics Information Solutions. Third-party writing assistance under the guidance of the authors was provided by James Everington and Ashlie Butler (Gardiner-Caldwell Communications, Macclesfield, UK) and funded by Roche Diagnostics International Ltd. (Rotkreuz, Switzerland).
Compliance with ethical standards
Conflicts of interest
N. Lane reports consultancy funding from Roche, and consultancy and speaker funding from Amgen. K. Saag reports grants from Amgen, Radius, and Mereo, and consultancy funding from Amgen, Daichi-Sankyo, and Roche. T. O’Neill is an employee of Roche Diagnostics Information Solutions and owner of stocks in Roche, Gilead, Pfizer, Regeneron, Abbott, and United Healthcare. M. Manion is an employee of Roche Diagnostics International Ltd. R. Shah is an employee of Roche Diagnostics International Ltd. and owner of stock in Roche. U. Klause is an employee of Roche Diabetes Care. R. Eastell reports consultancy funding from IDS, Sandoz, Nittobo, Roche Diagnostics, Samsung, Haoma Medica, CL Bio, Biocon, Lyramid, and Viking Therapeutics, and grant funding from Nittobo, Roche Diagnostics, and Alexion.
Ethics approval
All data were anonymized to comply with HIPAA and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required.
Consent to participate
Formal informed consent was not obtained.
Consent for publication
All authors consent to the publication of this study.
Code availability
Not applicable.
The original online version of this article was revised due to a retrospective Open Access order.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
4/13/2021
A Correction to this paper has been published: 10.1007/s00198-021-05828-3 | DENOSUMAB | DrugsGivenReaction | CC BY-NC | 33236195 | 19,311,011 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Femur fracture'. | Real-world bone turnover marker use: impact on treatment decisions and fracture.
The use of bone turnover marker (BTM) testing for patients with osteoporosis in the USA has not been well characterized. This retrospective US-based real-world data study found BTM testing has some association with treatment decision-making and lower fracture risk in patients with presumed osteoporosis, supporting its use in clinical practice.
BACKGROUND
The purpose of this study was to characterize bone turnover marker (BTM) testing patterns and estimate their clinical utility in treatment decision-making and fragility fracture risk in patients with osteoporosis using a retrospective claims database.
METHODS
Data from patients aged ≥ 50 years with newly diagnosed osteoporosis enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases from January 2008 to June 2018 were included. Osteoporosis was ascertained by explicit claims, fragility fracture events associated with osteoporosis, or prescribed anti-resorptive or anabolic therapy. BTM-tested patients were 1:1 propensity score matched to those untested following diagnosis. Generalized estimating equation models were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for testing versus no testing on both treatment decision-making and fragility fracture.
RESULTS
Of the 457,829 patients with osteoporosis, 6075 were identified with ≥ 1 BTM test following diagnosis; of these patients, 1345 had a unique treatment decision made ≤ 30 days from BTM testing. The percentage of patients receiving BTM tests increased significantly each year (average annual % change: + 8.1%; 95% CI: 5.6-9.0; p = 0.01). Patients tested were significantly more likely to have a treatment decision (OR: 1.14; 95% CI: 1.13-1.15), and testing was associated with lower odds of fracture versus those untested (OR: 0.87; 95% CI: 0.85-0.88).
CONCLUSIONS
In this large, heterogeneous population of patients with presumed osteoporosis, BTM testing was associated with treatment decision-making, likely leading to fragility fracture reduction following use.
Introduction
Osteoporosis, which is characterized by reduced bone mass and micro-architectural deterioration leading to increased bone fragility [1, 2], affects approximately 200 million people worldwide [3]. In 2020, the National Osteoporosis Foundation reported that approximately 54 million Americans, of all ages, are living with osteoporosis or low bone mass [4].
Bone turnover markers (BTMs) can be measured in serum, plasma, and urine [5], with bone formation and bone resorption marker levels relating to osteoblast and osteoclast activity, respectively. Bone formation markers include proteins such as osteocalcin or procollagen type I N propeptide (PINP), and the bone isoform of alkaline phosphatase (bone ALP). Bone resorption markers include fragments released from the telopeptide end region of type I collagen following its enzymatic degradation, such as the N-telopeptide of type I collagen (NTX), carboxy-terminal crosslinking telopeptide of type I collagen (CTX), deoxypyridinoline (DPD), and the enzyme tartrate-resistant acid phosphatase [6].
The International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine (IOF-IFCC) Bone Markers Working Group has identified CTX and PINP as promising markers for providing clinically useful information for monitoring osteoporosis treatment [7], and recommends that CTX and serum PINP, measured by standardized assays, be used as reference markers in observational and interventional studies [2]. American Association of Clinical Endocrinologists/American College of Endocrinology guideline recommendations for BTMs also advise use of CTX and PINP as monitoring tests for osteoporosis treatment [8], as do National Osteoporosis Foundation (NOF) guidelines [9]. An IOF and European Calcified Tissue Society taskforce has also suggested that PINP and CTX screening may be used to detect lack of adherence to oral bisphosphonates therapy [10].
In addition to monitoring osteoporosis treatment [11], and patients during treatment holiday [12, 13], a meta-analysis of published studies has shown that low levels of BTMs are modestly associated with reduced fracture risk [5]. A few studies have measured BTMs prior to hip fracture events [5, 14], and found conflicting reports with both positive [15] and negative [16] associations of BTM levels and the risk of osteoporosis-related hip fracture. In clinical practice, the use of BTM levels in predicting fracture outcomes is further complicated by significant within-patient variability of BTM levels due to patient age [17], comorbid conditions such as diabetes and chronic kidney disease [11], or ethnicity [18]. Sources of variability in BTM levels should be considered when interpreting test results. Particular attention should be paid to the appropriate use of reference intervals for determination of abnormal results, specifically related to the age and sex of the patient [19].
The majority of reports on the use of BTMs in clinical practice have tended to be single-site or small number multi-site studies [20] whose results may not be broadly applicable to the medically insured patients with osteoporosis in the USA. To help address this gap, we conducted an investigation using real-world data from a large patient population with osteoporosis in the USA. Our aims were threefold: (1) to assess trends in BTM test utilization; (2) to characterize the patterns of BTM testing and baseline characteristics of a heterogeneous population of patients in clinical practice; and (3) to estimate the potential clinical utility of BTM for treatment decision-making and association with fragility fracture.
Methods
Study design and data source
We undertook a population-based retrospective cohort analysis of patients enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases. These databases consist of the outpatient, inpatient, and pharmaceutical claims of approximately 50 million privately insured individuals and their dependents receiving care annually in the USA. Claims originated from more than 150 large employer-sponsored health insurance plans with patient coverage in all 50 states. The Medicare Supplemental and Co-ordination of Benefits databases represent commercially insured individuals, who have both Medicare coverage and supplemental employer-sponsored coverage, for Medicare-eligible active and retired employees and their Medicare-eligible dependents from employer-sponsored Medicare Supplemental plans. All data were anonymized to comply with the Health Insurance Portability and Accountability Act (HIPAA) and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required and formal informed consent was not obtained.
Study design and patient selection
Osteoporosis was defined at baseline in adult patients aged ≥ 50 years who were enrolled in a health plan with pharmaceutical coverage from January 1st 2008 to June 30th 2018. Osteoporosis was defined based on first recorded event according to (1) ≥ 1 inpatient or 2 outpatient claims (≥ 30 to ≤ 360 days apart) for osteoporosis, as defined under the International Classification of Diseases, Ninth (ICD-9-CM) or Tenth Revision (ICD-10-CM); (2) ≥ 1 claim for US Food and Drug Administration (FDA)-approved osteoporosis treatment (National Drug Code [NDC], Healthcare Common Procedure Coding System J- or C-codes); or (3) a fragility fracture considered to be associated with osteoporosis [6, 21, 22] (Online Resource Table 2). For hip fracture claims, ≥ 1 inpatient claim was required, and for other fracture types, ≥ 1 inpatient claim or ≥ 2 outpatient claims, ≥ 30 to ≤ 360 days apart (ICD-9-CM, ICD-10-CM codes, or Common Procedural Terminology [CPT] codes) were required. Patients were excluded if a claim of malignant neoplasm (excluding non-melanoma skin cancers), Paget’s disease of bone, or chronic kidney or end-stage renal disease was made at any time during the study period, to avoid misidentification of patients treated with medications as osteoporotic and inclusion of patients with malignancy-related fractures (Online Resource Table 3).
The index date was defined differently between BTM-tested and untested patients. In both cases, patients were required a minimum continuous enrollment ≥ 360 days prior to defined baseline (or washout period) and ≥ 360 days follow-up (Fig. 1) with allowable gap in coverage equivalent to ≤ 30 days. For those tested, the index date was defined as the date of the first BTM claim following osteoporosis diagnosis based on corresponding CPT codes for BTMs: osteocalcin (83937), bone-specific ALP (84080), and collagen cross-links (any method, 82523). PINP was not included in the present study as no unique CPT code (83519) is available to accurately classify receipt of this test. Untested patients were randomly assigned an index date based on a uniform distribution and the following criteria: to ensure adequate follow-up, the index date was required to fall before the final 360 days of data capture for the patient, and to ensure sufficient baseline washout period, the index date was required to fall after the first 360 days of data capture. Each patient was followed prospectively until an observed outcome, the end of continuous enrollment, reported death, or study end, whichever occurred first.Fig. 1 Study design schema of patients with osteoporosis aged ≥ 50 years enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Defining study outcomes
Study outcomes were compared between BTM-tested and untested groups in the follow-up period. Further details on how study outcomes were defined are provided in the Online Resource Methods section.
Outcome 1: Treatment decision-making
Osteoporosis treatments approved by the FDA during the study period were explored according to therapeutic mode of action: anti-resorptive (bisphosphonates, estrogen/progesterone, selective estrogen receptor modulators [SERMs], calcitonin, denosumab), or anabolic (teriparatide). Both injectable and oral routes were considered along with respective days of expected coverage or supply (i.e., 90/180/360 day intervals with allowable coverage gap of ≤ 30 days). Patients were classified according to the next observed treatment decision following a BTM test according to the days of coverage or supply: no treatment prescribed, treatment initiated, continue on the same treatment, restart following a treatment gap of > 30 days, between-class switch, or treatment discontinuation.
Outcome 2: Fragility fracture
Occurrence of a fragility fracture following index was assumed to be associated with osteoporosis and was classified according to methods reported by Song et al. [23]. Incident claims were captured by the presence of a qualified diagnosis of closed fractures of sites that may be associated with an increased risk of fracture, predominantly spine, hip, pelvis, and upper leg fractures [24]. Fractures were defined as those with ≥ 1 inpatient claims (primary or secondary discharge diagnosis) for hip fractures, and ≥ 1 inpatient (primary or secondary discharge diagnosis) or ≥ 2 outpatient claims (30–180 days apart) for all other sites. Fractures that were most likely the result of serious trauma were excluded, including compound or open fractures, multiple fractures within 7 days of a single claim, and vertebral fractures with concurrent spinal cord injury. Analyses were based on determination of the first claim for an osteoporotic fracture following index and any subsequent BTM event thereafter.
Statistical analysis
Descriptive statistics were used to characterize baseline socio-demographic and clinical characteristics of the osteoporotic patient cohort, summarizing continuous variables with means (standard deviation [SD]) or medians (interquartile range [IQR]) and categorical variables with counts and proportions (percentages). To explore trends in testing over calendar time [25], the annual period prevalence and associated 95% confidence intervals (CIs) were estimated among tested patients from 2008 forward. To evaluate longitudinal trends, the Cochran-Armitage test for trend and average annual percentage change (AAPC) were reported [26]. To account for variable enrollment in the MarketScan databases over time, the numerator was defined as the number of patients with one or more BTM tests and the denominator as total enrollment in a calendar year.
To examine the association between index testing on treatment decisions and fragility fracture, a multivariate logistic propensity score model conditioned on values at index (age, sex, year, region of care, insurance type, provider type [for treatment decision outcome model only]) and baseline (Charlson Comorbidity Index [CCI], score 1, 2, 3, or 6, where a higher score indicates a greater risk of 1-year mortality associated with more severe and/or greater co-morbidity burden) was fit [27]. The propensity score was used to match tested and untested patients using a fixed 1:1 ratio and nearest neighbor without replacement [25]. Propensity scores represent the conditional probability of assignment to the tested group and may be used to control for multiple observed covariates that are associated with the exposure and outcome [28]. That is, patients are assumed to have or not have been tested by chance and propensity score matching represents a non-parametric way to control for selection bias. Adequacy of matching in terms of patients’ baseline characteristics was evaluated using standardized differences; a value of < 0.1 was assumed to indicate a negligible difference in the characteristics between tested and untested patients [29]. A doubly robust method [30] was used where, in addition to the propensity score matching, generalized estimating equation (GEE) models were fit to estimate comparisons of odds and 95% CIs assessing the association between testing on treatment decision-making and fragility fracture. A binomial distribution and logistic link function were specified for both models fit with unstructured correlation structures, selected based on quasi-likelihood information criteria [31]. Additional covariates were not included in models as groups were well-balanced on baseline characteristics.
All statistical tests were two-sided and significance was determined using ɑ = 0.05. Analyses were conducted in SAS version 9.4 (SAS Institute, Inc., Cary, NC).
Results
Patient cohort
From 2008 to 2018, 457,829 individuals were classified as presumed osteoporotic (Fig. 2). Following application of inclusion criteria, 6075 patients (1.3%) were identified with one or more BTM test claims on or following diagnosis. Among all patients with osteoporosis, cohort entry declined over calendar time (Table 1), reflective of the annual decline in patients enrolled in Truven MarketScan, year-over-year. At the time of diagnosis, median age was 62 years (IQR: 57–74), with the majority of patients classified as female (79.6%), and 19.2% of patients having high CCI scores ≥ 2 (Table 1). Claims were most frequent from the South (33.7%) or North Central (29.9%) USA, while preferred provider organization (PPO) insurance coverage was common (49.7%). Compared with those untested, patients at osteoporosis diagnosis with BTM claims during follow-up were slightly younger; had lower CCI scores; were more likely to have PPO insurance coverage; and had higher proportions of diagnoses made at endocrinologists, rheumatologists, or primary care providers. Similarly, they were more likely to have an explicit osteoporosis diagnosis claim, not be covered via Medicare, have at least one bone mineral density (BMD) test during baseline, and have longer follow-up.Fig. 2 Cohort attrition of patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018, and 1:1 propensity score matched between those with tested and untested for bone turnover markers. BTM, bone turnover marker
Table 1 Characteristics at index or baseline of patients with presumed osteoporosis diagnosis and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018 (matched and all patients)
All patients with presumed osteoporosis (n = 457,829) Matched cohort
BTM tested (n = 6075) BTM untested, matched (n = 6075) Standard diffa (vs. tested)
Matched variables, n (%)
Cohort entry, calendar year
2008 61,642 (13.5) 1139 (18.8) 1134 (18.7) 0.9
2009 71,508 (15.6) 1064 (17.5) 1068 (17.6)
2010 62,365 (13.6) 859 (14.1) 858 (14.1)
2011 52,854 (11.5) 724 (11.9) 726 (12.0)
2012 49,357 (10.8) 575 (9.5) 576 (9.5)
2013 37,153 (8.1) 445 (7.3) 445 (7.3)
2014 38,941 (8.5) 444 (7.3) 447 (7.4)
2015 29,278 (6.4) 295 (4.9) 291 (4.8)
2016 24,639 (5.4) 235 (3.9) 234 (3.9)
2017 20,725 (4.5) 225 (3.7) 225 (3.7)
2018 9367 (2.1) 70 (1.2) 71 (1.2)
Median age, years (IQR) 62.0 (57.0–74.0) 59.0 (55.0–63.0) 59.0 (54.0–63.0) 1.3
Female sex 364,315 (79.6) 5511 (90.7) 5509 (90.7) 0.8
CCIb
0 263,726 (57.6) 3920 (64.5) 3918 (64.5) 0.2
1 106,551 (23.3) 1263 (20.8) 1261 (20.8)
≥ 2 87,552 (19.1) 892 (14.7) 896 (14.7)
Provider typec
Endocrinologist 3317 (0.7) 241 (4.0) 240 (4.0) 1.6
Rheumatologist 6118 (1.3) 212 (3.5) 212 (3.5)
Primary care provider 94,811 (20.7) 1465 (24.1) 1466 (24.1)
Acute, ambulatory, or urgent care 117,096 (25.6) 1362 (22.4) 1360 (22.4)
Other 131,331 (28.7) 1631 (26.9) 1632 (26.9)
Unknown 105,156 (23.0) 1164 (19.2) 1165 (19.2)
Other variables, n (%)
Claim at cohort entry
Osteoporosis therapy 159,032 (34.7) 4550 (74.9)
Anabolicd 7394 (1.6) 19 (0.3)
Anti-resorptivee 77,980 (17.0) 601 (9.9)
Fragility fracture 213,423 (46.6) 905 (14.9)
Database, n (%)
CCAE 276,970 (60.5) 4862 (80.0)
Medicare supplemental and CoB 180,859 (39.5) 1213 (20.0)
Bone mineral density claimb, n (%) 109,746 (24.0) 2952 (48.6)
Mortalityf, n (%) 734 (0.2) 13 (0.2)
Median follow-up time, years (IQR) 2.0 (1.1–3.6) 2.6 (1.1–3.6)
aStandard difference, p value < 0.01: values < 0.1 assumed to indicate negligible statistical difference between matched groups; bcharacteristics observed during the baseline period; cMatching on provider type only conducted for model 2 (impact of BTM on treatment decision-making). MarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care provider included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories; danabolic therapy (parathyroid hormone, dual-action bone agent, prostaglandin group E); eanti-resorptive therapy (bisphosphonate, estrogen, SERMs, calcitonin, denosumab); fin MarketScan databases, only inpatient mortality is captured. Therefore, mortality events outside of this setting are not captured in patient claims
BTM, bone turnover marker; CCI, Charlson Comorbidity Index; CCAE, Commercial Claims and Encounters; CoB, Co-ordination of Benefits; IQR, interquartile range
Following application of the propensity score model, 6075 BTM-tested patients were matched to 6075 untested patients (Table 1). Matched tested and untested patients were well-balanced on their baseline characteristics with none exhibiting a standard difference of > 0.1.
Real-world bone turnover marker test patterns
Among the 6075 tested patients, 8828 unique claims were made during the study period, with the majority being markers of resorption (76.6%; Table 2). In total, 14.4% (n = 875) of patients had concurrent claims for both resorption and formation markers. The annualized period prevalence of testing per 100 persons ranged from 0.23 (95% CI: 0.19–0.28) in 2008 to 0.47 (95% CI: 0.45–0.50) in 2018 (Fig. 3). During the study period, patients tested increased year-over-year (Cochran-Armitage test for trend, p = 0.03), with most of the increase occurring in the latter half of the study period (2015 onwards) and with an AAPC of 8.1% (95% CI: 5.6–9.0; p = 0.01). The AAPC prevalence for resorption markers was 4.2% (95% CI: 3.7–3.9; p = 0.04) and for formation markers, it was 6.9% (95% CI: 5.9–7.2; p = 0.02). No substantial difference in annual testing trends was observed when the analysis was repeated by age group deciles and sex (data not shown).Table 2 Characteristics of osteoporotic patients tested with bone turnover marker and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Patients tested (n = 6075) BTM tests (n = 8828)
Frequency (%) Frequency (%)
Year of BTM testa
2008 627 (10.3) 745 (8.4)
2009 868 (14.3) 994 (11.3)
2010 880 (14.5) 1015 (11.5)
2011 990 (16.3) 1122 (12.7)
2012 970 (16.0) 1092 (12.4)
2013 814 (13.4) 925 (10.5)
2014 698 (11.5) 803 (9.1)
2015 542 (8.9) 619 (7.0)
2016 539 (8.9) 615 (7.0)
2017 444 (7.3) 500 (5.7)
2018 341 (5.6) 398 (4.5)
Mode of action
Formation 2299 (37.8) 3100 (35.1)
Resorption 4622 (76.1) 6765 (76.6)
Place of BTM testb
Acute, ambulatory, or urgent care 8 (0.1) 11 (0.1)
Outpatient clinic/hospital 2094 (34.5) 2951 (33.4)
Inpatient clinic/hospital 16 (0.3) 24 (0.3)
Other 3958 (65.2) 5682 (64.4)
Unknown 122 (2.0) 160 (1.8)
Number of BTM tests per patient
Mean (SD) 2.2 (2.0)
Median (IQR) 1.0 (1.0–3.0)
1 test 4545 (74.8)
2 tests 937 (15.4)
≥ 3 tests 593 (9.8)
Median inter-test intervals, days (IQR)
Diagnosis to 1st test 160 (37–471)
1st to 2nd test 221 (125–384)
2nd to 3rd test 223 (134–377)
aCalendar year of first test claim (patient-level) or year of test claim (test-level); bMarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care providers included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories
BTM, bone turnover marker; IQR, interquartile range; SD, standard deviation
Fig. 3 Annual period prevalence (per 100 persons) of bone turnover marker testing and average testing per patient among patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
On average, patients had 2.2 test claims (SD 2.0) during the study period (Table 2), which remained stable irrespective of year of diagnosis (data not shown). Median claims suggest a non-normal distribution (1.0 IQR: 1.0–3.0) with only 593 patients (9.8%) reporting ≥ 3 BTM claims during follow-up. Follow-up BTM and dual-energy X-ray absorptiometry testing after osteoporosis diagnosis are recommended by clinical guidelines [8]; therefore, patterns of repeat testing were examined for those with > 1 test following index. Median time from osteoporosis diagnosis to first BTM claim was 160 days (IQR: 37–471), and for those with two or more claims the median inter-test interval was approximately 220 days between claimed tests. Approximately 30% of all tests were ordered by endocrinologists, rheumatologists, and primary care providers, with the majority of claims in the non-ambulatory or hospital or clinical setting.
Impact of bone turnover markers on treatment decision-making and fragility fracture
In total, 1345 patients (22%) had a unique treatment decision within 30 days of BTM testing. Treatment decisions were most common with anti-resorptives (89.1%) followed by anabolic (5.6%) and combination therapies (6.3%). This included treatment initiated (4.9%), continuation on the same treatment (8.4%), re-starting the same treatment following a gap of > 30 days (0.6%), and treatment discontinuation (8.2%). No observations for treatment switching were observed for tested patients. From the GEE propensity score model predicting treatment decision-making, tested patients were significantly more likely to have a treatment decision within 30 days compared to those untested (OR 1.14; 95% CI: 1.13–1.15). To further understand this observed effect, we conducted a post-hoc analysis of treatment decision-making by category of decision (new treatment, continuation, treatment restart, treatment switch, discontinuation). Assessment of BTMs was significantly associated with the decision to re-start treatment within 30 days of testing (OR 2.67; 95% CI: 2.51–2.93) and continue treatment (OR 1.03; 95% CI: 1.03–1.04), and treatment discontinuation (OR 1.03; 95% CI: 1.02–1.04). While no statistically significant association was observed for decision to initiate treatment (OR 1.01; 95% CI: 1.00–1.01) or switching treatment following testing (OR 1.02; 95% CI: 1.00–1.04), point observations suggest potential weak clinical significance.
The impact of testing on fracture events was also explored. A total of 1409 tested patients (23.2%) had a fragility fracture assumed to be due to osteoporosis following index, and this was linked to 3236 unique fracture events during the study period. The most common fracture type was wrist/forearm (562 events, 17.4%), followed by hip (440, 13.6%), vertebra (429, 13.2%), and femoral (381, 11.8%). In the model predicting fragility fracture following a BTM test, results suggest that testing was associated with lower odds of fracture compared to those patients untested (OR 0.87; 95% CI: 0.85–0.88).
Discussion
To our knowledge, this study represents the first known US nationwide epidemiological study of BTM testing among patients with presumed osteoporosis. We analyzed data from persons with a presumed osteoporosis diagnosis in the USA from 2008 to 2018 and observed that the annual proportion tested using BTMs rose from 0.23 tests per 100 patients in 2008 to 0.47 in 2018, with most of the increase occurring in the latter half of the study period. The observed rise in testing is encouraging, yet tested patients still remain below international guidelines for screening response to therapy. Among various BTMs, serum CTX-I and serum PINP are recently recommended as monitoring tests for osteoporosis treatment by several osteoporosis guidelines, including the NOF, the Japanese Osteoporosis Society, and the IOF [2, 9, 32].
BTMs may be employed as clinical tools for treatment decision-making at several important junctures of osteoporosis treatment. For example, baseline measurements of resorption and formation markers before commencement of anti-resorptive and anti-formation therapies, respectively, are of utility in monitoring treatment response and adherence. BTMs are also of potential clinical value in deciding whether patients should resume therapy following treatment holidays, and for monitoring patients during these periods [33]. Our results suggest that assessing BTM was significantly associated with the decision to re-start treatment for osteoporosis within 30 days of testing, to continue treatment, or to discontinue treatment. Published literature substantiates BTMs as having considerable utility in treatment decision-making in patients with osteoporosis [11]. In particular, measurement of BTMs can reflect response to therapies earlier than that of BMD, and can be used to monitor treatment compliance [6, 34]. PINP or CTX may be used to identify treatment responders and non-responders, and as a marker of poor patient adherence to common osteoporosis treatments [35, 36].
Our analysis showed that BTM testing was associated with lower odds of fracture compared to not testing patients with osteoporosis. This association could potentially be due to turnover data leading to change in pharmacotherapies reducing fracture risk. Supporting this, it has previously been reported that high levels of the BTMs NTX, DPD, and CTX are predictive of subsequent risk of hip fracture in women aged ≥ 75 years, independently of hip BMD [14]. High levels of NTX, DPD, CTX, and serum bone ALP have also been shown to be associated with increased risk of osteoporotic fracture in post-menopausal women, independently of BMD [37, 38]. BTM testing offers potential advantages versus traditional BMD testing, as the latter does not completely capture the risk of osteoporotic fracture, and the use of serial BMD measurements as a tool for treatment response requires an interval of more than a year. Bone turnover, by contrast, changes early and can be assessed within 3 months of starting treatment [34]. BTM measurements are also repeatable, relatively inexpensive, and non-invasive [39], potentially lowering the cost of care [40] and decreasing patient inconvenience as opposed to BMD testing. However, unlike BMD, BTM measurements are subject to a number of pre-analytical variations, including seasonal and diurnal variations [41].
As with all observational studies, and especially with studies using commercial insurance claims databases where changes in enrollment (including left censoring) and loss to follow-up (≥ 20%) [42] reduce the sample size of longitudinal studies, the results of the present study should be interpreted with caution. Firstly, the study provided an overall picture of BTM testing and it was not the intention of the claims data mining to determine which BTMs were being tested. It is, therefore, not possible to specify which BTMs are associated with an impact on treatment or predict fragility fracture risk. As previously mentioned, there is no unique CPT code (83519) available to accurately classify the receipt of PINP. Serum osteocalcin was included in this analysis and has been shown to correspond well with levels of PINP [33]. Secondly, outpatient claims may be recorded by a variety of staff with limited clinical training; therefore, misclassification is possible. In this study, the inclusion criterion for incident presumed osteoporosis diagnosis was based on > 1 claim, which may minimize the risk of misclassification bias. Finally, administrative claims do not provide insight into individual test results, which may be drivers of the observed association, or potential confounders not captured in the present database that may have biased the observations. The strengths of our study include the use of a large, longitudinal claims database from which we were able to analyze a heterogeneous, real-life population of patients in terms of decisions made about their treatment and incident fracture outcomes. MarketScan is a large, nationally representative database of individuals receiving employer-sponsored healthcare insurance, and the coding of inpatient claims in the USA is typically performed reliably by professional coders.
Conclusions
In this large, heterogeneous sample of US-based patients with presumed osteoporosis, we determined that BTM testing was associated with both treatment decision-making and a reduction of fragility fracture following use, conclusions which are consistent with published literature. While further investigation to validate the findings and understand the drivers is warranted, the evidence presented in this work provides further evidence of the value of monitoring osteoporotic patients with in vitro BTM monitoring diagnostic solutions.
Supplementary Information
ESM 1 (DOCX 25 kb)
The authors wish to acknowledge Dr. Andy Surinach of Genesis Research and Jaya Madala of Roche Diagnostics for their assistance in cohort development and code review.
Funding
This study was funded by Roche Diagnostics International Ltd. and Roche Diagnostics Information Solutions. Third-party writing assistance under the guidance of the authors was provided by James Everington and Ashlie Butler (Gardiner-Caldwell Communications, Macclesfield, UK) and funded by Roche Diagnostics International Ltd. (Rotkreuz, Switzerland).
Compliance with ethical standards
Conflicts of interest
N. Lane reports consultancy funding from Roche, and consultancy and speaker funding from Amgen. K. Saag reports grants from Amgen, Radius, and Mereo, and consultancy funding from Amgen, Daichi-Sankyo, and Roche. T. O’Neill is an employee of Roche Diagnostics Information Solutions and owner of stocks in Roche, Gilead, Pfizer, Regeneron, Abbott, and United Healthcare. M. Manion is an employee of Roche Diagnostics International Ltd. R. Shah is an employee of Roche Diagnostics International Ltd. and owner of stock in Roche. U. Klause is an employee of Roche Diabetes Care. R. Eastell reports consultancy funding from IDS, Sandoz, Nittobo, Roche Diagnostics, Samsung, Haoma Medica, CL Bio, Biocon, Lyramid, and Viking Therapeutics, and grant funding from Nittobo, Roche Diagnostics, and Alexion.
Ethics approval
All data were anonymized to comply with HIPAA and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required.
Consent to participate
Formal informed consent was not obtained.
Consent for publication
All authors consent to the publication of this study.
Code availability
Not applicable.
The original online version of this article was revised due to a retrospective Open Access order.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
4/13/2021
A Correction to this paper has been published: 10.1007/s00198-021-05828-3 | DENOSUMAB | DrugsGivenReaction | CC BY-NC | 33236195 | 19,311,011 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Forearm fracture'. | Real-world bone turnover marker use: impact on treatment decisions and fracture.
The use of bone turnover marker (BTM) testing for patients with osteoporosis in the USA has not been well characterized. This retrospective US-based real-world data study found BTM testing has some association with treatment decision-making and lower fracture risk in patients with presumed osteoporosis, supporting its use in clinical practice.
BACKGROUND
The purpose of this study was to characterize bone turnover marker (BTM) testing patterns and estimate their clinical utility in treatment decision-making and fragility fracture risk in patients with osteoporosis using a retrospective claims database.
METHODS
Data from patients aged ≥ 50 years with newly diagnosed osteoporosis enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases from January 2008 to June 2018 were included. Osteoporosis was ascertained by explicit claims, fragility fracture events associated with osteoporosis, or prescribed anti-resorptive or anabolic therapy. BTM-tested patients were 1:1 propensity score matched to those untested following diagnosis. Generalized estimating equation models were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for testing versus no testing on both treatment decision-making and fragility fracture.
RESULTS
Of the 457,829 patients with osteoporosis, 6075 were identified with ≥ 1 BTM test following diagnosis; of these patients, 1345 had a unique treatment decision made ≤ 30 days from BTM testing. The percentage of patients receiving BTM tests increased significantly each year (average annual % change: + 8.1%; 95% CI: 5.6-9.0; p = 0.01). Patients tested were significantly more likely to have a treatment decision (OR: 1.14; 95% CI: 1.13-1.15), and testing was associated with lower odds of fracture versus those untested (OR: 0.87; 95% CI: 0.85-0.88).
CONCLUSIONS
In this large, heterogeneous population of patients with presumed osteoporosis, BTM testing was associated with treatment decision-making, likely leading to fragility fracture reduction following use.
Introduction
Osteoporosis, which is characterized by reduced bone mass and micro-architectural deterioration leading to increased bone fragility [1, 2], affects approximately 200 million people worldwide [3]. In 2020, the National Osteoporosis Foundation reported that approximately 54 million Americans, of all ages, are living with osteoporosis or low bone mass [4].
Bone turnover markers (BTMs) can be measured in serum, plasma, and urine [5], with bone formation and bone resorption marker levels relating to osteoblast and osteoclast activity, respectively. Bone formation markers include proteins such as osteocalcin or procollagen type I N propeptide (PINP), and the bone isoform of alkaline phosphatase (bone ALP). Bone resorption markers include fragments released from the telopeptide end region of type I collagen following its enzymatic degradation, such as the N-telopeptide of type I collagen (NTX), carboxy-terminal crosslinking telopeptide of type I collagen (CTX), deoxypyridinoline (DPD), and the enzyme tartrate-resistant acid phosphatase [6].
The International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine (IOF-IFCC) Bone Markers Working Group has identified CTX and PINP as promising markers for providing clinically useful information for monitoring osteoporosis treatment [7], and recommends that CTX and serum PINP, measured by standardized assays, be used as reference markers in observational and interventional studies [2]. American Association of Clinical Endocrinologists/American College of Endocrinology guideline recommendations for BTMs also advise use of CTX and PINP as monitoring tests for osteoporosis treatment [8], as do National Osteoporosis Foundation (NOF) guidelines [9]. An IOF and European Calcified Tissue Society taskforce has also suggested that PINP and CTX screening may be used to detect lack of adherence to oral bisphosphonates therapy [10].
In addition to monitoring osteoporosis treatment [11], and patients during treatment holiday [12, 13], a meta-analysis of published studies has shown that low levels of BTMs are modestly associated with reduced fracture risk [5]. A few studies have measured BTMs prior to hip fracture events [5, 14], and found conflicting reports with both positive [15] and negative [16] associations of BTM levels and the risk of osteoporosis-related hip fracture. In clinical practice, the use of BTM levels in predicting fracture outcomes is further complicated by significant within-patient variability of BTM levels due to patient age [17], comorbid conditions such as diabetes and chronic kidney disease [11], or ethnicity [18]. Sources of variability in BTM levels should be considered when interpreting test results. Particular attention should be paid to the appropriate use of reference intervals for determination of abnormal results, specifically related to the age and sex of the patient [19].
The majority of reports on the use of BTMs in clinical practice have tended to be single-site or small number multi-site studies [20] whose results may not be broadly applicable to the medically insured patients with osteoporosis in the USA. To help address this gap, we conducted an investigation using real-world data from a large patient population with osteoporosis in the USA. Our aims were threefold: (1) to assess trends in BTM test utilization; (2) to characterize the patterns of BTM testing and baseline characteristics of a heterogeneous population of patients in clinical practice; and (3) to estimate the potential clinical utility of BTM for treatment decision-making and association with fragility fracture.
Methods
Study design and data source
We undertook a population-based retrospective cohort analysis of patients enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases. These databases consist of the outpatient, inpatient, and pharmaceutical claims of approximately 50 million privately insured individuals and their dependents receiving care annually in the USA. Claims originated from more than 150 large employer-sponsored health insurance plans with patient coverage in all 50 states. The Medicare Supplemental and Co-ordination of Benefits databases represent commercially insured individuals, who have both Medicare coverage and supplemental employer-sponsored coverage, for Medicare-eligible active and retired employees and their Medicare-eligible dependents from employer-sponsored Medicare Supplemental plans. All data were anonymized to comply with the Health Insurance Portability and Accountability Act (HIPAA) and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required and formal informed consent was not obtained.
Study design and patient selection
Osteoporosis was defined at baseline in adult patients aged ≥ 50 years who were enrolled in a health plan with pharmaceutical coverage from January 1st 2008 to June 30th 2018. Osteoporosis was defined based on first recorded event according to (1) ≥ 1 inpatient or 2 outpatient claims (≥ 30 to ≤ 360 days apart) for osteoporosis, as defined under the International Classification of Diseases, Ninth (ICD-9-CM) or Tenth Revision (ICD-10-CM); (2) ≥ 1 claim for US Food and Drug Administration (FDA)-approved osteoporosis treatment (National Drug Code [NDC], Healthcare Common Procedure Coding System J- or C-codes); or (3) a fragility fracture considered to be associated with osteoporosis [6, 21, 22] (Online Resource Table 2). For hip fracture claims, ≥ 1 inpatient claim was required, and for other fracture types, ≥ 1 inpatient claim or ≥ 2 outpatient claims, ≥ 30 to ≤ 360 days apart (ICD-9-CM, ICD-10-CM codes, or Common Procedural Terminology [CPT] codes) were required. Patients were excluded if a claim of malignant neoplasm (excluding non-melanoma skin cancers), Paget’s disease of bone, or chronic kidney or end-stage renal disease was made at any time during the study period, to avoid misidentification of patients treated with medications as osteoporotic and inclusion of patients with malignancy-related fractures (Online Resource Table 3).
The index date was defined differently between BTM-tested and untested patients. In both cases, patients were required a minimum continuous enrollment ≥ 360 days prior to defined baseline (or washout period) and ≥ 360 days follow-up (Fig. 1) with allowable gap in coverage equivalent to ≤ 30 days. For those tested, the index date was defined as the date of the first BTM claim following osteoporosis diagnosis based on corresponding CPT codes for BTMs: osteocalcin (83937), bone-specific ALP (84080), and collagen cross-links (any method, 82523). PINP was not included in the present study as no unique CPT code (83519) is available to accurately classify receipt of this test. Untested patients were randomly assigned an index date based on a uniform distribution and the following criteria: to ensure adequate follow-up, the index date was required to fall before the final 360 days of data capture for the patient, and to ensure sufficient baseline washout period, the index date was required to fall after the first 360 days of data capture. Each patient was followed prospectively until an observed outcome, the end of continuous enrollment, reported death, or study end, whichever occurred first.Fig. 1 Study design schema of patients with osteoporosis aged ≥ 50 years enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Defining study outcomes
Study outcomes were compared between BTM-tested and untested groups in the follow-up period. Further details on how study outcomes were defined are provided in the Online Resource Methods section.
Outcome 1: Treatment decision-making
Osteoporosis treatments approved by the FDA during the study period were explored according to therapeutic mode of action: anti-resorptive (bisphosphonates, estrogen/progesterone, selective estrogen receptor modulators [SERMs], calcitonin, denosumab), or anabolic (teriparatide). Both injectable and oral routes were considered along with respective days of expected coverage or supply (i.e., 90/180/360 day intervals with allowable coverage gap of ≤ 30 days). Patients were classified according to the next observed treatment decision following a BTM test according to the days of coverage or supply: no treatment prescribed, treatment initiated, continue on the same treatment, restart following a treatment gap of > 30 days, between-class switch, or treatment discontinuation.
Outcome 2: Fragility fracture
Occurrence of a fragility fracture following index was assumed to be associated with osteoporosis and was classified according to methods reported by Song et al. [23]. Incident claims were captured by the presence of a qualified diagnosis of closed fractures of sites that may be associated with an increased risk of fracture, predominantly spine, hip, pelvis, and upper leg fractures [24]. Fractures were defined as those with ≥ 1 inpatient claims (primary or secondary discharge diagnosis) for hip fractures, and ≥ 1 inpatient (primary or secondary discharge diagnosis) or ≥ 2 outpatient claims (30–180 days apart) for all other sites. Fractures that were most likely the result of serious trauma were excluded, including compound or open fractures, multiple fractures within 7 days of a single claim, and vertebral fractures with concurrent spinal cord injury. Analyses were based on determination of the first claim for an osteoporotic fracture following index and any subsequent BTM event thereafter.
Statistical analysis
Descriptive statistics were used to characterize baseline socio-demographic and clinical characteristics of the osteoporotic patient cohort, summarizing continuous variables with means (standard deviation [SD]) or medians (interquartile range [IQR]) and categorical variables with counts and proportions (percentages). To explore trends in testing over calendar time [25], the annual period prevalence and associated 95% confidence intervals (CIs) were estimated among tested patients from 2008 forward. To evaluate longitudinal trends, the Cochran-Armitage test for trend and average annual percentage change (AAPC) were reported [26]. To account for variable enrollment in the MarketScan databases over time, the numerator was defined as the number of patients with one or more BTM tests and the denominator as total enrollment in a calendar year.
To examine the association between index testing on treatment decisions and fragility fracture, a multivariate logistic propensity score model conditioned on values at index (age, sex, year, region of care, insurance type, provider type [for treatment decision outcome model only]) and baseline (Charlson Comorbidity Index [CCI], score 1, 2, 3, or 6, where a higher score indicates a greater risk of 1-year mortality associated with more severe and/or greater co-morbidity burden) was fit [27]. The propensity score was used to match tested and untested patients using a fixed 1:1 ratio and nearest neighbor without replacement [25]. Propensity scores represent the conditional probability of assignment to the tested group and may be used to control for multiple observed covariates that are associated with the exposure and outcome [28]. That is, patients are assumed to have or not have been tested by chance and propensity score matching represents a non-parametric way to control for selection bias. Adequacy of matching in terms of patients’ baseline characteristics was evaluated using standardized differences; a value of < 0.1 was assumed to indicate a negligible difference in the characteristics between tested and untested patients [29]. A doubly robust method [30] was used where, in addition to the propensity score matching, generalized estimating equation (GEE) models were fit to estimate comparisons of odds and 95% CIs assessing the association between testing on treatment decision-making and fragility fracture. A binomial distribution and logistic link function were specified for both models fit with unstructured correlation structures, selected based on quasi-likelihood information criteria [31]. Additional covariates were not included in models as groups were well-balanced on baseline characteristics.
All statistical tests were two-sided and significance was determined using ɑ = 0.05. Analyses were conducted in SAS version 9.4 (SAS Institute, Inc., Cary, NC).
Results
Patient cohort
From 2008 to 2018, 457,829 individuals were classified as presumed osteoporotic (Fig. 2). Following application of inclusion criteria, 6075 patients (1.3%) were identified with one or more BTM test claims on or following diagnosis. Among all patients with osteoporosis, cohort entry declined over calendar time (Table 1), reflective of the annual decline in patients enrolled in Truven MarketScan, year-over-year. At the time of diagnosis, median age was 62 years (IQR: 57–74), with the majority of patients classified as female (79.6%), and 19.2% of patients having high CCI scores ≥ 2 (Table 1). Claims were most frequent from the South (33.7%) or North Central (29.9%) USA, while preferred provider organization (PPO) insurance coverage was common (49.7%). Compared with those untested, patients at osteoporosis diagnosis with BTM claims during follow-up were slightly younger; had lower CCI scores; were more likely to have PPO insurance coverage; and had higher proportions of diagnoses made at endocrinologists, rheumatologists, or primary care providers. Similarly, they were more likely to have an explicit osteoporosis diagnosis claim, not be covered via Medicare, have at least one bone mineral density (BMD) test during baseline, and have longer follow-up.Fig. 2 Cohort attrition of patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018, and 1:1 propensity score matched between those with tested and untested for bone turnover markers. BTM, bone turnover marker
Table 1 Characteristics at index or baseline of patients with presumed osteoporosis diagnosis and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018 (matched and all patients)
All patients with presumed osteoporosis (n = 457,829) Matched cohort
BTM tested (n = 6075) BTM untested, matched (n = 6075) Standard diffa (vs. tested)
Matched variables, n (%)
Cohort entry, calendar year
2008 61,642 (13.5) 1139 (18.8) 1134 (18.7) 0.9
2009 71,508 (15.6) 1064 (17.5) 1068 (17.6)
2010 62,365 (13.6) 859 (14.1) 858 (14.1)
2011 52,854 (11.5) 724 (11.9) 726 (12.0)
2012 49,357 (10.8) 575 (9.5) 576 (9.5)
2013 37,153 (8.1) 445 (7.3) 445 (7.3)
2014 38,941 (8.5) 444 (7.3) 447 (7.4)
2015 29,278 (6.4) 295 (4.9) 291 (4.8)
2016 24,639 (5.4) 235 (3.9) 234 (3.9)
2017 20,725 (4.5) 225 (3.7) 225 (3.7)
2018 9367 (2.1) 70 (1.2) 71 (1.2)
Median age, years (IQR) 62.0 (57.0–74.0) 59.0 (55.0–63.0) 59.0 (54.0–63.0) 1.3
Female sex 364,315 (79.6) 5511 (90.7) 5509 (90.7) 0.8
CCIb
0 263,726 (57.6) 3920 (64.5) 3918 (64.5) 0.2
1 106,551 (23.3) 1263 (20.8) 1261 (20.8)
≥ 2 87,552 (19.1) 892 (14.7) 896 (14.7)
Provider typec
Endocrinologist 3317 (0.7) 241 (4.0) 240 (4.0) 1.6
Rheumatologist 6118 (1.3) 212 (3.5) 212 (3.5)
Primary care provider 94,811 (20.7) 1465 (24.1) 1466 (24.1)
Acute, ambulatory, or urgent care 117,096 (25.6) 1362 (22.4) 1360 (22.4)
Other 131,331 (28.7) 1631 (26.9) 1632 (26.9)
Unknown 105,156 (23.0) 1164 (19.2) 1165 (19.2)
Other variables, n (%)
Claim at cohort entry
Osteoporosis therapy 159,032 (34.7) 4550 (74.9)
Anabolicd 7394 (1.6) 19 (0.3)
Anti-resorptivee 77,980 (17.0) 601 (9.9)
Fragility fracture 213,423 (46.6) 905 (14.9)
Database, n (%)
CCAE 276,970 (60.5) 4862 (80.0)
Medicare supplemental and CoB 180,859 (39.5) 1213 (20.0)
Bone mineral density claimb, n (%) 109,746 (24.0) 2952 (48.6)
Mortalityf, n (%) 734 (0.2) 13 (0.2)
Median follow-up time, years (IQR) 2.0 (1.1–3.6) 2.6 (1.1–3.6)
aStandard difference, p value < 0.01: values < 0.1 assumed to indicate negligible statistical difference between matched groups; bcharacteristics observed during the baseline period; cMatching on provider type only conducted for model 2 (impact of BTM on treatment decision-making). MarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care provider included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories; danabolic therapy (parathyroid hormone, dual-action bone agent, prostaglandin group E); eanti-resorptive therapy (bisphosphonate, estrogen, SERMs, calcitonin, denosumab); fin MarketScan databases, only inpatient mortality is captured. Therefore, mortality events outside of this setting are not captured in patient claims
BTM, bone turnover marker; CCI, Charlson Comorbidity Index; CCAE, Commercial Claims and Encounters; CoB, Co-ordination of Benefits; IQR, interquartile range
Following application of the propensity score model, 6075 BTM-tested patients were matched to 6075 untested patients (Table 1). Matched tested and untested patients were well-balanced on their baseline characteristics with none exhibiting a standard difference of > 0.1.
Real-world bone turnover marker test patterns
Among the 6075 tested patients, 8828 unique claims were made during the study period, with the majority being markers of resorption (76.6%; Table 2). In total, 14.4% (n = 875) of patients had concurrent claims for both resorption and formation markers. The annualized period prevalence of testing per 100 persons ranged from 0.23 (95% CI: 0.19–0.28) in 2008 to 0.47 (95% CI: 0.45–0.50) in 2018 (Fig. 3). During the study period, patients tested increased year-over-year (Cochran-Armitage test for trend, p = 0.03), with most of the increase occurring in the latter half of the study period (2015 onwards) and with an AAPC of 8.1% (95% CI: 5.6–9.0; p = 0.01). The AAPC prevalence for resorption markers was 4.2% (95% CI: 3.7–3.9; p = 0.04) and for formation markers, it was 6.9% (95% CI: 5.9–7.2; p = 0.02). No substantial difference in annual testing trends was observed when the analysis was repeated by age group deciles and sex (data not shown).Table 2 Characteristics of osteoporotic patients tested with bone turnover marker and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Patients tested (n = 6075) BTM tests (n = 8828)
Frequency (%) Frequency (%)
Year of BTM testa
2008 627 (10.3) 745 (8.4)
2009 868 (14.3) 994 (11.3)
2010 880 (14.5) 1015 (11.5)
2011 990 (16.3) 1122 (12.7)
2012 970 (16.0) 1092 (12.4)
2013 814 (13.4) 925 (10.5)
2014 698 (11.5) 803 (9.1)
2015 542 (8.9) 619 (7.0)
2016 539 (8.9) 615 (7.0)
2017 444 (7.3) 500 (5.7)
2018 341 (5.6) 398 (4.5)
Mode of action
Formation 2299 (37.8) 3100 (35.1)
Resorption 4622 (76.1) 6765 (76.6)
Place of BTM testb
Acute, ambulatory, or urgent care 8 (0.1) 11 (0.1)
Outpatient clinic/hospital 2094 (34.5) 2951 (33.4)
Inpatient clinic/hospital 16 (0.3) 24 (0.3)
Other 3958 (65.2) 5682 (64.4)
Unknown 122 (2.0) 160 (1.8)
Number of BTM tests per patient
Mean (SD) 2.2 (2.0)
Median (IQR) 1.0 (1.0–3.0)
1 test 4545 (74.8)
2 tests 937 (15.4)
≥ 3 tests 593 (9.8)
Median inter-test intervals, days (IQR)
Diagnosis to 1st test 160 (37–471)
1st to 2nd test 221 (125–384)
2nd to 3rd test 223 (134–377)
aCalendar year of first test claim (patient-level) or year of test claim (test-level); bMarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care providers included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories
BTM, bone turnover marker; IQR, interquartile range; SD, standard deviation
Fig. 3 Annual period prevalence (per 100 persons) of bone turnover marker testing and average testing per patient among patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
On average, patients had 2.2 test claims (SD 2.0) during the study period (Table 2), which remained stable irrespective of year of diagnosis (data not shown). Median claims suggest a non-normal distribution (1.0 IQR: 1.0–3.0) with only 593 patients (9.8%) reporting ≥ 3 BTM claims during follow-up. Follow-up BTM and dual-energy X-ray absorptiometry testing after osteoporosis diagnosis are recommended by clinical guidelines [8]; therefore, patterns of repeat testing were examined for those with > 1 test following index. Median time from osteoporosis diagnosis to first BTM claim was 160 days (IQR: 37–471), and for those with two or more claims the median inter-test interval was approximately 220 days between claimed tests. Approximately 30% of all tests were ordered by endocrinologists, rheumatologists, and primary care providers, with the majority of claims in the non-ambulatory or hospital or clinical setting.
Impact of bone turnover markers on treatment decision-making and fragility fracture
In total, 1345 patients (22%) had a unique treatment decision within 30 days of BTM testing. Treatment decisions were most common with anti-resorptives (89.1%) followed by anabolic (5.6%) and combination therapies (6.3%). This included treatment initiated (4.9%), continuation on the same treatment (8.4%), re-starting the same treatment following a gap of > 30 days (0.6%), and treatment discontinuation (8.2%). No observations for treatment switching were observed for tested patients. From the GEE propensity score model predicting treatment decision-making, tested patients were significantly more likely to have a treatment decision within 30 days compared to those untested (OR 1.14; 95% CI: 1.13–1.15). To further understand this observed effect, we conducted a post-hoc analysis of treatment decision-making by category of decision (new treatment, continuation, treatment restart, treatment switch, discontinuation). Assessment of BTMs was significantly associated with the decision to re-start treatment within 30 days of testing (OR 2.67; 95% CI: 2.51–2.93) and continue treatment (OR 1.03; 95% CI: 1.03–1.04), and treatment discontinuation (OR 1.03; 95% CI: 1.02–1.04). While no statistically significant association was observed for decision to initiate treatment (OR 1.01; 95% CI: 1.00–1.01) or switching treatment following testing (OR 1.02; 95% CI: 1.00–1.04), point observations suggest potential weak clinical significance.
The impact of testing on fracture events was also explored. A total of 1409 tested patients (23.2%) had a fragility fracture assumed to be due to osteoporosis following index, and this was linked to 3236 unique fracture events during the study period. The most common fracture type was wrist/forearm (562 events, 17.4%), followed by hip (440, 13.6%), vertebra (429, 13.2%), and femoral (381, 11.8%). In the model predicting fragility fracture following a BTM test, results suggest that testing was associated with lower odds of fracture compared to those patients untested (OR 0.87; 95% CI: 0.85–0.88).
Discussion
To our knowledge, this study represents the first known US nationwide epidemiological study of BTM testing among patients with presumed osteoporosis. We analyzed data from persons with a presumed osteoporosis diagnosis in the USA from 2008 to 2018 and observed that the annual proportion tested using BTMs rose from 0.23 tests per 100 patients in 2008 to 0.47 in 2018, with most of the increase occurring in the latter half of the study period. The observed rise in testing is encouraging, yet tested patients still remain below international guidelines for screening response to therapy. Among various BTMs, serum CTX-I and serum PINP are recently recommended as monitoring tests for osteoporosis treatment by several osteoporosis guidelines, including the NOF, the Japanese Osteoporosis Society, and the IOF [2, 9, 32].
BTMs may be employed as clinical tools for treatment decision-making at several important junctures of osteoporosis treatment. For example, baseline measurements of resorption and formation markers before commencement of anti-resorptive and anti-formation therapies, respectively, are of utility in monitoring treatment response and adherence. BTMs are also of potential clinical value in deciding whether patients should resume therapy following treatment holidays, and for monitoring patients during these periods [33]. Our results suggest that assessing BTM was significantly associated with the decision to re-start treatment for osteoporosis within 30 days of testing, to continue treatment, or to discontinue treatment. Published literature substantiates BTMs as having considerable utility in treatment decision-making in patients with osteoporosis [11]. In particular, measurement of BTMs can reflect response to therapies earlier than that of BMD, and can be used to monitor treatment compliance [6, 34]. PINP or CTX may be used to identify treatment responders and non-responders, and as a marker of poor patient adherence to common osteoporosis treatments [35, 36].
Our analysis showed that BTM testing was associated with lower odds of fracture compared to not testing patients with osteoporosis. This association could potentially be due to turnover data leading to change in pharmacotherapies reducing fracture risk. Supporting this, it has previously been reported that high levels of the BTMs NTX, DPD, and CTX are predictive of subsequent risk of hip fracture in women aged ≥ 75 years, independently of hip BMD [14]. High levels of NTX, DPD, CTX, and serum bone ALP have also been shown to be associated with increased risk of osteoporotic fracture in post-menopausal women, independently of BMD [37, 38]. BTM testing offers potential advantages versus traditional BMD testing, as the latter does not completely capture the risk of osteoporotic fracture, and the use of serial BMD measurements as a tool for treatment response requires an interval of more than a year. Bone turnover, by contrast, changes early and can be assessed within 3 months of starting treatment [34]. BTM measurements are also repeatable, relatively inexpensive, and non-invasive [39], potentially lowering the cost of care [40] and decreasing patient inconvenience as opposed to BMD testing. However, unlike BMD, BTM measurements are subject to a number of pre-analytical variations, including seasonal and diurnal variations [41].
As with all observational studies, and especially with studies using commercial insurance claims databases where changes in enrollment (including left censoring) and loss to follow-up (≥ 20%) [42] reduce the sample size of longitudinal studies, the results of the present study should be interpreted with caution. Firstly, the study provided an overall picture of BTM testing and it was not the intention of the claims data mining to determine which BTMs were being tested. It is, therefore, not possible to specify which BTMs are associated with an impact on treatment or predict fragility fracture risk. As previously mentioned, there is no unique CPT code (83519) available to accurately classify the receipt of PINP. Serum osteocalcin was included in this analysis and has been shown to correspond well with levels of PINP [33]. Secondly, outpatient claims may be recorded by a variety of staff with limited clinical training; therefore, misclassification is possible. In this study, the inclusion criterion for incident presumed osteoporosis diagnosis was based on > 1 claim, which may minimize the risk of misclassification bias. Finally, administrative claims do not provide insight into individual test results, which may be drivers of the observed association, or potential confounders not captured in the present database that may have biased the observations. The strengths of our study include the use of a large, longitudinal claims database from which we were able to analyze a heterogeneous, real-life population of patients in terms of decisions made about their treatment and incident fracture outcomes. MarketScan is a large, nationally representative database of individuals receiving employer-sponsored healthcare insurance, and the coding of inpatient claims in the USA is typically performed reliably by professional coders.
Conclusions
In this large, heterogeneous sample of US-based patients with presumed osteoporosis, we determined that BTM testing was associated with both treatment decision-making and a reduction of fragility fracture following use, conclusions which are consistent with published literature. While further investigation to validate the findings and understand the drivers is warranted, the evidence presented in this work provides further evidence of the value of monitoring osteoporotic patients with in vitro BTM monitoring diagnostic solutions.
Supplementary Information
ESM 1 (DOCX 25 kb)
The authors wish to acknowledge Dr. Andy Surinach of Genesis Research and Jaya Madala of Roche Diagnostics for their assistance in cohort development and code review.
Funding
This study was funded by Roche Diagnostics International Ltd. and Roche Diagnostics Information Solutions. Third-party writing assistance under the guidance of the authors was provided by James Everington and Ashlie Butler (Gardiner-Caldwell Communications, Macclesfield, UK) and funded by Roche Diagnostics International Ltd. (Rotkreuz, Switzerland).
Compliance with ethical standards
Conflicts of interest
N. Lane reports consultancy funding from Roche, and consultancy and speaker funding from Amgen. K. Saag reports grants from Amgen, Radius, and Mereo, and consultancy funding from Amgen, Daichi-Sankyo, and Roche. T. O’Neill is an employee of Roche Diagnostics Information Solutions and owner of stocks in Roche, Gilead, Pfizer, Regeneron, Abbott, and United Healthcare. M. Manion is an employee of Roche Diagnostics International Ltd. R. Shah is an employee of Roche Diagnostics International Ltd. and owner of stock in Roche. U. Klause is an employee of Roche Diabetes Care. R. Eastell reports consultancy funding from IDS, Sandoz, Nittobo, Roche Diagnostics, Samsung, Haoma Medica, CL Bio, Biocon, Lyramid, and Viking Therapeutics, and grant funding from Nittobo, Roche Diagnostics, and Alexion.
Ethics approval
All data were anonymized to comply with HIPAA and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required.
Consent to participate
Formal informed consent was not obtained.
Consent for publication
All authors consent to the publication of this study.
Code availability
Not applicable.
The original online version of this article was revised due to a retrospective Open Access order.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
4/13/2021
A Correction to this paper has been published: 10.1007/s00198-021-05828-3 | DENOSUMAB | DrugsGivenReaction | CC BY-NC | 33236195 | 19,311,011 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hip fracture'. | Real-world bone turnover marker use: impact on treatment decisions and fracture.
The use of bone turnover marker (BTM) testing for patients with osteoporosis in the USA has not been well characterized. This retrospective US-based real-world data study found BTM testing has some association with treatment decision-making and lower fracture risk in patients with presumed osteoporosis, supporting its use in clinical practice.
BACKGROUND
The purpose of this study was to characterize bone turnover marker (BTM) testing patterns and estimate their clinical utility in treatment decision-making and fragility fracture risk in patients with osteoporosis using a retrospective claims database.
METHODS
Data from patients aged ≥ 50 years with newly diagnosed osteoporosis enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases from January 2008 to June 2018 were included. Osteoporosis was ascertained by explicit claims, fragility fracture events associated with osteoporosis, or prescribed anti-resorptive or anabolic therapy. BTM-tested patients were 1:1 propensity score matched to those untested following diagnosis. Generalized estimating equation models were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for testing versus no testing on both treatment decision-making and fragility fracture.
RESULTS
Of the 457,829 patients with osteoporosis, 6075 were identified with ≥ 1 BTM test following diagnosis; of these patients, 1345 had a unique treatment decision made ≤ 30 days from BTM testing. The percentage of patients receiving BTM tests increased significantly each year (average annual % change: + 8.1%; 95% CI: 5.6-9.0; p = 0.01). Patients tested were significantly more likely to have a treatment decision (OR: 1.14; 95% CI: 1.13-1.15), and testing was associated with lower odds of fracture versus those untested (OR: 0.87; 95% CI: 0.85-0.88).
CONCLUSIONS
In this large, heterogeneous population of patients with presumed osteoporosis, BTM testing was associated with treatment decision-making, likely leading to fragility fracture reduction following use.
Introduction
Osteoporosis, which is characterized by reduced bone mass and micro-architectural deterioration leading to increased bone fragility [1, 2], affects approximately 200 million people worldwide [3]. In 2020, the National Osteoporosis Foundation reported that approximately 54 million Americans, of all ages, are living with osteoporosis or low bone mass [4].
Bone turnover markers (BTMs) can be measured in serum, plasma, and urine [5], with bone formation and bone resorption marker levels relating to osteoblast and osteoclast activity, respectively. Bone formation markers include proteins such as osteocalcin or procollagen type I N propeptide (PINP), and the bone isoform of alkaline phosphatase (bone ALP). Bone resorption markers include fragments released from the telopeptide end region of type I collagen following its enzymatic degradation, such as the N-telopeptide of type I collagen (NTX), carboxy-terminal crosslinking telopeptide of type I collagen (CTX), deoxypyridinoline (DPD), and the enzyme tartrate-resistant acid phosphatase [6].
The International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine (IOF-IFCC) Bone Markers Working Group has identified CTX and PINP as promising markers for providing clinically useful information for monitoring osteoporosis treatment [7], and recommends that CTX and serum PINP, measured by standardized assays, be used as reference markers in observational and interventional studies [2]. American Association of Clinical Endocrinologists/American College of Endocrinology guideline recommendations for BTMs also advise use of CTX and PINP as monitoring tests for osteoporosis treatment [8], as do National Osteoporosis Foundation (NOF) guidelines [9]. An IOF and European Calcified Tissue Society taskforce has also suggested that PINP and CTX screening may be used to detect lack of adherence to oral bisphosphonates therapy [10].
In addition to monitoring osteoporosis treatment [11], and patients during treatment holiday [12, 13], a meta-analysis of published studies has shown that low levels of BTMs are modestly associated with reduced fracture risk [5]. A few studies have measured BTMs prior to hip fracture events [5, 14], and found conflicting reports with both positive [15] and negative [16] associations of BTM levels and the risk of osteoporosis-related hip fracture. In clinical practice, the use of BTM levels in predicting fracture outcomes is further complicated by significant within-patient variability of BTM levels due to patient age [17], comorbid conditions such as diabetes and chronic kidney disease [11], or ethnicity [18]. Sources of variability in BTM levels should be considered when interpreting test results. Particular attention should be paid to the appropriate use of reference intervals for determination of abnormal results, specifically related to the age and sex of the patient [19].
The majority of reports on the use of BTMs in clinical practice have tended to be single-site or small number multi-site studies [20] whose results may not be broadly applicable to the medically insured patients with osteoporosis in the USA. To help address this gap, we conducted an investigation using real-world data from a large patient population with osteoporosis in the USA. Our aims were threefold: (1) to assess trends in BTM test utilization; (2) to characterize the patterns of BTM testing and baseline characteristics of a heterogeneous population of patients in clinical practice; and (3) to estimate the potential clinical utility of BTM for treatment decision-making and association with fragility fracture.
Methods
Study design and data source
We undertook a population-based retrospective cohort analysis of patients enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases. These databases consist of the outpatient, inpatient, and pharmaceutical claims of approximately 50 million privately insured individuals and their dependents receiving care annually in the USA. Claims originated from more than 150 large employer-sponsored health insurance plans with patient coverage in all 50 states. The Medicare Supplemental and Co-ordination of Benefits databases represent commercially insured individuals, who have both Medicare coverage and supplemental employer-sponsored coverage, for Medicare-eligible active and retired employees and their Medicare-eligible dependents from employer-sponsored Medicare Supplemental plans. All data were anonymized to comply with the Health Insurance Portability and Accountability Act (HIPAA) and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required and formal informed consent was not obtained.
Study design and patient selection
Osteoporosis was defined at baseline in adult patients aged ≥ 50 years who were enrolled in a health plan with pharmaceutical coverage from January 1st 2008 to June 30th 2018. Osteoporosis was defined based on first recorded event according to (1) ≥ 1 inpatient or 2 outpatient claims (≥ 30 to ≤ 360 days apart) for osteoporosis, as defined under the International Classification of Diseases, Ninth (ICD-9-CM) or Tenth Revision (ICD-10-CM); (2) ≥ 1 claim for US Food and Drug Administration (FDA)-approved osteoporosis treatment (National Drug Code [NDC], Healthcare Common Procedure Coding System J- or C-codes); or (3) a fragility fracture considered to be associated with osteoporosis [6, 21, 22] (Online Resource Table 2). For hip fracture claims, ≥ 1 inpatient claim was required, and for other fracture types, ≥ 1 inpatient claim or ≥ 2 outpatient claims, ≥ 30 to ≤ 360 days apart (ICD-9-CM, ICD-10-CM codes, or Common Procedural Terminology [CPT] codes) were required. Patients were excluded if a claim of malignant neoplasm (excluding non-melanoma skin cancers), Paget’s disease of bone, or chronic kidney or end-stage renal disease was made at any time during the study period, to avoid misidentification of patients treated with medications as osteoporotic and inclusion of patients with malignancy-related fractures (Online Resource Table 3).
The index date was defined differently between BTM-tested and untested patients. In both cases, patients were required a minimum continuous enrollment ≥ 360 days prior to defined baseline (or washout period) and ≥ 360 days follow-up (Fig. 1) with allowable gap in coverage equivalent to ≤ 30 days. For those tested, the index date was defined as the date of the first BTM claim following osteoporosis diagnosis based on corresponding CPT codes for BTMs: osteocalcin (83937), bone-specific ALP (84080), and collagen cross-links (any method, 82523). PINP was not included in the present study as no unique CPT code (83519) is available to accurately classify receipt of this test. Untested patients were randomly assigned an index date based on a uniform distribution and the following criteria: to ensure adequate follow-up, the index date was required to fall before the final 360 days of data capture for the patient, and to ensure sufficient baseline washout period, the index date was required to fall after the first 360 days of data capture. Each patient was followed prospectively until an observed outcome, the end of continuous enrollment, reported death, or study end, whichever occurred first.Fig. 1 Study design schema of patients with osteoporosis aged ≥ 50 years enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Defining study outcomes
Study outcomes were compared between BTM-tested and untested groups in the follow-up period. Further details on how study outcomes were defined are provided in the Online Resource Methods section.
Outcome 1: Treatment decision-making
Osteoporosis treatments approved by the FDA during the study period were explored according to therapeutic mode of action: anti-resorptive (bisphosphonates, estrogen/progesterone, selective estrogen receptor modulators [SERMs], calcitonin, denosumab), or anabolic (teriparatide). Both injectable and oral routes were considered along with respective days of expected coverage or supply (i.e., 90/180/360 day intervals with allowable coverage gap of ≤ 30 days). Patients were classified according to the next observed treatment decision following a BTM test according to the days of coverage or supply: no treatment prescribed, treatment initiated, continue on the same treatment, restart following a treatment gap of > 30 days, between-class switch, or treatment discontinuation.
Outcome 2: Fragility fracture
Occurrence of a fragility fracture following index was assumed to be associated with osteoporosis and was classified according to methods reported by Song et al. [23]. Incident claims were captured by the presence of a qualified diagnosis of closed fractures of sites that may be associated with an increased risk of fracture, predominantly spine, hip, pelvis, and upper leg fractures [24]. Fractures were defined as those with ≥ 1 inpatient claims (primary or secondary discharge diagnosis) for hip fractures, and ≥ 1 inpatient (primary or secondary discharge diagnosis) or ≥ 2 outpatient claims (30–180 days apart) for all other sites. Fractures that were most likely the result of serious trauma were excluded, including compound or open fractures, multiple fractures within 7 days of a single claim, and vertebral fractures with concurrent spinal cord injury. Analyses were based on determination of the first claim for an osteoporotic fracture following index and any subsequent BTM event thereafter.
Statistical analysis
Descriptive statistics were used to characterize baseline socio-demographic and clinical characteristics of the osteoporotic patient cohort, summarizing continuous variables with means (standard deviation [SD]) or medians (interquartile range [IQR]) and categorical variables with counts and proportions (percentages). To explore trends in testing over calendar time [25], the annual period prevalence and associated 95% confidence intervals (CIs) were estimated among tested patients from 2008 forward. To evaluate longitudinal trends, the Cochran-Armitage test for trend and average annual percentage change (AAPC) were reported [26]. To account for variable enrollment in the MarketScan databases over time, the numerator was defined as the number of patients with one or more BTM tests and the denominator as total enrollment in a calendar year.
To examine the association between index testing on treatment decisions and fragility fracture, a multivariate logistic propensity score model conditioned on values at index (age, sex, year, region of care, insurance type, provider type [for treatment decision outcome model only]) and baseline (Charlson Comorbidity Index [CCI], score 1, 2, 3, or 6, where a higher score indicates a greater risk of 1-year mortality associated with more severe and/or greater co-morbidity burden) was fit [27]. The propensity score was used to match tested and untested patients using a fixed 1:1 ratio and nearest neighbor without replacement [25]. Propensity scores represent the conditional probability of assignment to the tested group and may be used to control for multiple observed covariates that are associated with the exposure and outcome [28]. That is, patients are assumed to have or not have been tested by chance and propensity score matching represents a non-parametric way to control for selection bias. Adequacy of matching in terms of patients’ baseline characteristics was evaluated using standardized differences; a value of < 0.1 was assumed to indicate a negligible difference in the characteristics between tested and untested patients [29]. A doubly robust method [30] was used where, in addition to the propensity score matching, generalized estimating equation (GEE) models were fit to estimate comparisons of odds and 95% CIs assessing the association between testing on treatment decision-making and fragility fracture. A binomial distribution and logistic link function were specified for both models fit with unstructured correlation structures, selected based on quasi-likelihood information criteria [31]. Additional covariates were not included in models as groups were well-balanced on baseline characteristics.
All statistical tests were two-sided and significance was determined using ɑ = 0.05. Analyses were conducted in SAS version 9.4 (SAS Institute, Inc., Cary, NC).
Results
Patient cohort
From 2008 to 2018, 457,829 individuals were classified as presumed osteoporotic (Fig. 2). Following application of inclusion criteria, 6075 patients (1.3%) were identified with one or more BTM test claims on or following diagnosis. Among all patients with osteoporosis, cohort entry declined over calendar time (Table 1), reflective of the annual decline in patients enrolled in Truven MarketScan, year-over-year. At the time of diagnosis, median age was 62 years (IQR: 57–74), with the majority of patients classified as female (79.6%), and 19.2% of patients having high CCI scores ≥ 2 (Table 1). Claims were most frequent from the South (33.7%) or North Central (29.9%) USA, while preferred provider organization (PPO) insurance coverage was common (49.7%). Compared with those untested, patients at osteoporosis diagnosis with BTM claims during follow-up were slightly younger; had lower CCI scores; were more likely to have PPO insurance coverage; and had higher proportions of diagnoses made at endocrinologists, rheumatologists, or primary care providers. Similarly, they were more likely to have an explicit osteoporosis diagnosis claim, not be covered via Medicare, have at least one bone mineral density (BMD) test during baseline, and have longer follow-up.Fig. 2 Cohort attrition of patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018, and 1:1 propensity score matched between those with tested and untested for bone turnover markers. BTM, bone turnover marker
Table 1 Characteristics at index or baseline of patients with presumed osteoporosis diagnosis and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018 (matched and all patients)
All patients with presumed osteoporosis (n = 457,829) Matched cohort
BTM tested (n = 6075) BTM untested, matched (n = 6075) Standard diffa (vs. tested)
Matched variables, n (%)
Cohort entry, calendar year
2008 61,642 (13.5) 1139 (18.8) 1134 (18.7) 0.9
2009 71,508 (15.6) 1064 (17.5) 1068 (17.6)
2010 62,365 (13.6) 859 (14.1) 858 (14.1)
2011 52,854 (11.5) 724 (11.9) 726 (12.0)
2012 49,357 (10.8) 575 (9.5) 576 (9.5)
2013 37,153 (8.1) 445 (7.3) 445 (7.3)
2014 38,941 (8.5) 444 (7.3) 447 (7.4)
2015 29,278 (6.4) 295 (4.9) 291 (4.8)
2016 24,639 (5.4) 235 (3.9) 234 (3.9)
2017 20,725 (4.5) 225 (3.7) 225 (3.7)
2018 9367 (2.1) 70 (1.2) 71 (1.2)
Median age, years (IQR) 62.0 (57.0–74.0) 59.0 (55.0–63.0) 59.0 (54.0–63.0) 1.3
Female sex 364,315 (79.6) 5511 (90.7) 5509 (90.7) 0.8
CCIb
0 263,726 (57.6) 3920 (64.5) 3918 (64.5) 0.2
1 106,551 (23.3) 1263 (20.8) 1261 (20.8)
≥ 2 87,552 (19.1) 892 (14.7) 896 (14.7)
Provider typec
Endocrinologist 3317 (0.7) 241 (4.0) 240 (4.0) 1.6
Rheumatologist 6118 (1.3) 212 (3.5) 212 (3.5)
Primary care provider 94,811 (20.7) 1465 (24.1) 1466 (24.1)
Acute, ambulatory, or urgent care 117,096 (25.6) 1362 (22.4) 1360 (22.4)
Other 131,331 (28.7) 1631 (26.9) 1632 (26.9)
Unknown 105,156 (23.0) 1164 (19.2) 1165 (19.2)
Other variables, n (%)
Claim at cohort entry
Osteoporosis therapy 159,032 (34.7) 4550 (74.9)
Anabolicd 7394 (1.6) 19 (0.3)
Anti-resorptivee 77,980 (17.0) 601 (9.9)
Fragility fracture 213,423 (46.6) 905 (14.9)
Database, n (%)
CCAE 276,970 (60.5) 4862 (80.0)
Medicare supplemental and CoB 180,859 (39.5) 1213 (20.0)
Bone mineral density claimb, n (%) 109,746 (24.0) 2952 (48.6)
Mortalityf, n (%) 734 (0.2) 13 (0.2)
Median follow-up time, years (IQR) 2.0 (1.1–3.6) 2.6 (1.1–3.6)
aStandard difference, p value < 0.01: values < 0.1 assumed to indicate negligible statistical difference between matched groups; bcharacteristics observed during the baseline period; cMatching on provider type only conducted for model 2 (impact of BTM on treatment decision-making). MarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care provider included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories; danabolic therapy (parathyroid hormone, dual-action bone agent, prostaglandin group E); eanti-resorptive therapy (bisphosphonate, estrogen, SERMs, calcitonin, denosumab); fin MarketScan databases, only inpatient mortality is captured. Therefore, mortality events outside of this setting are not captured in patient claims
BTM, bone turnover marker; CCI, Charlson Comorbidity Index; CCAE, Commercial Claims and Encounters; CoB, Co-ordination of Benefits; IQR, interquartile range
Following application of the propensity score model, 6075 BTM-tested patients were matched to 6075 untested patients (Table 1). Matched tested and untested patients were well-balanced on their baseline characteristics with none exhibiting a standard difference of > 0.1.
Real-world bone turnover marker test patterns
Among the 6075 tested patients, 8828 unique claims were made during the study period, with the majority being markers of resorption (76.6%; Table 2). In total, 14.4% (n = 875) of patients had concurrent claims for both resorption and formation markers. The annualized period prevalence of testing per 100 persons ranged from 0.23 (95% CI: 0.19–0.28) in 2008 to 0.47 (95% CI: 0.45–0.50) in 2018 (Fig. 3). During the study period, patients tested increased year-over-year (Cochran-Armitage test for trend, p = 0.03), with most of the increase occurring in the latter half of the study period (2015 onwards) and with an AAPC of 8.1% (95% CI: 5.6–9.0; p = 0.01). The AAPC prevalence for resorption markers was 4.2% (95% CI: 3.7–3.9; p = 0.04) and for formation markers, it was 6.9% (95% CI: 5.9–7.2; p = 0.02). No substantial difference in annual testing trends was observed when the analysis was repeated by age group deciles and sex (data not shown).Table 2 Characteristics of osteoporotic patients tested with bone turnover marker and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Patients tested (n = 6075) BTM tests (n = 8828)
Frequency (%) Frequency (%)
Year of BTM testa
2008 627 (10.3) 745 (8.4)
2009 868 (14.3) 994 (11.3)
2010 880 (14.5) 1015 (11.5)
2011 990 (16.3) 1122 (12.7)
2012 970 (16.0) 1092 (12.4)
2013 814 (13.4) 925 (10.5)
2014 698 (11.5) 803 (9.1)
2015 542 (8.9) 619 (7.0)
2016 539 (8.9) 615 (7.0)
2017 444 (7.3) 500 (5.7)
2018 341 (5.6) 398 (4.5)
Mode of action
Formation 2299 (37.8) 3100 (35.1)
Resorption 4622 (76.1) 6765 (76.6)
Place of BTM testb
Acute, ambulatory, or urgent care 8 (0.1) 11 (0.1)
Outpatient clinic/hospital 2094 (34.5) 2951 (33.4)
Inpatient clinic/hospital 16 (0.3) 24 (0.3)
Other 3958 (65.2) 5682 (64.4)
Unknown 122 (2.0) 160 (1.8)
Number of BTM tests per patient
Mean (SD) 2.2 (2.0)
Median (IQR) 1.0 (1.0–3.0)
1 test 4545 (74.8)
2 tests 937 (15.4)
≥ 3 tests 593 (9.8)
Median inter-test intervals, days (IQR)
Diagnosis to 1st test 160 (37–471)
1st to 2nd test 221 (125–384)
2nd to 3rd test 223 (134–377)
aCalendar year of first test claim (patient-level) or year of test claim (test-level); bMarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care providers included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories
BTM, bone turnover marker; IQR, interquartile range; SD, standard deviation
Fig. 3 Annual period prevalence (per 100 persons) of bone turnover marker testing and average testing per patient among patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
On average, patients had 2.2 test claims (SD 2.0) during the study period (Table 2), which remained stable irrespective of year of diagnosis (data not shown). Median claims suggest a non-normal distribution (1.0 IQR: 1.0–3.0) with only 593 patients (9.8%) reporting ≥ 3 BTM claims during follow-up. Follow-up BTM and dual-energy X-ray absorptiometry testing after osteoporosis diagnosis are recommended by clinical guidelines [8]; therefore, patterns of repeat testing were examined for those with > 1 test following index. Median time from osteoporosis diagnosis to first BTM claim was 160 days (IQR: 37–471), and for those with two or more claims the median inter-test interval was approximately 220 days between claimed tests. Approximately 30% of all tests were ordered by endocrinologists, rheumatologists, and primary care providers, with the majority of claims in the non-ambulatory or hospital or clinical setting.
Impact of bone turnover markers on treatment decision-making and fragility fracture
In total, 1345 patients (22%) had a unique treatment decision within 30 days of BTM testing. Treatment decisions were most common with anti-resorptives (89.1%) followed by anabolic (5.6%) and combination therapies (6.3%). This included treatment initiated (4.9%), continuation on the same treatment (8.4%), re-starting the same treatment following a gap of > 30 days (0.6%), and treatment discontinuation (8.2%). No observations for treatment switching were observed for tested patients. From the GEE propensity score model predicting treatment decision-making, tested patients were significantly more likely to have a treatment decision within 30 days compared to those untested (OR 1.14; 95% CI: 1.13–1.15). To further understand this observed effect, we conducted a post-hoc analysis of treatment decision-making by category of decision (new treatment, continuation, treatment restart, treatment switch, discontinuation). Assessment of BTMs was significantly associated with the decision to re-start treatment within 30 days of testing (OR 2.67; 95% CI: 2.51–2.93) and continue treatment (OR 1.03; 95% CI: 1.03–1.04), and treatment discontinuation (OR 1.03; 95% CI: 1.02–1.04). While no statistically significant association was observed for decision to initiate treatment (OR 1.01; 95% CI: 1.00–1.01) or switching treatment following testing (OR 1.02; 95% CI: 1.00–1.04), point observations suggest potential weak clinical significance.
The impact of testing on fracture events was also explored. A total of 1409 tested patients (23.2%) had a fragility fracture assumed to be due to osteoporosis following index, and this was linked to 3236 unique fracture events during the study period. The most common fracture type was wrist/forearm (562 events, 17.4%), followed by hip (440, 13.6%), vertebra (429, 13.2%), and femoral (381, 11.8%). In the model predicting fragility fracture following a BTM test, results suggest that testing was associated with lower odds of fracture compared to those patients untested (OR 0.87; 95% CI: 0.85–0.88).
Discussion
To our knowledge, this study represents the first known US nationwide epidemiological study of BTM testing among patients with presumed osteoporosis. We analyzed data from persons with a presumed osteoporosis diagnosis in the USA from 2008 to 2018 and observed that the annual proportion tested using BTMs rose from 0.23 tests per 100 patients in 2008 to 0.47 in 2018, with most of the increase occurring in the latter half of the study period. The observed rise in testing is encouraging, yet tested patients still remain below international guidelines for screening response to therapy. Among various BTMs, serum CTX-I and serum PINP are recently recommended as monitoring tests for osteoporosis treatment by several osteoporosis guidelines, including the NOF, the Japanese Osteoporosis Society, and the IOF [2, 9, 32].
BTMs may be employed as clinical tools for treatment decision-making at several important junctures of osteoporosis treatment. For example, baseline measurements of resorption and formation markers before commencement of anti-resorptive and anti-formation therapies, respectively, are of utility in monitoring treatment response and adherence. BTMs are also of potential clinical value in deciding whether patients should resume therapy following treatment holidays, and for monitoring patients during these periods [33]. Our results suggest that assessing BTM was significantly associated with the decision to re-start treatment for osteoporosis within 30 days of testing, to continue treatment, or to discontinue treatment. Published literature substantiates BTMs as having considerable utility in treatment decision-making in patients with osteoporosis [11]. In particular, measurement of BTMs can reflect response to therapies earlier than that of BMD, and can be used to monitor treatment compliance [6, 34]. PINP or CTX may be used to identify treatment responders and non-responders, and as a marker of poor patient adherence to common osteoporosis treatments [35, 36].
Our analysis showed that BTM testing was associated with lower odds of fracture compared to not testing patients with osteoporosis. This association could potentially be due to turnover data leading to change in pharmacotherapies reducing fracture risk. Supporting this, it has previously been reported that high levels of the BTMs NTX, DPD, and CTX are predictive of subsequent risk of hip fracture in women aged ≥ 75 years, independently of hip BMD [14]. High levels of NTX, DPD, CTX, and serum bone ALP have also been shown to be associated with increased risk of osteoporotic fracture in post-menopausal women, independently of BMD [37, 38]. BTM testing offers potential advantages versus traditional BMD testing, as the latter does not completely capture the risk of osteoporotic fracture, and the use of serial BMD measurements as a tool for treatment response requires an interval of more than a year. Bone turnover, by contrast, changes early and can be assessed within 3 months of starting treatment [34]. BTM measurements are also repeatable, relatively inexpensive, and non-invasive [39], potentially lowering the cost of care [40] and decreasing patient inconvenience as opposed to BMD testing. However, unlike BMD, BTM measurements are subject to a number of pre-analytical variations, including seasonal and diurnal variations [41].
As with all observational studies, and especially with studies using commercial insurance claims databases where changes in enrollment (including left censoring) and loss to follow-up (≥ 20%) [42] reduce the sample size of longitudinal studies, the results of the present study should be interpreted with caution. Firstly, the study provided an overall picture of BTM testing and it was not the intention of the claims data mining to determine which BTMs were being tested. It is, therefore, not possible to specify which BTMs are associated with an impact on treatment or predict fragility fracture risk. As previously mentioned, there is no unique CPT code (83519) available to accurately classify the receipt of PINP. Serum osteocalcin was included in this analysis and has been shown to correspond well with levels of PINP [33]. Secondly, outpatient claims may be recorded by a variety of staff with limited clinical training; therefore, misclassification is possible. In this study, the inclusion criterion for incident presumed osteoporosis diagnosis was based on > 1 claim, which may minimize the risk of misclassification bias. Finally, administrative claims do not provide insight into individual test results, which may be drivers of the observed association, or potential confounders not captured in the present database that may have biased the observations. The strengths of our study include the use of a large, longitudinal claims database from which we were able to analyze a heterogeneous, real-life population of patients in terms of decisions made about their treatment and incident fracture outcomes. MarketScan is a large, nationally representative database of individuals receiving employer-sponsored healthcare insurance, and the coding of inpatient claims in the USA is typically performed reliably by professional coders.
Conclusions
In this large, heterogeneous sample of US-based patients with presumed osteoporosis, we determined that BTM testing was associated with both treatment decision-making and a reduction of fragility fracture following use, conclusions which are consistent with published literature. While further investigation to validate the findings and understand the drivers is warranted, the evidence presented in this work provides further evidence of the value of monitoring osteoporotic patients with in vitro BTM monitoring diagnostic solutions.
Supplementary Information
ESM 1 (DOCX 25 kb)
The authors wish to acknowledge Dr. Andy Surinach of Genesis Research and Jaya Madala of Roche Diagnostics for their assistance in cohort development and code review.
Funding
This study was funded by Roche Diagnostics International Ltd. and Roche Diagnostics Information Solutions. Third-party writing assistance under the guidance of the authors was provided by James Everington and Ashlie Butler (Gardiner-Caldwell Communications, Macclesfield, UK) and funded by Roche Diagnostics International Ltd. (Rotkreuz, Switzerland).
Compliance with ethical standards
Conflicts of interest
N. Lane reports consultancy funding from Roche, and consultancy and speaker funding from Amgen. K. Saag reports grants from Amgen, Radius, and Mereo, and consultancy funding from Amgen, Daichi-Sankyo, and Roche. T. O’Neill is an employee of Roche Diagnostics Information Solutions and owner of stocks in Roche, Gilead, Pfizer, Regeneron, Abbott, and United Healthcare. M. Manion is an employee of Roche Diagnostics International Ltd. R. Shah is an employee of Roche Diagnostics International Ltd. and owner of stock in Roche. U. Klause is an employee of Roche Diabetes Care. R. Eastell reports consultancy funding from IDS, Sandoz, Nittobo, Roche Diagnostics, Samsung, Haoma Medica, CL Bio, Biocon, Lyramid, and Viking Therapeutics, and grant funding from Nittobo, Roche Diagnostics, and Alexion.
Ethics approval
All data were anonymized to comply with HIPAA and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required.
Consent to participate
Formal informed consent was not obtained.
Consent for publication
All authors consent to the publication of this study.
Code availability
Not applicable.
The original online version of this article was revised due to a retrospective Open Access order.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
4/13/2021
A Correction to this paper has been published: 10.1007/s00198-021-05828-3 | DENOSUMAB | DrugsGivenReaction | CC BY-NC | 33236195 | 19,311,011 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Spinal fracture'. | Real-world bone turnover marker use: impact on treatment decisions and fracture.
The use of bone turnover marker (BTM) testing for patients with osteoporosis in the USA has not been well characterized. This retrospective US-based real-world data study found BTM testing has some association with treatment decision-making and lower fracture risk in patients with presumed osteoporosis, supporting its use in clinical practice.
BACKGROUND
The purpose of this study was to characterize bone turnover marker (BTM) testing patterns and estimate their clinical utility in treatment decision-making and fragility fracture risk in patients with osteoporosis using a retrospective claims database.
METHODS
Data from patients aged ≥ 50 years with newly diagnosed osteoporosis enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases from January 2008 to June 2018 were included. Osteoporosis was ascertained by explicit claims, fragility fracture events associated with osteoporosis, or prescribed anti-resorptive or anabolic therapy. BTM-tested patients were 1:1 propensity score matched to those untested following diagnosis. Generalized estimating equation models were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for testing versus no testing on both treatment decision-making and fragility fracture.
RESULTS
Of the 457,829 patients with osteoporosis, 6075 were identified with ≥ 1 BTM test following diagnosis; of these patients, 1345 had a unique treatment decision made ≤ 30 days from BTM testing. The percentage of patients receiving BTM tests increased significantly each year (average annual % change: + 8.1%; 95% CI: 5.6-9.0; p = 0.01). Patients tested were significantly more likely to have a treatment decision (OR: 1.14; 95% CI: 1.13-1.15), and testing was associated with lower odds of fracture versus those untested (OR: 0.87; 95% CI: 0.85-0.88).
CONCLUSIONS
In this large, heterogeneous population of patients with presumed osteoporosis, BTM testing was associated with treatment decision-making, likely leading to fragility fracture reduction following use.
Introduction
Osteoporosis, which is characterized by reduced bone mass and micro-architectural deterioration leading to increased bone fragility [1, 2], affects approximately 200 million people worldwide [3]. In 2020, the National Osteoporosis Foundation reported that approximately 54 million Americans, of all ages, are living with osteoporosis or low bone mass [4].
Bone turnover markers (BTMs) can be measured in serum, plasma, and urine [5], with bone formation and bone resorption marker levels relating to osteoblast and osteoclast activity, respectively. Bone formation markers include proteins such as osteocalcin or procollagen type I N propeptide (PINP), and the bone isoform of alkaline phosphatase (bone ALP). Bone resorption markers include fragments released from the telopeptide end region of type I collagen following its enzymatic degradation, such as the N-telopeptide of type I collagen (NTX), carboxy-terminal crosslinking telopeptide of type I collagen (CTX), deoxypyridinoline (DPD), and the enzyme tartrate-resistant acid phosphatase [6].
The International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine (IOF-IFCC) Bone Markers Working Group has identified CTX and PINP as promising markers for providing clinically useful information for monitoring osteoporosis treatment [7], and recommends that CTX and serum PINP, measured by standardized assays, be used as reference markers in observational and interventional studies [2]. American Association of Clinical Endocrinologists/American College of Endocrinology guideline recommendations for BTMs also advise use of CTX and PINP as monitoring tests for osteoporosis treatment [8], as do National Osteoporosis Foundation (NOF) guidelines [9]. An IOF and European Calcified Tissue Society taskforce has also suggested that PINP and CTX screening may be used to detect lack of adherence to oral bisphosphonates therapy [10].
In addition to monitoring osteoporosis treatment [11], and patients during treatment holiday [12, 13], a meta-analysis of published studies has shown that low levels of BTMs are modestly associated with reduced fracture risk [5]. A few studies have measured BTMs prior to hip fracture events [5, 14], and found conflicting reports with both positive [15] and negative [16] associations of BTM levels and the risk of osteoporosis-related hip fracture. In clinical practice, the use of BTM levels in predicting fracture outcomes is further complicated by significant within-patient variability of BTM levels due to patient age [17], comorbid conditions such as diabetes and chronic kidney disease [11], or ethnicity [18]. Sources of variability in BTM levels should be considered when interpreting test results. Particular attention should be paid to the appropriate use of reference intervals for determination of abnormal results, specifically related to the age and sex of the patient [19].
The majority of reports on the use of BTMs in clinical practice have tended to be single-site or small number multi-site studies [20] whose results may not be broadly applicable to the medically insured patients with osteoporosis in the USA. To help address this gap, we conducted an investigation using real-world data from a large patient population with osteoporosis in the USA. Our aims were threefold: (1) to assess trends in BTM test utilization; (2) to characterize the patterns of BTM testing and baseline characteristics of a heterogeneous population of patients in clinical practice; and (3) to estimate the potential clinical utility of BTM for treatment decision-making and association with fragility fracture.
Methods
Study design and data source
We undertook a population-based retrospective cohort analysis of patients enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases. These databases consist of the outpatient, inpatient, and pharmaceutical claims of approximately 50 million privately insured individuals and their dependents receiving care annually in the USA. Claims originated from more than 150 large employer-sponsored health insurance plans with patient coverage in all 50 states. The Medicare Supplemental and Co-ordination of Benefits databases represent commercially insured individuals, who have both Medicare coverage and supplemental employer-sponsored coverage, for Medicare-eligible active and retired employees and their Medicare-eligible dependents from employer-sponsored Medicare Supplemental plans. All data were anonymized to comply with the Health Insurance Portability and Accountability Act (HIPAA) and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required and formal informed consent was not obtained.
Study design and patient selection
Osteoporosis was defined at baseline in adult patients aged ≥ 50 years who were enrolled in a health plan with pharmaceutical coverage from January 1st 2008 to June 30th 2018. Osteoporosis was defined based on first recorded event according to (1) ≥ 1 inpatient or 2 outpatient claims (≥ 30 to ≤ 360 days apart) for osteoporosis, as defined under the International Classification of Diseases, Ninth (ICD-9-CM) or Tenth Revision (ICD-10-CM); (2) ≥ 1 claim for US Food and Drug Administration (FDA)-approved osteoporosis treatment (National Drug Code [NDC], Healthcare Common Procedure Coding System J- or C-codes); or (3) a fragility fracture considered to be associated with osteoporosis [6, 21, 22] (Online Resource Table 2). For hip fracture claims, ≥ 1 inpatient claim was required, and for other fracture types, ≥ 1 inpatient claim or ≥ 2 outpatient claims, ≥ 30 to ≤ 360 days apart (ICD-9-CM, ICD-10-CM codes, or Common Procedural Terminology [CPT] codes) were required. Patients were excluded if a claim of malignant neoplasm (excluding non-melanoma skin cancers), Paget’s disease of bone, or chronic kidney or end-stage renal disease was made at any time during the study period, to avoid misidentification of patients treated with medications as osteoporotic and inclusion of patients with malignancy-related fractures (Online Resource Table 3).
The index date was defined differently between BTM-tested and untested patients. In both cases, patients were required a minimum continuous enrollment ≥ 360 days prior to defined baseline (or washout period) and ≥ 360 days follow-up (Fig. 1) with allowable gap in coverage equivalent to ≤ 30 days. For those tested, the index date was defined as the date of the first BTM claim following osteoporosis diagnosis based on corresponding CPT codes for BTMs: osteocalcin (83937), bone-specific ALP (84080), and collagen cross-links (any method, 82523). PINP was not included in the present study as no unique CPT code (83519) is available to accurately classify receipt of this test. Untested patients were randomly assigned an index date based on a uniform distribution and the following criteria: to ensure adequate follow-up, the index date was required to fall before the final 360 days of data capture for the patient, and to ensure sufficient baseline washout period, the index date was required to fall after the first 360 days of data capture. Each patient was followed prospectively until an observed outcome, the end of continuous enrollment, reported death, or study end, whichever occurred first.Fig. 1 Study design schema of patients with osteoporosis aged ≥ 50 years enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Defining study outcomes
Study outcomes were compared between BTM-tested and untested groups in the follow-up period. Further details on how study outcomes were defined are provided in the Online Resource Methods section.
Outcome 1: Treatment decision-making
Osteoporosis treatments approved by the FDA during the study period were explored according to therapeutic mode of action: anti-resorptive (bisphosphonates, estrogen/progesterone, selective estrogen receptor modulators [SERMs], calcitonin, denosumab), or anabolic (teriparatide). Both injectable and oral routes were considered along with respective days of expected coverage or supply (i.e., 90/180/360 day intervals with allowable coverage gap of ≤ 30 days). Patients were classified according to the next observed treatment decision following a BTM test according to the days of coverage or supply: no treatment prescribed, treatment initiated, continue on the same treatment, restart following a treatment gap of > 30 days, between-class switch, or treatment discontinuation.
Outcome 2: Fragility fracture
Occurrence of a fragility fracture following index was assumed to be associated with osteoporosis and was classified according to methods reported by Song et al. [23]. Incident claims were captured by the presence of a qualified diagnosis of closed fractures of sites that may be associated with an increased risk of fracture, predominantly spine, hip, pelvis, and upper leg fractures [24]. Fractures were defined as those with ≥ 1 inpatient claims (primary or secondary discharge diagnosis) for hip fractures, and ≥ 1 inpatient (primary or secondary discharge diagnosis) or ≥ 2 outpatient claims (30–180 days apart) for all other sites. Fractures that were most likely the result of serious trauma were excluded, including compound or open fractures, multiple fractures within 7 days of a single claim, and vertebral fractures with concurrent spinal cord injury. Analyses were based on determination of the first claim for an osteoporotic fracture following index and any subsequent BTM event thereafter.
Statistical analysis
Descriptive statistics were used to characterize baseline socio-demographic and clinical characteristics of the osteoporotic patient cohort, summarizing continuous variables with means (standard deviation [SD]) or medians (interquartile range [IQR]) and categorical variables with counts and proportions (percentages). To explore trends in testing over calendar time [25], the annual period prevalence and associated 95% confidence intervals (CIs) were estimated among tested patients from 2008 forward. To evaluate longitudinal trends, the Cochran-Armitage test for trend and average annual percentage change (AAPC) were reported [26]. To account for variable enrollment in the MarketScan databases over time, the numerator was defined as the number of patients with one or more BTM tests and the denominator as total enrollment in a calendar year.
To examine the association between index testing on treatment decisions and fragility fracture, a multivariate logistic propensity score model conditioned on values at index (age, sex, year, region of care, insurance type, provider type [for treatment decision outcome model only]) and baseline (Charlson Comorbidity Index [CCI], score 1, 2, 3, or 6, where a higher score indicates a greater risk of 1-year mortality associated with more severe and/or greater co-morbidity burden) was fit [27]. The propensity score was used to match tested and untested patients using a fixed 1:1 ratio and nearest neighbor without replacement [25]. Propensity scores represent the conditional probability of assignment to the tested group and may be used to control for multiple observed covariates that are associated with the exposure and outcome [28]. That is, patients are assumed to have or not have been tested by chance and propensity score matching represents a non-parametric way to control for selection bias. Adequacy of matching in terms of patients’ baseline characteristics was evaluated using standardized differences; a value of < 0.1 was assumed to indicate a negligible difference in the characteristics between tested and untested patients [29]. A doubly robust method [30] was used where, in addition to the propensity score matching, generalized estimating equation (GEE) models were fit to estimate comparisons of odds and 95% CIs assessing the association between testing on treatment decision-making and fragility fracture. A binomial distribution and logistic link function were specified for both models fit with unstructured correlation structures, selected based on quasi-likelihood information criteria [31]. Additional covariates were not included in models as groups were well-balanced on baseline characteristics.
All statistical tests were two-sided and significance was determined using ɑ = 0.05. Analyses were conducted in SAS version 9.4 (SAS Institute, Inc., Cary, NC).
Results
Patient cohort
From 2008 to 2018, 457,829 individuals were classified as presumed osteoporotic (Fig. 2). Following application of inclusion criteria, 6075 patients (1.3%) were identified with one or more BTM test claims on or following diagnosis. Among all patients with osteoporosis, cohort entry declined over calendar time (Table 1), reflective of the annual decline in patients enrolled in Truven MarketScan, year-over-year. At the time of diagnosis, median age was 62 years (IQR: 57–74), with the majority of patients classified as female (79.6%), and 19.2% of patients having high CCI scores ≥ 2 (Table 1). Claims were most frequent from the South (33.7%) or North Central (29.9%) USA, while preferred provider organization (PPO) insurance coverage was common (49.7%). Compared with those untested, patients at osteoporosis diagnosis with BTM claims during follow-up were slightly younger; had lower CCI scores; were more likely to have PPO insurance coverage; and had higher proportions of diagnoses made at endocrinologists, rheumatologists, or primary care providers. Similarly, they were more likely to have an explicit osteoporosis diagnosis claim, not be covered via Medicare, have at least one bone mineral density (BMD) test during baseline, and have longer follow-up.Fig. 2 Cohort attrition of patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018, and 1:1 propensity score matched between those with tested and untested for bone turnover markers. BTM, bone turnover marker
Table 1 Characteristics at index or baseline of patients with presumed osteoporosis diagnosis and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018 (matched and all patients)
All patients with presumed osteoporosis (n = 457,829) Matched cohort
BTM tested (n = 6075) BTM untested, matched (n = 6075) Standard diffa (vs. tested)
Matched variables, n (%)
Cohort entry, calendar year
2008 61,642 (13.5) 1139 (18.8) 1134 (18.7) 0.9
2009 71,508 (15.6) 1064 (17.5) 1068 (17.6)
2010 62,365 (13.6) 859 (14.1) 858 (14.1)
2011 52,854 (11.5) 724 (11.9) 726 (12.0)
2012 49,357 (10.8) 575 (9.5) 576 (9.5)
2013 37,153 (8.1) 445 (7.3) 445 (7.3)
2014 38,941 (8.5) 444 (7.3) 447 (7.4)
2015 29,278 (6.4) 295 (4.9) 291 (4.8)
2016 24,639 (5.4) 235 (3.9) 234 (3.9)
2017 20,725 (4.5) 225 (3.7) 225 (3.7)
2018 9367 (2.1) 70 (1.2) 71 (1.2)
Median age, years (IQR) 62.0 (57.0–74.0) 59.0 (55.0–63.0) 59.0 (54.0–63.0) 1.3
Female sex 364,315 (79.6) 5511 (90.7) 5509 (90.7) 0.8
CCIb
0 263,726 (57.6) 3920 (64.5) 3918 (64.5) 0.2
1 106,551 (23.3) 1263 (20.8) 1261 (20.8)
≥ 2 87,552 (19.1) 892 (14.7) 896 (14.7)
Provider typec
Endocrinologist 3317 (0.7) 241 (4.0) 240 (4.0) 1.6
Rheumatologist 6118 (1.3) 212 (3.5) 212 (3.5)
Primary care provider 94,811 (20.7) 1465 (24.1) 1466 (24.1)
Acute, ambulatory, or urgent care 117,096 (25.6) 1362 (22.4) 1360 (22.4)
Other 131,331 (28.7) 1631 (26.9) 1632 (26.9)
Unknown 105,156 (23.0) 1164 (19.2) 1165 (19.2)
Other variables, n (%)
Claim at cohort entry
Osteoporosis therapy 159,032 (34.7) 4550 (74.9)
Anabolicd 7394 (1.6) 19 (0.3)
Anti-resorptivee 77,980 (17.0) 601 (9.9)
Fragility fracture 213,423 (46.6) 905 (14.9)
Database, n (%)
CCAE 276,970 (60.5) 4862 (80.0)
Medicare supplemental and CoB 180,859 (39.5) 1213 (20.0)
Bone mineral density claimb, n (%) 109,746 (24.0) 2952 (48.6)
Mortalityf, n (%) 734 (0.2) 13 (0.2)
Median follow-up time, years (IQR) 2.0 (1.1–3.6) 2.6 (1.1–3.6)
aStandard difference, p value < 0.01: values < 0.1 assumed to indicate negligible statistical difference between matched groups; bcharacteristics observed during the baseline period; cMatching on provider type only conducted for model 2 (impact of BTM on treatment decision-making). MarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care provider included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories; danabolic therapy (parathyroid hormone, dual-action bone agent, prostaglandin group E); eanti-resorptive therapy (bisphosphonate, estrogen, SERMs, calcitonin, denosumab); fin MarketScan databases, only inpatient mortality is captured. Therefore, mortality events outside of this setting are not captured in patient claims
BTM, bone turnover marker; CCI, Charlson Comorbidity Index; CCAE, Commercial Claims and Encounters; CoB, Co-ordination of Benefits; IQR, interquartile range
Following application of the propensity score model, 6075 BTM-tested patients were matched to 6075 untested patients (Table 1). Matched tested and untested patients were well-balanced on their baseline characteristics with none exhibiting a standard difference of > 0.1.
Real-world bone turnover marker test patterns
Among the 6075 tested patients, 8828 unique claims were made during the study period, with the majority being markers of resorption (76.6%; Table 2). In total, 14.4% (n = 875) of patients had concurrent claims for both resorption and formation markers. The annualized period prevalence of testing per 100 persons ranged from 0.23 (95% CI: 0.19–0.28) in 2008 to 0.47 (95% CI: 0.45–0.50) in 2018 (Fig. 3). During the study period, patients tested increased year-over-year (Cochran-Armitage test for trend, p = 0.03), with most of the increase occurring in the latter half of the study period (2015 onwards) and with an AAPC of 8.1% (95% CI: 5.6–9.0; p = 0.01). The AAPC prevalence for resorption markers was 4.2% (95% CI: 3.7–3.9; p = 0.04) and for formation markers, it was 6.9% (95% CI: 5.9–7.2; p = 0.02). No substantial difference in annual testing trends was observed when the analysis was repeated by age group deciles and sex (data not shown).Table 2 Characteristics of osteoporotic patients tested with bone turnover marker and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Patients tested (n = 6075) BTM tests (n = 8828)
Frequency (%) Frequency (%)
Year of BTM testa
2008 627 (10.3) 745 (8.4)
2009 868 (14.3) 994 (11.3)
2010 880 (14.5) 1015 (11.5)
2011 990 (16.3) 1122 (12.7)
2012 970 (16.0) 1092 (12.4)
2013 814 (13.4) 925 (10.5)
2014 698 (11.5) 803 (9.1)
2015 542 (8.9) 619 (7.0)
2016 539 (8.9) 615 (7.0)
2017 444 (7.3) 500 (5.7)
2018 341 (5.6) 398 (4.5)
Mode of action
Formation 2299 (37.8) 3100 (35.1)
Resorption 4622 (76.1) 6765 (76.6)
Place of BTM testb
Acute, ambulatory, or urgent care 8 (0.1) 11 (0.1)
Outpatient clinic/hospital 2094 (34.5) 2951 (33.4)
Inpatient clinic/hospital 16 (0.3) 24 (0.3)
Other 3958 (65.2) 5682 (64.4)
Unknown 122 (2.0) 160 (1.8)
Number of BTM tests per patient
Mean (SD) 2.2 (2.0)
Median (IQR) 1.0 (1.0–3.0)
1 test 4545 (74.8)
2 tests 937 (15.4)
≥ 3 tests 593 (9.8)
Median inter-test intervals, days (IQR)
Diagnosis to 1st test 160 (37–471)
1st to 2nd test 221 (125–384)
2nd to 3rd test 223 (134–377)
aCalendar year of first test claim (patient-level) or year of test claim (test-level); bMarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care providers included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories
BTM, bone turnover marker; IQR, interquartile range; SD, standard deviation
Fig. 3 Annual period prevalence (per 100 persons) of bone turnover marker testing and average testing per patient among patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
On average, patients had 2.2 test claims (SD 2.0) during the study period (Table 2), which remained stable irrespective of year of diagnosis (data not shown). Median claims suggest a non-normal distribution (1.0 IQR: 1.0–3.0) with only 593 patients (9.8%) reporting ≥ 3 BTM claims during follow-up. Follow-up BTM and dual-energy X-ray absorptiometry testing after osteoporosis diagnosis are recommended by clinical guidelines [8]; therefore, patterns of repeat testing were examined for those with > 1 test following index. Median time from osteoporosis diagnosis to first BTM claim was 160 days (IQR: 37–471), and for those with two or more claims the median inter-test interval was approximately 220 days between claimed tests. Approximately 30% of all tests were ordered by endocrinologists, rheumatologists, and primary care providers, with the majority of claims in the non-ambulatory or hospital or clinical setting.
Impact of bone turnover markers on treatment decision-making and fragility fracture
In total, 1345 patients (22%) had a unique treatment decision within 30 days of BTM testing. Treatment decisions were most common with anti-resorptives (89.1%) followed by anabolic (5.6%) and combination therapies (6.3%). This included treatment initiated (4.9%), continuation on the same treatment (8.4%), re-starting the same treatment following a gap of > 30 days (0.6%), and treatment discontinuation (8.2%). No observations for treatment switching were observed for tested patients. From the GEE propensity score model predicting treatment decision-making, tested patients were significantly more likely to have a treatment decision within 30 days compared to those untested (OR 1.14; 95% CI: 1.13–1.15). To further understand this observed effect, we conducted a post-hoc analysis of treatment decision-making by category of decision (new treatment, continuation, treatment restart, treatment switch, discontinuation). Assessment of BTMs was significantly associated with the decision to re-start treatment within 30 days of testing (OR 2.67; 95% CI: 2.51–2.93) and continue treatment (OR 1.03; 95% CI: 1.03–1.04), and treatment discontinuation (OR 1.03; 95% CI: 1.02–1.04). While no statistically significant association was observed for decision to initiate treatment (OR 1.01; 95% CI: 1.00–1.01) or switching treatment following testing (OR 1.02; 95% CI: 1.00–1.04), point observations suggest potential weak clinical significance.
The impact of testing on fracture events was also explored. A total of 1409 tested patients (23.2%) had a fragility fracture assumed to be due to osteoporosis following index, and this was linked to 3236 unique fracture events during the study period. The most common fracture type was wrist/forearm (562 events, 17.4%), followed by hip (440, 13.6%), vertebra (429, 13.2%), and femoral (381, 11.8%). In the model predicting fragility fracture following a BTM test, results suggest that testing was associated with lower odds of fracture compared to those patients untested (OR 0.87; 95% CI: 0.85–0.88).
Discussion
To our knowledge, this study represents the first known US nationwide epidemiological study of BTM testing among patients with presumed osteoporosis. We analyzed data from persons with a presumed osteoporosis diagnosis in the USA from 2008 to 2018 and observed that the annual proportion tested using BTMs rose from 0.23 tests per 100 patients in 2008 to 0.47 in 2018, with most of the increase occurring in the latter half of the study period. The observed rise in testing is encouraging, yet tested patients still remain below international guidelines for screening response to therapy. Among various BTMs, serum CTX-I and serum PINP are recently recommended as monitoring tests for osteoporosis treatment by several osteoporosis guidelines, including the NOF, the Japanese Osteoporosis Society, and the IOF [2, 9, 32].
BTMs may be employed as clinical tools for treatment decision-making at several important junctures of osteoporosis treatment. For example, baseline measurements of resorption and formation markers before commencement of anti-resorptive and anti-formation therapies, respectively, are of utility in monitoring treatment response and adherence. BTMs are also of potential clinical value in deciding whether patients should resume therapy following treatment holidays, and for monitoring patients during these periods [33]. Our results suggest that assessing BTM was significantly associated with the decision to re-start treatment for osteoporosis within 30 days of testing, to continue treatment, or to discontinue treatment. Published literature substantiates BTMs as having considerable utility in treatment decision-making in patients with osteoporosis [11]. In particular, measurement of BTMs can reflect response to therapies earlier than that of BMD, and can be used to monitor treatment compliance [6, 34]. PINP or CTX may be used to identify treatment responders and non-responders, and as a marker of poor patient adherence to common osteoporosis treatments [35, 36].
Our analysis showed that BTM testing was associated with lower odds of fracture compared to not testing patients with osteoporosis. This association could potentially be due to turnover data leading to change in pharmacotherapies reducing fracture risk. Supporting this, it has previously been reported that high levels of the BTMs NTX, DPD, and CTX are predictive of subsequent risk of hip fracture in women aged ≥ 75 years, independently of hip BMD [14]. High levels of NTX, DPD, CTX, and serum bone ALP have also been shown to be associated with increased risk of osteoporotic fracture in post-menopausal women, independently of BMD [37, 38]. BTM testing offers potential advantages versus traditional BMD testing, as the latter does not completely capture the risk of osteoporotic fracture, and the use of serial BMD measurements as a tool for treatment response requires an interval of more than a year. Bone turnover, by contrast, changes early and can be assessed within 3 months of starting treatment [34]. BTM measurements are also repeatable, relatively inexpensive, and non-invasive [39], potentially lowering the cost of care [40] and decreasing patient inconvenience as opposed to BMD testing. However, unlike BMD, BTM measurements are subject to a number of pre-analytical variations, including seasonal and diurnal variations [41].
As with all observational studies, and especially with studies using commercial insurance claims databases where changes in enrollment (including left censoring) and loss to follow-up (≥ 20%) [42] reduce the sample size of longitudinal studies, the results of the present study should be interpreted with caution. Firstly, the study provided an overall picture of BTM testing and it was not the intention of the claims data mining to determine which BTMs were being tested. It is, therefore, not possible to specify which BTMs are associated with an impact on treatment or predict fragility fracture risk. As previously mentioned, there is no unique CPT code (83519) available to accurately classify the receipt of PINP. Serum osteocalcin was included in this analysis and has been shown to correspond well with levels of PINP [33]. Secondly, outpatient claims may be recorded by a variety of staff with limited clinical training; therefore, misclassification is possible. In this study, the inclusion criterion for incident presumed osteoporosis diagnosis was based on > 1 claim, which may minimize the risk of misclassification bias. Finally, administrative claims do not provide insight into individual test results, which may be drivers of the observed association, or potential confounders not captured in the present database that may have biased the observations. The strengths of our study include the use of a large, longitudinal claims database from which we were able to analyze a heterogeneous, real-life population of patients in terms of decisions made about their treatment and incident fracture outcomes. MarketScan is a large, nationally representative database of individuals receiving employer-sponsored healthcare insurance, and the coding of inpatient claims in the USA is typically performed reliably by professional coders.
Conclusions
In this large, heterogeneous sample of US-based patients with presumed osteoporosis, we determined that BTM testing was associated with both treatment decision-making and a reduction of fragility fracture following use, conclusions which are consistent with published literature. While further investigation to validate the findings and understand the drivers is warranted, the evidence presented in this work provides further evidence of the value of monitoring osteoporotic patients with in vitro BTM monitoring diagnostic solutions.
Supplementary Information
ESM 1 (DOCX 25 kb)
The authors wish to acknowledge Dr. Andy Surinach of Genesis Research and Jaya Madala of Roche Diagnostics for their assistance in cohort development and code review.
Funding
This study was funded by Roche Diagnostics International Ltd. and Roche Diagnostics Information Solutions. Third-party writing assistance under the guidance of the authors was provided by James Everington and Ashlie Butler (Gardiner-Caldwell Communications, Macclesfield, UK) and funded by Roche Diagnostics International Ltd. (Rotkreuz, Switzerland).
Compliance with ethical standards
Conflicts of interest
N. Lane reports consultancy funding from Roche, and consultancy and speaker funding from Amgen. K. Saag reports grants from Amgen, Radius, and Mereo, and consultancy funding from Amgen, Daichi-Sankyo, and Roche. T. O’Neill is an employee of Roche Diagnostics Information Solutions and owner of stocks in Roche, Gilead, Pfizer, Regeneron, Abbott, and United Healthcare. M. Manion is an employee of Roche Diagnostics International Ltd. R. Shah is an employee of Roche Diagnostics International Ltd. and owner of stock in Roche. U. Klause is an employee of Roche Diabetes Care. R. Eastell reports consultancy funding from IDS, Sandoz, Nittobo, Roche Diagnostics, Samsung, Haoma Medica, CL Bio, Biocon, Lyramid, and Viking Therapeutics, and grant funding from Nittobo, Roche Diagnostics, and Alexion.
Ethics approval
All data were anonymized to comply with HIPAA and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required.
Consent to participate
Formal informed consent was not obtained.
Consent for publication
All authors consent to the publication of this study.
Code availability
Not applicable.
The original online version of this article was revised due to a retrospective Open Access order.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
4/13/2021
A Correction to this paper has been published: 10.1007/s00198-021-05828-3 | DENOSUMAB | DrugsGivenReaction | CC BY-NC | 33236195 | 19,311,011 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Wrist fracture'. | Real-world bone turnover marker use: impact on treatment decisions and fracture.
The use of bone turnover marker (BTM) testing for patients with osteoporosis in the USA has not been well characterized. This retrospective US-based real-world data study found BTM testing has some association with treatment decision-making and lower fracture risk in patients with presumed osteoporosis, supporting its use in clinical practice.
BACKGROUND
The purpose of this study was to characterize bone turnover marker (BTM) testing patterns and estimate their clinical utility in treatment decision-making and fragility fracture risk in patients with osteoporosis using a retrospective claims database.
METHODS
Data from patients aged ≥ 50 years with newly diagnosed osteoporosis enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases from January 2008 to June 2018 were included. Osteoporosis was ascertained by explicit claims, fragility fracture events associated with osteoporosis, or prescribed anti-resorptive or anabolic therapy. BTM-tested patients were 1:1 propensity score matched to those untested following diagnosis. Generalized estimating equation models were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for testing versus no testing on both treatment decision-making and fragility fracture.
RESULTS
Of the 457,829 patients with osteoporosis, 6075 were identified with ≥ 1 BTM test following diagnosis; of these patients, 1345 had a unique treatment decision made ≤ 30 days from BTM testing. The percentage of patients receiving BTM tests increased significantly each year (average annual % change: + 8.1%; 95% CI: 5.6-9.0; p = 0.01). Patients tested were significantly more likely to have a treatment decision (OR: 1.14; 95% CI: 1.13-1.15), and testing was associated with lower odds of fracture versus those untested (OR: 0.87; 95% CI: 0.85-0.88).
CONCLUSIONS
In this large, heterogeneous population of patients with presumed osteoporosis, BTM testing was associated with treatment decision-making, likely leading to fragility fracture reduction following use.
Introduction
Osteoporosis, which is characterized by reduced bone mass and micro-architectural deterioration leading to increased bone fragility [1, 2], affects approximately 200 million people worldwide [3]. In 2020, the National Osteoporosis Foundation reported that approximately 54 million Americans, of all ages, are living with osteoporosis or low bone mass [4].
Bone turnover markers (BTMs) can be measured in serum, plasma, and urine [5], with bone formation and bone resorption marker levels relating to osteoblast and osteoclast activity, respectively. Bone formation markers include proteins such as osteocalcin or procollagen type I N propeptide (PINP), and the bone isoform of alkaline phosphatase (bone ALP). Bone resorption markers include fragments released from the telopeptide end region of type I collagen following its enzymatic degradation, such as the N-telopeptide of type I collagen (NTX), carboxy-terminal crosslinking telopeptide of type I collagen (CTX), deoxypyridinoline (DPD), and the enzyme tartrate-resistant acid phosphatase [6].
The International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine (IOF-IFCC) Bone Markers Working Group has identified CTX and PINP as promising markers for providing clinically useful information for monitoring osteoporosis treatment [7], and recommends that CTX and serum PINP, measured by standardized assays, be used as reference markers in observational and interventional studies [2]. American Association of Clinical Endocrinologists/American College of Endocrinology guideline recommendations for BTMs also advise use of CTX and PINP as monitoring tests for osteoporosis treatment [8], as do National Osteoporosis Foundation (NOF) guidelines [9]. An IOF and European Calcified Tissue Society taskforce has also suggested that PINP and CTX screening may be used to detect lack of adherence to oral bisphosphonates therapy [10].
In addition to monitoring osteoporosis treatment [11], and patients during treatment holiday [12, 13], a meta-analysis of published studies has shown that low levels of BTMs are modestly associated with reduced fracture risk [5]. A few studies have measured BTMs prior to hip fracture events [5, 14], and found conflicting reports with both positive [15] and negative [16] associations of BTM levels and the risk of osteoporosis-related hip fracture. In clinical practice, the use of BTM levels in predicting fracture outcomes is further complicated by significant within-patient variability of BTM levels due to patient age [17], comorbid conditions such as diabetes and chronic kidney disease [11], or ethnicity [18]. Sources of variability in BTM levels should be considered when interpreting test results. Particular attention should be paid to the appropriate use of reference intervals for determination of abnormal results, specifically related to the age and sex of the patient [19].
The majority of reports on the use of BTMs in clinical practice have tended to be single-site or small number multi-site studies [20] whose results may not be broadly applicable to the medically insured patients with osteoporosis in the USA. To help address this gap, we conducted an investigation using real-world data from a large patient population with osteoporosis in the USA. Our aims were threefold: (1) to assess trends in BTM test utilization; (2) to characterize the patterns of BTM testing and baseline characteristics of a heterogeneous population of patients in clinical practice; and (3) to estimate the potential clinical utility of BTM for treatment decision-making and association with fragility fracture.
Methods
Study design and data source
We undertook a population-based retrospective cohort analysis of patients enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases. These databases consist of the outpatient, inpatient, and pharmaceutical claims of approximately 50 million privately insured individuals and their dependents receiving care annually in the USA. Claims originated from more than 150 large employer-sponsored health insurance plans with patient coverage in all 50 states. The Medicare Supplemental and Co-ordination of Benefits databases represent commercially insured individuals, who have both Medicare coverage and supplemental employer-sponsored coverage, for Medicare-eligible active and retired employees and their Medicare-eligible dependents from employer-sponsored Medicare Supplemental plans. All data were anonymized to comply with the Health Insurance Portability and Accountability Act (HIPAA) and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required and formal informed consent was not obtained.
Study design and patient selection
Osteoporosis was defined at baseline in adult patients aged ≥ 50 years who were enrolled in a health plan with pharmaceutical coverage from January 1st 2008 to June 30th 2018. Osteoporosis was defined based on first recorded event according to (1) ≥ 1 inpatient or 2 outpatient claims (≥ 30 to ≤ 360 days apart) for osteoporosis, as defined under the International Classification of Diseases, Ninth (ICD-9-CM) or Tenth Revision (ICD-10-CM); (2) ≥ 1 claim for US Food and Drug Administration (FDA)-approved osteoporosis treatment (National Drug Code [NDC], Healthcare Common Procedure Coding System J- or C-codes); or (3) a fragility fracture considered to be associated with osteoporosis [6, 21, 22] (Online Resource Table 2). For hip fracture claims, ≥ 1 inpatient claim was required, and for other fracture types, ≥ 1 inpatient claim or ≥ 2 outpatient claims, ≥ 30 to ≤ 360 days apart (ICD-9-CM, ICD-10-CM codes, or Common Procedural Terminology [CPT] codes) were required. Patients were excluded if a claim of malignant neoplasm (excluding non-melanoma skin cancers), Paget’s disease of bone, or chronic kidney or end-stage renal disease was made at any time during the study period, to avoid misidentification of patients treated with medications as osteoporotic and inclusion of patients with malignancy-related fractures (Online Resource Table 3).
The index date was defined differently between BTM-tested and untested patients. In both cases, patients were required a minimum continuous enrollment ≥ 360 days prior to defined baseline (or washout period) and ≥ 360 days follow-up (Fig. 1) with allowable gap in coverage equivalent to ≤ 30 days. For those tested, the index date was defined as the date of the first BTM claim following osteoporosis diagnosis based on corresponding CPT codes for BTMs: osteocalcin (83937), bone-specific ALP (84080), and collagen cross-links (any method, 82523). PINP was not included in the present study as no unique CPT code (83519) is available to accurately classify receipt of this test. Untested patients were randomly assigned an index date based on a uniform distribution and the following criteria: to ensure adequate follow-up, the index date was required to fall before the final 360 days of data capture for the patient, and to ensure sufficient baseline washout period, the index date was required to fall after the first 360 days of data capture. Each patient was followed prospectively until an observed outcome, the end of continuous enrollment, reported death, or study end, whichever occurred first.Fig. 1 Study design schema of patients with osteoporosis aged ≥ 50 years enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Defining study outcomes
Study outcomes were compared between BTM-tested and untested groups in the follow-up period. Further details on how study outcomes were defined are provided in the Online Resource Methods section.
Outcome 1: Treatment decision-making
Osteoporosis treatments approved by the FDA during the study period were explored according to therapeutic mode of action: anti-resorptive (bisphosphonates, estrogen/progesterone, selective estrogen receptor modulators [SERMs], calcitonin, denosumab), or anabolic (teriparatide). Both injectable and oral routes were considered along with respective days of expected coverage or supply (i.e., 90/180/360 day intervals with allowable coverage gap of ≤ 30 days). Patients were classified according to the next observed treatment decision following a BTM test according to the days of coverage or supply: no treatment prescribed, treatment initiated, continue on the same treatment, restart following a treatment gap of > 30 days, between-class switch, or treatment discontinuation.
Outcome 2: Fragility fracture
Occurrence of a fragility fracture following index was assumed to be associated with osteoporosis and was classified according to methods reported by Song et al. [23]. Incident claims were captured by the presence of a qualified diagnosis of closed fractures of sites that may be associated with an increased risk of fracture, predominantly spine, hip, pelvis, and upper leg fractures [24]. Fractures were defined as those with ≥ 1 inpatient claims (primary or secondary discharge diagnosis) for hip fractures, and ≥ 1 inpatient (primary or secondary discharge diagnosis) or ≥ 2 outpatient claims (30–180 days apart) for all other sites. Fractures that were most likely the result of serious trauma were excluded, including compound or open fractures, multiple fractures within 7 days of a single claim, and vertebral fractures with concurrent spinal cord injury. Analyses were based on determination of the first claim for an osteoporotic fracture following index and any subsequent BTM event thereafter.
Statistical analysis
Descriptive statistics were used to characterize baseline socio-demographic and clinical characteristics of the osteoporotic patient cohort, summarizing continuous variables with means (standard deviation [SD]) or medians (interquartile range [IQR]) and categorical variables with counts and proportions (percentages). To explore trends in testing over calendar time [25], the annual period prevalence and associated 95% confidence intervals (CIs) were estimated among tested patients from 2008 forward. To evaluate longitudinal trends, the Cochran-Armitage test for trend and average annual percentage change (AAPC) were reported [26]. To account for variable enrollment in the MarketScan databases over time, the numerator was defined as the number of patients with one or more BTM tests and the denominator as total enrollment in a calendar year.
To examine the association between index testing on treatment decisions and fragility fracture, a multivariate logistic propensity score model conditioned on values at index (age, sex, year, region of care, insurance type, provider type [for treatment decision outcome model only]) and baseline (Charlson Comorbidity Index [CCI], score 1, 2, 3, or 6, where a higher score indicates a greater risk of 1-year mortality associated with more severe and/or greater co-morbidity burden) was fit [27]. The propensity score was used to match tested and untested patients using a fixed 1:1 ratio and nearest neighbor without replacement [25]. Propensity scores represent the conditional probability of assignment to the tested group and may be used to control for multiple observed covariates that are associated with the exposure and outcome [28]. That is, patients are assumed to have or not have been tested by chance and propensity score matching represents a non-parametric way to control for selection bias. Adequacy of matching in terms of patients’ baseline characteristics was evaluated using standardized differences; a value of < 0.1 was assumed to indicate a negligible difference in the characteristics between tested and untested patients [29]. A doubly robust method [30] was used where, in addition to the propensity score matching, generalized estimating equation (GEE) models were fit to estimate comparisons of odds and 95% CIs assessing the association between testing on treatment decision-making and fragility fracture. A binomial distribution and logistic link function were specified for both models fit with unstructured correlation structures, selected based on quasi-likelihood information criteria [31]. Additional covariates were not included in models as groups were well-balanced on baseline characteristics.
All statistical tests were two-sided and significance was determined using ɑ = 0.05. Analyses were conducted in SAS version 9.4 (SAS Institute, Inc., Cary, NC).
Results
Patient cohort
From 2008 to 2018, 457,829 individuals were classified as presumed osteoporotic (Fig. 2). Following application of inclusion criteria, 6075 patients (1.3%) were identified with one or more BTM test claims on or following diagnosis. Among all patients with osteoporosis, cohort entry declined over calendar time (Table 1), reflective of the annual decline in patients enrolled in Truven MarketScan, year-over-year. At the time of diagnosis, median age was 62 years (IQR: 57–74), with the majority of patients classified as female (79.6%), and 19.2% of patients having high CCI scores ≥ 2 (Table 1). Claims were most frequent from the South (33.7%) or North Central (29.9%) USA, while preferred provider organization (PPO) insurance coverage was common (49.7%). Compared with those untested, patients at osteoporosis diagnosis with BTM claims during follow-up were slightly younger; had lower CCI scores; were more likely to have PPO insurance coverage; and had higher proportions of diagnoses made at endocrinologists, rheumatologists, or primary care providers. Similarly, they were more likely to have an explicit osteoporosis diagnosis claim, not be covered via Medicare, have at least one bone mineral density (BMD) test during baseline, and have longer follow-up.Fig. 2 Cohort attrition of patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018, and 1:1 propensity score matched between those with tested and untested for bone turnover markers. BTM, bone turnover marker
Table 1 Characteristics at index or baseline of patients with presumed osteoporosis diagnosis and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018 (matched and all patients)
All patients with presumed osteoporosis (n = 457,829) Matched cohort
BTM tested (n = 6075) BTM untested, matched (n = 6075) Standard diffa (vs. tested)
Matched variables, n (%)
Cohort entry, calendar year
2008 61,642 (13.5) 1139 (18.8) 1134 (18.7) 0.9
2009 71,508 (15.6) 1064 (17.5) 1068 (17.6)
2010 62,365 (13.6) 859 (14.1) 858 (14.1)
2011 52,854 (11.5) 724 (11.9) 726 (12.0)
2012 49,357 (10.8) 575 (9.5) 576 (9.5)
2013 37,153 (8.1) 445 (7.3) 445 (7.3)
2014 38,941 (8.5) 444 (7.3) 447 (7.4)
2015 29,278 (6.4) 295 (4.9) 291 (4.8)
2016 24,639 (5.4) 235 (3.9) 234 (3.9)
2017 20,725 (4.5) 225 (3.7) 225 (3.7)
2018 9367 (2.1) 70 (1.2) 71 (1.2)
Median age, years (IQR) 62.0 (57.0–74.0) 59.0 (55.0–63.0) 59.0 (54.0–63.0) 1.3
Female sex 364,315 (79.6) 5511 (90.7) 5509 (90.7) 0.8
CCIb
0 263,726 (57.6) 3920 (64.5) 3918 (64.5) 0.2
1 106,551 (23.3) 1263 (20.8) 1261 (20.8)
≥ 2 87,552 (19.1) 892 (14.7) 896 (14.7)
Provider typec
Endocrinologist 3317 (0.7) 241 (4.0) 240 (4.0) 1.6
Rheumatologist 6118 (1.3) 212 (3.5) 212 (3.5)
Primary care provider 94,811 (20.7) 1465 (24.1) 1466 (24.1)
Acute, ambulatory, or urgent care 117,096 (25.6) 1362 (22.4) 1360 (22.4)
Other 131,331 (28.7) 1631 (26.9) 1632 (26.9)
Unknown 105,156 (23.0) 1164 (19.2) 1165 (19.2)
Other variables, n (%)
Claim at cohort entry
Osteoporosis therapy 159,032 (34.7) 4550 (74.9)
Anabolicd 7394 (1.6) 19 (0.3)
Anti-resorptivee 77,980 (17.0) 601 (9.9)
Fragility fracture 213,423 (46.6) 905 (14.9)
Database, n (%)
CCAE 276,970 (60.5) 4862 (80.0)
Medicare supplemental and CoB 180,859 (39.5) 1213 (20.0)
Bone mineral density claimb, n (%) 109,746 (24.0) 2952 (48.6)
Mortalityf, n (%) 734 (0.2) 13 (0.2)
Median follow-up time, years (IQR) 2.0 (1.1–3.6) 2.6 (1.1–3.6)
aStandard difference, p value < 0.01: values < 0.1 assumed to indicate negligible statistical difference between matched groups; bcharacteristics observed during the baseline period; cMatching on provider type only conducted for model 2 (impact of BTM on treatment decision-making). MarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care provider included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories; danabolic therapy (parathyroid hormone, dual-action bone agent, prostaglandin group E); eanti-resorptive therapy (bisphosphonate, estrogen, SERMs, calcitonin, denosumab); fin MarketScan databases, only inpatient mortality is captured. Therefore, mortality events outside of this setting are not captured in patient claims
BTM, bone turnover marker; CCI, Charlson Comorbidity Index; CCAE, Commercial Claims and Encounters; CoB, Co-ordination of Benefits; IQR, interquartile range
Following application of the propensity score model, 6075 BTM-tested patients were matched to 6075 untested patients (Table 1). Matched tested and untested patients were well-balanced on their baseline characteristics with none exhibiting a standard difference of > 0.1.
Real-world bone turnover marker test patterns
Among the 6075 tested patients, 8828 unique claims were made during the study period, with the majority being markers of resorption (76.6%; Table 2). In total, 14.4% (n = 875) of patients had concurrent claims for both resorption and formation markers. The annualized period prevalence of testing per 100 persons ranged from 0.23 (95% CI: 0.19–0.28) in 2008 to 0.47 (95% CI: 0.45–0.50) in 2018 (Fig. 3). During the study period, patients tested increased year-over-year (Cochran-Armitage test for trend, p = 0.03), with most of the increase occurring in the latter half of the study period (2015 onwards) and with an AAPC of 8.1% (95% CI: 5.6–9.0; p = 0.01). The AAPC prevalence for resorption markers was 4.2% (95% CI: 3.7–3.9; p = 0.04) and for formation markers, it was 6.9% (95% CI: 5.9–7.2; p = 0.02). No substantial difference in annual testing trends was observed when the analysis was repeated by age group deciles and sex (data not shown).Table 2 Characteristics of osteoporotic patients tested with bone turnover marker and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Patients tested (n = 6075) BTM tests (n = 8828)
Frequency (%) Frequency (%)
Year of BTM testa
2008 627 (10.3) 745 (8.4)
2009 868 (14.3) 994 (11.3)
2010 880 (14.5) 1015 (11.5)
2011 990 (16.3) 1122 (12.7)
2012 970 (16.0) 1092 (12.4)
2013 814 (13.4) 925 (10.5)
2014 698 (11.5) 803 (9.1)
2015 542 (8.9) 619 (7.0)
2016 539 (8.9) 615 (7.0)
2017 444 (7.3) 500 (5.7)
2018 341 (5.6) 398 (4.5)
Mode of action
Formation 2299 (37.8) 3100 (35.1)
Resorption 4622 (76.1) 6765 (76.6)
Place of BTM testb
Acute, ambulatory, or urgent care 8 (0.1) 11 (0.1)
Outpatient clinic/hospital 2094 (34.5) 2951 (33.4)
Inpatient clinic/hospital 16 (0.3) 24 (0.3)
Other 3958 (65.2) 5682 (64.4)
Unknown 122 (2.0) 160 (1.8)
Number of BTM tests per patient
Mean (SD) 2.2 (2.0)
Median (IQR) 1.0 (1.0–3.0)
1 test 4545 (74.8)
2 tests 937 (15.4)
≥ 3 tests 593 (9.8)
Median inter-test intervals, days (IQR)
Diagnosis to 1st test 160 (37–471)
1st to 2nd test 221 (125–384)
2nd to 3rd test 223 (134–377)
aCalendar year of first test claim (patient-level) or year of test claim (test-level); bMarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care providers included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories
BTM, bone turnover marker; IQR, interquartile range; SD, standard deviation
Fig. 3 Annual period prevalence (per 100 persons) of bone turnover marker testing and average testing per patient among patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
On average, patients had 2.2 test claims (SD 2.0) during the study period (Table 2), which remained stable irrespective of year of diagnosis (data not shown). Median claims suggest a non-normal distribution (1.0 IQR: 1.0–3.0) with only 593 patients (9.8%) reporting ≥ 3 BTM claims during follow-up. Follow-up BTM and dual-energy X-ray absorptiometry testing after osteoporosis diagnosis are recommended by clinical guidelines [8]; therefore, patterns of repeat testing were examined for those with > 1 test following index. Median time from osteoporosis diagnosis to first BTM claim was 160 days (IQR: 37–471), and for those with two or more claims the median inter-test interval was approximately 220 days between claimed tests. Approximately 30% of all tests were ordered by endocrinologists, rheumatologists, and primary care providers, with the majority of claims in the non-ambulatory or hospital or clinical setting.
Impact of bone turnover markers on treatment decision-making and fragility fracture
In total, 1345 patients (22%) had a unique treatment decision within 30 days of BTM testing. Treatment decisions were most common with anti-resorptives (89.1%) followed by anabolic (5.6%) and combination therapies (6.3%). This included treatment initiated (4.9%), continuation on the same treatment (8.4%), re-starting the same treatment following a gap of > 30 days (0.6%), and treatment discontinuation (8.2%). No observations for treatment switching were observed for tested patients. From the GEE propensity score model predicting treatment decision-making, tested patients were significantly more likely to have a treatment decision within 30 days compared to those untested (OR 1.14; 95% CI: 1.13–1.15). To further understand this observed effect, we conducted a post-hoc analysis of treatment decision-making by category of decision (new treatment, continuation, treatment restart, treatment switch, discontinuation). Assessment of BTMs was significantly associated with the decision to re-start treatment within 30 days of testing (OR 2.67; 95% CI: 2.51–2.93) and continue treatment (OR 1.03; 95% CI: 1.03–1.04), and treatment discontinuation (OR 1.03; 95% CI: 1.02–1.04). While no statistically significant association was observed for decision to initiate treatment (OR 1.01; 95% CI: 1.00–1.01) or switching treatment following testing (OR 1.02; 95% CI: 1.00–1.04), point observations suggest potential weak clinical significance.
The impact of testing on fracture events was also explored. A total of 1409 tested patients (23.2%) had a fragility fracture assumed to be due to osteoporosis following index, and this was linked to 3236 unique fracture events during the study period. The most common fracture type was wrist/forearm (562 events, 17.4%), followed by hip (440, 13.6%), vertebra (429, 13.2%), and femoral (381, 11.8%). In the model predicting fragility fracture following a BTM test, results suggest that testing was associated with lower odds of fracture compared to those patients untested (OR 0.87; 95% CI: 0.85–0.88).
Discussion
To our knowledge, this study represents the first known US nationwide epidemiological study of BTM testing among patients with presumed osteoporosis. We analyzed data from persons with a presumed osteoporosis diagnosis in the USA from 2008 to 2018 and observed that the annual proportion tested using BTMs rose from 0.23 tests per 100 patients in 2008 to 0.47 in 2018, with most of the increase occurring in the latter half of the study period. The observed rise in testing is encouraging, yet tested patients still remain below international guidelines for screening response to therapy. Among various BTMs, serum CTX-I and serum PINP are recently recommended as monitoring tests for osteoporosis treatment by several osteoporosis guidelines, including the NOF, the Japanese Osteoporosis Society, and the IOF [2, 9, 32].
BTMs may be employed as clinical tools for treatment decision-making at several important junctures of osteoporosis treatment. For example, baseline measurements of resorption and formation markers before commencement of anti-resorptive and anti-formation therapies, respectively, are of utility in monitoring treatment response and adherence. BTMs are also of potential clinical value in deciding whether patients should resume therapy following treatment holidays, and for monitoring patients during these periods [33]. Our results suggest that assessing BTM was significantly associated with the decision to re-start treatment for osteoporosis within 30 days of testing, to continue treatment, or to discontinue treatment. Published literature substantiates BTMs as having considerable utility in treatment decision-making in patients with osteoporosis [11]. In particular, measurement of BTMs can reflect response to therapies earlier than that of BMD, and can be used to monitor treatment compliance [6, 34]. PINP or CTX may be used to identify treatment responders and non-responders, and as a marker of poor patient adherence to common osteoporosis treatments [35, 36].
Our analysis showed that BTM testing was associated with lower odds of fracture compared to not testing patients with osteoporosis. This association could potentially be due to turnover data leading to change in pharmacotherapies reducing fracture risk. Supporting this, it has previously been reported that high levels of the BTMs NTX, DPD, and CTX are predictive of subsequent risk of hip fracture in women aged ≥ 75 years, independently of hip BMD [14]. High levels of NTX, DPD, CTX, and serum bone ALP have also been shown to be associated with increased risk of osteoporotic fracture in post-menopausal women, independently of BMD [37, 38]. BTM testing offers potential advantages versus traditional BMD testing, as the latter does not completely capture the risk of osteoporotic fracture, and the use of serial BMD measurements as a tool for treatment response requires an interval of more than a year. Bone turnover, by contrast, changes early and can be assessed within 3 months of starting treatment [34]. BTM measurements are also repeatable, relatively inexpensive, and non-invasive [39], potentially lowering the cost of care [40] and decreasing patient inconvenience as opposed to BMD testing. However, unlike BMD, BTM measurements are subject to a number of pre-analytical variations, including seasonal and diurnal variations [41].
As with all observational studies, and especially with studies using commercial insurance claims databases where changes in enrollment (including left censoring) and loss to follow-up (≥ 20%) [42] reduce the sample size of longitudinal studies, the results of the present study should be interpreted with caution. Firstly, the study provided an overall picture of BTM testing and it was not the intention of the claims data mining to determine which BTMs were being tested. It is, therefore, not possible to specify which BTMs are associated with an impact on treatment or predict fragility fracture risk. As previously mentioned, there is no unique CPT code (83519) available to accurately classify the receipt of PINP. Serum osteocalcin was included in this analysis and has been shown to correspond well with levels of PINP [33]. Secondly, outpatient claims may be recorded by a variety of staff with limited clinical training; therefore, misclassification is possible. In this study, the inclusion criterion for incident presumed osteoporosis diagnosis was based on > 1 claim, which may minimize the risk of misclassification bias. Finally, administrative claims do not provide insight into individual test results, which may be drivers of the observed association, or potential confounders not captured in the present database that may have biased the observations. The strengths of our study include the use of a large, longitudinal claims database from which we were able to analyze a heterogeneous, real-life population of patients in terms of decisions made about their treatment and incident fracture outcomes. MarketScan is a large, nationally representative database of individuals receiving employer-sponsored healthcare insurance, and the coding of inpatient claims in the USA is typically performed reliably by professional coders.
Conclusions
In this large, heterogeneous sample of US-based patients with presumed osteoporosis, we determined that BTM testing was associated with both treatment decision-making and a reduction of fragility fracture following use, conclusions which are consistent with published literature. While further investigation to validate the findings and understand the drivers is warranted, the evidence presented in this work provides further evidence of the value of monitoring osteoporotic patients with in vitro BTM monitoring diagnostic solutions.
Supplementary Information
ESM 1 (DOCX 25 kb)
The authors wish to acknowledge Dr. Andy Surinach of Genesis Research and Jaya Madala of Roche Diagnostics for their assistance in cohort development and code review.
Funding
This study was funded by Roche Diagnostics International Ltd. and Roche Diagnostics Information Solutions. Third-party writing assistance under the guidance of the authors was provided by James Everington and Ashlie Butler (Gardiner-Caldwell Communications, Macclesfield, UK) and funded by Roche Diagnostics International Ltd. (Rotkreuz, Switzerland).
Compliance with ethical standards
Conflicts of interest
N. Lane reports consultancy funding from Roche, and consultancy and speaker funding from Amgen. K. Saag reports grants from Amgen, Radius, and Mereo, and consultancy funding from Amgen, Daichi-Sankyo, and Roche. T. O’Neill is an employee of Roche Diagnostics Information Solutions and owner of stocks in Roche, Gilead, Pfizer, Regeneron, Abbott, and United Healthcare. M. Manion is an employee of Roche Diagnostics International Ltd. R. Shah is an employee of Roche Diagnostics International Ltd. and owner of stock in Roche. U. Klause is an employee of Roche Diabetes Care. R. Eastell reports consultancy funding from IDS, Sandoz, Nittobo, Roche Diagnostics, Samsung, Haoma Medica, CL Bio, Biocon, Lyramid, and Viking Therapeutics, and grant funding from Nittobo, Roche Diagnostics, and Alexion.
Ethics approval
All data were anonymized to comply with HIPAA and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required.
Consent to participate
Formal informed consent was not obtained.
Consent for publication
All authors consent to the publication of this study.
Code availability
Not applicable.
The original online version of this article was revised due to a retrospective Open Access order.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
4/13/2021
A Correction to this paper has been published: 10.1007/s00198-021-05828-3 | DENOSUMAB | DrugsGivenReaction | CC BY-NC | 33236195 | 19,311,011 | 2021-05 |
What was the outcome of reaction 'Death'? | Real-world bone turnover marker use: impact on treatment decisions and fracture.
The use of bone turnover marker (BTM) testing for patients with osteoporosis in the USA has not been well characterized. This retrospective US-based real-world data study found BTM testing has some association with treatment decision-making and lower fracture risk in patients with presumed osteoporosis, supporting its use in clinical practice.
BACKGROUND
The purpose of this study was to characterize bone turnover marker (BTM) testing patterns and estimate their clinical utility in treatment decision-making and fragility fracture risk in patients with osteoporosis using a retrospective claims database.
METHODS
Data from patients aged ≥ 50 years with newly diagnosed osteoporosis enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases from January 2008 to June 2018 were included. Osteoporosis was ascertained by explicit claims, fragility fracture events associated with osteoporosis, or prescribed anti-resorptive or anabolic therapy. BTM-tested patients were 1:1 propensity score matched to those untested following diagnosis. Generalized estimating equation models were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for testing versus no testing on both treatment decision-making and fragility fracture.
RESULTS
Of the 457,829 patients with osteoporosis, 6075 were identified with ≥ 1 BTM test following diagnosis; of these patients, 1345 had a unique treatment decision made ≤ 30 days from BTM testing. The percentage of patients receiving BTM tests increased significantly each year (average annual % change: + 8.1%; 95% CI: 5.6-9.0; p = 0.01). Patients tested were significantly more likely to have a treatment decision (OR: 1.14; 95% CI: 1.13-1.15), and testing was associated with lower odds of fracture versus those untested (OR: 0.87; 95% CI: 0.85-0.88).
CONCLUSIONS
In this large, heterogeneous population of patients with presumed osteoporosis, BTM testing was associated with treatment decision-making, likely leading to fragility fracture reduction following use.
Introduction
Osteoporosis, which is characterized by reduced bone mass and micro-architectural deterioration leading to increased bone fragility [1, 2], affects approximately 200 million people worldwide [3]. In 2020, the National Osteoporosis Foundation reported that approximately 54 million Americans, of all ages, are living with osteoporosis or low bone mass [4].
Bone turnover markers (BTMs) can be measured in serum, plasma, and urine [5], with bone formation and bone resorption marker levels relating to osteoblast and osteoclast activity, respectively. Bone formation markers include proteins such as osteocalcin or procollagen type I N propeptide (PINP), and the bone isoform of alkaline phosphatase (bone ALP). Bone resorption markers include fragments released from the telopeptide end region of type I collagen following its enzymatic degradation, such as the N-telopeptide of type I collagen (NTX), carboxy-terminal crosslinking telopeptide of type I collagen (CTX), deoxypyridinoline (DPD), and the enzyme tartrate-resistant acid phosphatase [6].
The International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine (IOF-IFCC) Bone Markers Working Group has identified CTX and PINP as promising markers for providing clinically useful information for monitoring osteoporosis treatment [7], and recommends that CTX and serum PINP, measured by standardized assays, be used as reference markers in observational and interventional studies [2]. American Association of Clinical Endocrinologists/American College of Endocrinology guideline recommendations for BTMs also advise use of CTX and PINP as monitoring tests for osteoporosis treatment [8], as do National Osteoporosis Foundation (NOF) guidelines [9]. An IOF and European Calcified Tissue Society taskforce has also suggested that PINP and CTX screening may be used to detect lack of adherence to oral bisphosphonates therapy [10].
In addition to monitoring osteoporosis treatment [11], and patients during treatment holiday [12, 13], a meta-analysis of published studies has shown that low levels of BTMs are modestly associated with reduced fracture risk [5]. A few studies have measured BTMs prior to hip fracture events [5, 14], and found conflicting reports with both positive [15] and negative [16] associations of BTM levels and the risk of osteoporosis-related hip fracture. In clinical practice, the use of BTM levels in predicting fracture outcomes is further complicated by significant within-patient variability of BTM levels due to patient age [17], comorbid conditions such as diabetes and chronic kidney disease [11], or ethnicity [18]. Sources of variability in BTM levels should be considered when interpreting test results. Particular attention should be paid to the appropriate use of reference intervals for determination of abnormal results, specifically related to the age and sex of the patient [19].
The majority of reports on the use of BTMs in clinical practice have tended to be single-site or small number multi-site studies [20] whose results may not be broadly applicable to the medically insured patients with osteoporosis in the USA. To help address this gap, we conducted an investigation using real-world data from a large patient population with osteoporosis in the USA. Our aims were threefold: (1) to assess trends in BTM test utilization; (2) to characterize the patterns of BTM testing and baseline characteristics of a heterogeneous population of patients in clinical practice; and (3) to estimate the potential clinical utility of BTM for treatment decision-making and association with fragility fracture.
Methods
Study design and data source
We undertook a population-based retrospective cohort analysis of patients enrolled in the Truven MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases. These databases consist of the outpatient, inpatient, and pharmaceutical claims of approximately 50 million privately insured individuals and their dependents receiving care annually in the USA. Claims originated from more than 150 large employer-sponsored health insurance plans with patient coverage in all 50 states. The Medicare Supplemental and Co-ordination of Benefits databases represent commercially insured individuals, who have both Medicare coverage and supplemental employer-sponsored coverage, for Medicare-eligible active and retired employees and their Medicare-eligible dependents from employer-sponsored Medicare Supplemental plans. All data were anonymized to comply with the Health Insurance Portability and Accountability Act (HIPAA) and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required and formal informed consent was not obtained.
Study design and patient selection
Osteoporosis was defined at baseline in adult patients aged ≥ 50 years who were enrolled in a health plan with pharmaceutical coverage from January 1st 2008 to June 30th 2018. Osteoporosis was defined based on first recorded event according to (1) ≥ 1 inpatient or 2 outpatient claims (≥ 30 to ≤ 360 days apart) for osteoporosis, as defined under the International Classification of Diseases, Ninth (ICD-9-CM) or Tenth Revision (ICD-10-CM); (2) ≥ 1 claim for US Food and Drug Administration (FDA)-approved osteoporosis treatment (National Drug Code [NDC], Healthcare Common Procedure Coding System J- or C-codes); or (3) a fragility fracture considered to be associated with osteoporosis [6, 21, 22] (Online Resource Table 2). For hip fracture claims, ≥ 1 inpatient claim was required, and for other fracture types, ≥ 1 inpatient claim or ≥ 2 outpatient claims, ≥ 30 to ≤ 360 days apart (ICD-9-CM, ICD-10-CM codes, or Common Procedural Terminology [CPT] codes) were required. Patients were excluded if a claim of malignant neoplasm (excluding non-melanoma skin cancers), Paget’s disease of bone, or chronic kidney or end-stage renal disease was made at any time during the study period, to avoid misidentification of patients treated with medications as osteoporotic and inclusion of patients with malignancy-related fractures (Online Resource Table 3).
The index date was defined differently between BTM-tested and untested patients. In both cases, patients were required a minimum continuous enrollment ≥ 360 days prior to defined baseline (or washout period) and ≥ 360 days follow-up (Fig. 1) with allowable gap in coverage equivalent to ≤ 30 days. For those tested, the index date was defined as the date of the first BTM claim following osteoporosis diagnosis based on corresponding CPT codes for BTMs: osteocalcin (83937), bone-specific ALP (84080), and collagen cross-links (any method, 82523). PINP was not included in the present study as no unique CPT code (83519) is available to accurately classify receipt of this test. Untested patients were randomly assigned an index date based on a uniform distribution and the following criteria: to ensure adequate follow-up, the index date was required to fall before the final 360 days of data capture for the patient, and to ensure sufficient baseline washout period, the index date was required to fall after the first 360 days of data capture. Each patient was followed prospectively until an observed outcome, the end of continuous enrollment, reported death, or study end, whichever occurred first.Fig. 1 Study design schema of patients with osteoporosis aged ≥ 50 years enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Defining study outcomes
Study outcomes were compared between BTM-tested and untested groups in the follow-up period. Further details on how study outcomes were defined are provided in the Online Resource Methods section.
Outcome 1: Treatment decision-making
Osteoporosis treatments approved by the FDA during the study period were explored according to therapeutic mode of action: anti-resorptive (bisphosphonates, estrogen/progesterone, selective estrogen receptor modulators [SERMs], calcitonin, denosumab), or anabolic (teriparatide). Both injectable and oral routes were considered along with respective days of expected coverage or supply (i.e., 90/180/360 day intervals with allowable coverage gap of ≤ 30 days). Patients were classified according to the next observed treatment decision following a BTM test according to the days of coverage or supply: no treatment prescribed, treatment initiated, continue on the same treatment, restart following a treatment gap of > 30 days, between-class switch, or treatment discontinuation.
Outcome 2: Fragility fracture
Occurrence of a fragility fracture following index was assumed to be associated with osteoporosis and was classified according to methods reported by Song et al. [23]. Incident claims were captured by the presence of a qualified diagnosis of closed fractures of sites that may be associated with an increased risk of fracture, predominantly spine, hip, pelvis, and upper leg fractures [24]. Fractures were defined as those with ≥ 1 inpatient claims (primary or secondary discharge diagnosis) for hip fractures, and ≥ 1 inpatient (primary or secondary discharge diagnosis) or ≥ 2 outpatient claims (30–180 days apart) for all other sites. Fractures that were most likely the result of serious trauma were excluded, including compound or open fractures, multiple fractures within 7 days of a single claim, and vertebral fractures with concurrent spinal cord injury. Analyses were based on determination of the first claim for an osteoporotic fracture following index and any subsequent BTM event thereafter.
Statistical analysis
Descriptive statistics were used to characterize baseline socio-demographic and clinical characteristics of the osteoporotic patient cohort, summarizing continuous variables with means (standard deviation [SD]) or medians (interquartile range [IQR]) and categorical variables with counts and proportions (percentages). To explore trends in testing over calendar time [25], the annual period prevalence and associated 95% confidence intervals (CIs) were estimated among tested patients from 2008 forward. To evaluate longitudinal trends, the Cochran-Armitage test for trend and average annual percentage change (AAPC) were reported [26]. To account for variable enrollment in the MarketScan databases over time, the numerator was defined as the number of patients with one or more BTM tests and the denominator as total enrollment in a calendar year.
To examine the association between index testing on treatment decisions and fragility fracture, a multivariate logistic propensity score model conditioned on values at index (age, sex, year, region of care, insurance type, provider type [for treatment decision outcome model only]) and baseline (Charlson Comorbidity Index [CCI], score 1, 2, 3, or 6, where a higher score indicates a greater risk of 1-year mortality associated with more severe and/or greater co-morbidity burden) was fit [27]. The propensity score was used to match tested and untested patients using a fixed 1:1 ratio and nearest neighbor without replacement [25]. Propensity scores represent the conditional probability of assignment to the tested group and may be used to control for multiple observed covariates that are associated with the exposure and outcome [28]. That is, patients are assumed to have or not have been tested by chance and propensity score matching represents a non-parametric way to control for selection bias. Adequacy of matching in terms of patients’ baseline characteristics was evaluated using standardized differences; a value of < 0.1 was assumed to indicate a negligible difference in the characteristics between tested and untested patients [29]. A doubly robust method [30] was used where, in addition to the propensity score matching, generalized estimating equation (GEE) models were fit to estimate comparisons of odds and 95% CIs assessing the association between testing on treatment decision-making and fragility fracture. A binomial distribution and logistic link function were specified for both models fit with unstructured correlation structures, selected based on quasi-likelihood information criteria [31]. Additional covariates were not included in models as groups were well-balanced on baseline characteristics.
All statistical tests were two-sided and significance was determined using ɑ = 0.05. Analyses were conducted in SAS version 9.4 (SAS Institute, Inc., Cary, NC).
Results
Patient cohort
From 2008 to 2018, 457,829 individuals were classified as presumed osteoporotic (Fig. 2). Following application of inclusion criteria, 6075 patients (1.3%) were identified with one or more BTM test claims on or following diagnosis. Among all patients with osteoporosis, cohort entry declined over calendar time (Table 1), reflective of the annual decline in patients enrolled in Truven MarketScan, year-over-year. At the time of diagnosis, median age was 62 years (IQR: 57–74), with the majority of patients classified as female (79.6%), and 19.2% of patients having high CCI scores ≥ 2 (Table 1). Claims were most frequent from the South (33.7%) or North Central (29.9%) USA, while preferred provider organization (PPO) insurance coverage was common (49.7%). Compared with those untested, patients at osteoporosis diagnosis with BTM claims during follow-up were slightly younger; had lower CCI scores; were more likely to have PPO insurance coverage; and had higher proportions of diagnoses made at endocrinologists, rheumatologists, or primary care providers. Similarly, they were more likely to have an explicit osteoporosis diagnosis claim, not be covered via Medicare, have at least one bone mineral density (BMD) test during baseline, and have longer follow-up.Fig. 2 Cohort attrition of patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018, and 1:1 propensity score matched between those with tested and untested for bone turnover markers. BTM, bone turnover marker
Table 1 Characteristics at index or baseline of patients with presumed osteoporosis diagnosis and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018 (matched and all patients)
All patients with presumed osteoporosis (n = 457,829) Matched cohort
BTM tested (n = 6075) BTM untested, matched (n = 6075) Standard diffa (vs. tested)
Matched variables, n (%)
Cohort entry, calendar year
2008 61,642 (13.5) 1139 (18.8) 1134 (18.7) 0.9
2009 71,508 (15.6) 1064 (17.5) 1068 (17.6)
2010 62,365 (13.6) 859 (14.1) 858 (14.1)
2011 52,854 (11.5) 724 (11.9) 726 (12.0)
2012 49,357 (10.8) 575 (9.5) 576 (9.5)
2013 37,153 (8.1) 445 (7.3) 445 (7.3)
2014 38,941 (8.5) 444 (7.3) 447 (7.4)
2015 29,278 (6.4) 295 (4.9) 291 (4.8)
2016 24,639 (5.4) 235 (3.9) 234 (3.9)
2017 20,725 (4.5) 225 (3.7) 225 (3.7)
2018 9367 (2.1) 70 (1.2) 71 (1.2)
Median age, years (IQR) 62.0 (57.0–74.0) 59.0 (55.0–63.0) 59.0 (54.0–63.0) 1.3
Female sex 364,315 (79.6) 5511 (90.7) 5509 (90.7) 0.8
CCIb
0 263,726 (57.6) 3920 (64.5) 3918 (64.5) 0.2
1 106,551 (23.3) 1263 (20.8) 1261 (20.8)
≥ 2 87,552 (19.1) 892 (14.7) 896 (14.7)
Provider typec
Endocrinologist 3317 (0.7) 241 (4.0) 240 (4.0) 1.6
Rheumatologist 6118 (1.3) 212 (3.5) 212 (3.5)
Primary care provider 94,811 (20.7) 1465 (24.1) 1466 (24.1)
Acute, ambulatory, or urgent care 117,096 (25.6) 1362 (22.4) 1360 (22.4)
Other 131,331 (28.7) 1631 (26.9) 1632 (26.9)
Unknown 105,156 (23.0) 1164 (19.2) 1165 (19.2)
Other variables, n (%)
Claim at cohort entry
Osteoporosis therapy 159,032 (34.7) 4550 (74.9)
Anabolicd 7394 (1.6) 19 (0.3)
Anti-resorptivee 77,980 (17.0) 601 (9.9)
Fragility fracture 213,423 (46.6) 905 (14.9)
Database, n (%)
CCAE 276,970 (60.5) 4862 (80.0)
Medicare supplemental and CoB 180,859 (39.5) 1213 (20.0)
Bone mineral density claimb, n (%) 109,746 (24.0) 2952 (48.6)
Mortalityf, n (%) 734 (0.2) 13 (0.2)
Median follow-up time, years (IQR) 2.0 (1.1–3.6) 2.6 (1.1–3.6)
aStandard difference, p value < 0.01: values < 0.1 assumed to indicate negligible statistical difference between matched groups; bcharacteristics observed during the baseline period; cMatching on provider type only conducted for model 2 (impact of BTM on treatment decision-making). MarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care provider included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories; danabolic therapy (parathyroid hormone, dual-action bone agent, prostaglandin group E); eanti-resorptive therapy (bisphosphonate, estrogen, SERMs, calcitonin, denosumab); fin MarketScan databases, only inpatient mortality is captured. Therefore, mortality events outside of this setting are not captured in patient claims
BTM, bone turnover marker; CCI, Charlson Comorbidity Index; CCAE, Commercial Claims and Encounters; CoB, Co-ordination of Benefits; IQR, interquartile range
Following application of the propensity score model, 6075 BTM-tested patients were matched to 6075 untested patients (Table 1). Matched tested and untested patients were well-balanced on their baseline characteristics with none exhibiting a standard difference of > 0.1.
Real-world bone turnover marker test patterns
Among the 6075 tested patients, 8828 unique claims were made during the study period, with the majority being markers of resorption (76.6%; Table 2). In total, 14.4% (n = 875) of patients had concurrent claims for both resorption and formation markers. The annualized period prevalence of testing per 100 persons ranged from 0.23 (95% CI: 0.19–0.28) in 2008 to 0.47 (95% CI: 0.45–0.50) in 2018 (Fig. 3). During the study period, patients tested increased year-over-year (Cochran-Armitage test for trend, p = 0.03), with most of the increase occurring in the latter half of the study period (2015 onwards) and with an AAPC of 8.1% (95% CI: 5.6–9.0; p = 0.01). The AAPC prevalence for resorption markers was 4.2% (95% CI: 3.7–3.9; p = 0.04) and for formation markers, it was 6.9% (95% CI: 5.9–7.2; p = 0.02). No substantial difference in annual testing trends was observed when the analysis was repeated by age group deciles and sex (data not shown).Table 2 Characteristics of osteoporotic patients tested with bone turnover marker and enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
Patients tested (n = 6075) BTM tests (n = 8828)
Frequency (%) Frequency (%)
Year of BTM testa
2008 627 (10.3) 745 (8.4)
2009 868 (14.3) 994 (11.3)
2010 880 (14.5) 1015 (11.5)
2011 990 (16.3) 1122 (12.7)
2012 970 (16.0) 1092 (12.4)
2013 814 (13.4) 925 (10.5)
2014 698 (11.5) 803 (9.1)
2015 542 (8.9) 619 (7.0)
2016 539 (8.9) 615 (7.0)
2017 444 (7.3) 500 (5.7)
2018 341 (5.6) 398 (4.5)
Mode of action
Formation 2299 (37.8) 3100 (35.1)
Resorption 4622 (76.1) 6765 (76.6)
Place of BTM testb
Acute, ambulatory, or urgent care 8 (0.1) 11 (0.1)
Outpatient clinic/hospital 2094 (34.5) 2951 (33.4)
Inpatient clinic/hospital 16 (0.3) 24 (0.3)
Other 3958 (65.2) 5682 (64.4)
Unknown 122 (2.0) 160 (1.8)
Number of BTM tests per patient
Mean (SD) 2.2 (2.0)
Median (IQR) 1.0 (1.0–3.0)
1 test 4545 (74.8)
2 tests 937 (15.4)
≥ 3 tests 593 (9.8)
Median inter-test intervals, days (IQR)
Diagnosis to 1st test 160 (37–471)
1st to 2nd test 221 (125–384)
2nd to 3rd test 223 (134–377)
aCalendar year of first test claim (patient-level) or year of test claim (test-level); bMarketScan classifies providers in a single category, although in reality these categories overlap (e.g., rheumatologist and family physician). Primary care providers included medical doctor, osteopathic medicine, internal medicine, multidisciplinary physician group, hospitalist, family practice, geriatric medicine, preventative medicine, and nurse practitioners. The other category includes provider types who billed for markers for the tested patients but did not fit into the other provider type categories
BTM, bone turnover marker; IQR, interquartile range; SD, standard deviation
Fig. 3 Annual period prevalence (per 100 persons) of bone turnover marker testing and average testing per patient among patients with osteoporosis enrolled in Truven MarketScan Commercial Claims and Encounters and Medicare Supplemental and Co-ordination of Benefits databases, 2008–2018
On average, patients had 2.2 test claims (SD 2.0) during the study period (Table 2), which remained stable irrespective of year of diagnosis (data not shown). Median claims suggest a non-normal distribution (1.0 IQR: 1.0–3.0) with only 593 patients (9.8%) reporting ≥ 3 BTM claims during follow-up. Follow-up BTM and dual-energy X-ray absorptiometry testing after osteoporosis diagnosis are recommended by clinical guidelines [8]; therefore, patterns of repeat testing were examined for those with > 1 test following index. Median time from osteoporosis diagnosis to first BTM claim was 160 days (IQR: 37–471), and for those with two or more claims the median inter-test interval was approximately 220 days between claimed tests. Approximately 30% of all tests were ordered by endocrinologists, rheumatologists, and primary care providers, with the majority of claims in the non-ambulatory or hospital or clinical setting.
Impact of bone turnover markers on treatment decision-making and fragility fracture
In total, 1345 patients (22%) had a unique treatment decision within 30 days of BTM testing. Treatment decisions were most common with anti-resorptives (89.1%) followed by anabolic (5.6%) and combination therapies (6.3%). This included treatment initiated (4.9%), continuation on the same treatment (8.4%), re-starting the same treatment following a gap of > 30 days (0.6%), and treatment discontinuation (8.2%). No observations for treatment switching were observed for tested patients. From the GEE propensity score model predicting treatment decision-making, tested patients were significantly more likely to have a treatment decision within 30 days compared to those untested (OR 1.14; 95% CI: 1.13–1.15). To further understand this observed effect, we conducted a post-hoc analysis of treatment decision-making by category of decision (new treatment, continuation, treatment restart, treatment switch, discontinuation). Assessment of BTMs was significantly associated with the decision to re-start treatment within 30 days of testing (OR 2.67; 95% CI: 2.51–2.93) and continue treatment (OR 1.03; 95% CI: 1.03–1.04), and treatment discontinuation (OR 1.03; 95% CI: 1.02–1.04). While no statistically significant association was observed for decision to initiate treatment (OR 1.01; 95% CI: 1.00–1.01) or switching treatment following testing (OR 1.02; 95% CI: 1.00–1.04), point observations suggest potential weak clinical significance.
The impact of testing on fracture events was also explored. A total of 1409 tested patients (23.2%) had a fragility fracture assumed to be due to osteoporosis following index, and this was linked to 3236 unique fracture events during the study period. The most common fracture type was wrist/forearm (562 events, 17.4%), followed by hip (440, 13.6%), vertebra (429, 13.2%), and femoral (381, 11.8%). In the model predicting fragility fracture following a BTM test, results suggest that testing was associated with lower odds of fracture compared to those patients untested (OR 0.87; 95% CI: 0.85–0.88).
Discussion
To our knowledge, this study represents the first known US nationwide epidemiological study of BTM testing among patients with presumed osteoporosis. We analyzed data from persons with a presumed osteoporosis diagnosis in the USA from 2008 to 2018 and observed that the annual proportion tested using BTMs rose from 0.23 tests per 100 patients in 2008 to 0.47 in 2018, with most of the increase occurring in the latter half of the study period. The observed rise in testing is encouraging, yet tested patients still remain below international guidelines for screening response to therapy. Among various BTMs, serum CTX-I and serum PINP are recently recommended as monitoring tests for osteoporosis treatment by several osteoporosis guidelines, including the NOF, the Japanese Osteoporosis Society, and the IOF [2, 9, 32].
BTMs may be employed as clinical tools for treatment decision-making at several important junctures of osteoporosis treatment. For example, baseline measurements of resorption and formation markers before commencement of anti-resorptive and anti-formation therapies, respectively, are of utility in monitoring treatment response and adherence. BTMs are also of potential clinical value in deciding whether patients should resume therapy following treatment holidays, and for monitoring patients during these periods [33]. Our results suggest that assessing BTM was significantly associated with the decision to re-start treatment for osteoporosis within 30 days of testing, to continue treatment, or to discontinue treatment. Published literature substantiates BTMs as having considerable utility in treatment decision-making in patients with osteoporosis [11]. In particular, measurement of BTMs can reflect response to therapies earlier than that of BMD, and can be used to monitor treatment compliance [6, 34]. PINP or CTX may be used to identify treatment responders and non-responders, and as a marker of poor patient adherence to common osteoporosis treatments [35, 36].
Our analysis showed that BTM testing was associated with lower odds of fracture compared to not testing patients with osteoporosis. This association could potentially be due to turnover data leading to change in pharmacotherapies reducing fracture risk. Supporting this, it has previously been reported that high levels of the BTMs NTX, DPD, and CTX are predictive of subsequent risk of hip fracture in women aged ≥ 75 years, independently of hip BMD [14]. High levels of NTX, DPD, CTX, and serum bone ALP have also been shown to be associated with increased risk of osteoporotic fracture in post-menopausal women, independently of BMD [37, 38]. BTM testing offers potential advantages versus traditional BMD testing, as the latter does not completely capture the risk of osteoporotic fracture, and the use of serial BMD measurements as a tool for treatment response requires an interval of more than a year. Bone turnover, by contrast, changes early and can be assessed within 3 months of starting treatment [34]. BTM measurements are also repeatable, relatively inexpensive, and non-invasive [39], potentially lowering the cost of care [40] and decreasing patient inconvenience as opposed to BMD testing. However, unlike BMD, BTM measurements are subject to a number of pre-analytical variations, including seasonal and diurnal variations [41].
As with all observational studies, and especially with studies using commercial insurance claims databases where changes in enrollment (including left censoring) and loss to follow-up (≥ 20%) [42] reduce the sample size of longitudinal studies, the results of the present study should be interpreted with caution. Firstly, the study provided an overall picture of BTM testing and it was not the intention of the claims data mining to determine which BTMs were being tested. It is, therefore, not possible to specify which BTMs are associated with an impact on treatment or predict fragility fracture risk. As previously mentioned, there is no unique CPT code (83519) available to accurately classify the receipt of PINP. Serum osteocalcin was included in this analysis and has been shown to correspond well with levels of PINP [33]. Secondly, outpatient claims may be recorded by a variety of staff with limited clinical training; therefore, misclassification is possible. In this study, the inclusion criterion for incident presumed osteoporosis diagnosis was based on > 1 claim, which may minimize the risk of misclassification bias. Finally, administrative claims do not provide insight into individual test results, which may be drivers of the observed association, or potential confounders not captured in the present database that may have biased the observations. The strengths of our study include the use of a large, longitudinal claims database from which we were able to analyze a heterogeneous, real-life population of patients in terms of decisions made about their treatment and incident fracture outcomes. MarketScan is a large, nationally representative database of individuals receiving employer-sponsored healthcare insurance, and the coding of inpatient claims in the USA is typically performed reliably by professional coders.
Conclusions
In this large, heterogeneous sample of US-based patients with presumed osteoporosis, we determined that BTM testing was associated with both treatment decision-making and a reduction of fragility fracture following use, conclusions which are consistent with published literature. While further investigation to validate the findings and understand the drivers is warranted, the evidence presented in this work provides further evidence of the value of monitoring osteoporotic patients with in vitro BTM monitoring diagnostic solutions.
Supplementary Information
ESM 1 (DOCX 25 kb)
The authors wish to acknowledge Dr. Andy Surinach of Genesis Research and Jaya Madala of Roche Diagnostics for their assistance in cohort development and code review.
Funding
This study was funded by Roche Diagnostics International Ltd. and Roche Diagnostics Information Solutions. Third-party writing assistance under the guidance of the authors was provided by James Everington and Ashlie Butler (Gardiner-Caldwell Communications, Macclesfield, UK) and funded by Roche Diagnostics International Ltd. (Rotkreuz, Switzerland).
Compliance with ethical standards
Conflicts of interest
N. Lane reports consultancy funding from Roche, and consultancy and speaker funding from Amgen. K. Saag reports grants from Amgen, Radius, and Mereo, and consultancy funding from Amgen, Daichi-Sankyo, and Roche. T. O’Neill is an employee of Roche Diagnostics Information Solutions and owner of stocks in Roche, Gilead, Pfizer, Regeneron, Abbott, and United Healthcare. M. Manion is an employee of Roche Diagnostics International Ltd. R. Shah is an employee of Roche Diagnostics International Ltd. and owner of stock in Roche. U. Klause is an employee of Roche Diabetes Care. R. Eastell reports consultancy funding from IDS, Sandoz, Nittobo, Roche Diagnostics, Samsung, Haoma Medica, CL Bio, Biocon, Lyramid, and Viking Therapeutics, and grant funding from Nittobo, Roche Diagnostics, and Alexion.
Ethics approval
All data were anonymized to comply with HIPAA and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Thus, Institutional Review Board approval was not required.
Consent to participate
Formal informed consent was not obtained.
Consent for publication
All authors consent to the publication of this study.
Code availability
Not applicable.
The original online version of this article was revised due to a retrospective Open Access order.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
4/13/2021
A Correction to this paper has been published: 10.1007/s00198-021-05828-3 | Fatal | ReactionOutcome | CC BY-NC | 33236195 | 19,311,011 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | CISPLATIN, DEXAMETHASONE, GEMCITABINE, GRANULOCYTE COLONY-STIMULATING FACTOR NOS, RITUXIMAB | DrugsGivenReaction | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'. | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | CISPLATIN, DEXAMETHASONE, GEMCITABINE, GRANULOCYTE COLONY-STIMULATING FACTOR NOS, RITUXIMAB | DrugsGivenReaction | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'. | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | CISPLATIN, DEXAMETHASONE, GEMCITABINE, GRANULOCYTE COLONY-STIMULATING FACTOR NOS, RITUXIMAB | DrugsGivenReaction | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mucosal inflammation'. | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | CISPLATIN, DEXAMETHASONE, GEMCITABINE, GRANULOCYTE COLONY-STIMULATING FACTOR NOS, RITUXIMAB | DrugsGivenReaction | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephropathy toxic'. | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | CISPLATIN, DEXAMETHASONE, GEMCITABINE, GRANULOCYTE COLONY-STIMULATING FACTOR NOS, RITUXIMAB | DrugsGivenReaction | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | CISPLATIN, DEXAMETHASONE, GEMCITABINE, GRANULOCYTE COLONY-STIMULATING FACTOR NOS, RITUXIMAB | DrugsGivenReaction | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | CISPLATIN, DEXAMETHASONE, GEMCITABINE, GRANULOCYTE COLONY-STIMULATING FACTOR NOS, RITUXIMAB | DrugsGivenReaction | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ototoxicity'. | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | CISPLATIN, DEXAMETHASONE, GEMCITABINE, GRANULOCYTE COLONY-STIMULATING FACTOR NOS, RITUXIMAB | DrugsGivenReaction | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Platelet count decreased'. | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | CISPLATIN, DEXAMETHASONE, GEMCITABINE, GRANULOCYTE COLONY-STIMULATING FACTOR NOS, RITUXIMAB | DrugsGivenReaction | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
What was the dosage of drug 'CISPLATIN'? | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | 75 MG/M2 ON DAY 1 | DrugDosageText | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
What was the dosage of drug 'DEXAMETHASONE'? | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | 40 MG ON DAY 1, 2, 3, 4 | DrugDosageText | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
What was the dosage of drug 'GEMCITABINE'? | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | 1000 MG/M2 ON DAYS 1 AND 8 | DrugDosageText | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
What was the dosage of drug 'GRANULOCYTE COLONY-STIMULATING FACTOR NOS'? | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | 2 X 5 UG/KG/DAY | DrugDosageText | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
What was the dosage of drug 'RITUXIMAB'? | Gemcitabine, dexamethasone and cisplatin (GDP) is an effective and well-tolerated mobilization regimen for relapsed and refractory lymphoma: a single center experience
Gemcitabine, dexamethasone and cisplatin (GDP) is a well-established salvage regimen for relapsed and refractory lymphomas. In this study, we aimed to share our experience with the patients who received GDP/R-GDP (rituximab-gemcitabine, dexamethasone and cisplatin) for stem cell mobilization.
Data of 69 relapsed and refractory Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL) patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. After the evaluation of response, 52 patients had a chemosensitive disease and underwent mobilization with GDP/R-GDP plus G–CSF (granulocyte colony-stimulating factor). Collected CD34+ stem cells and related parameters were compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients aged under 60 and over 60.
On the 15th day on average (range 11–20), a median number of 8.7 × 106 /kg (4.1–41.5) CD34+ stem cells were collected in 51 (98%) of our 52 chemosensitive patients and 1 (2%) patients failed to mobilize. We observed acceptable hematological and nonhematological toxicity. The targeted amount of 2 × 106 /kg CD34+ stem cells was attained by 98% (n: 51) patients, and all of them underwent autologous stem cell transplantation. Moreover, low toxicity profiles provide outpatient utilization option clinics with close follow-up and adequate supportive care.
We suggest that GDP/R-GDP plus G-CSF can be used as an effective chemotherapy regimen for mobilizing CD34+ stem cells from peripheral blood in relapsed and refractory lymphoma patients due to low toxicity, effective tumor reduction, and successful stem cell mobilization. It can also be assumed that the GDP mobilization regimen may be more effective, especially in patients with early-stage disease and in HL patients.
1. Introduction
Autologous stem cell transplantation (ASCT), which is a highly therapeutic approach to the treatment of relapsed and refractory lymphoma, is extremely dependent on the mobilization and collection of hematopoietic stem cells (HSC) [1,2]. HSCs can be collected directly from the bone marrow or peripheral blood (PB) by apheresis. ASCTs are performed primarily with peripheral blood stem cells (PBSC). The release of HSCs to PB after granulocyte colony-stimulating factor (G-CSF) treatment and/or chemotherapy is known as mobilization. CD34+ cells do not exceed 0.05% of white blood cells (WBCs) under normal conditions in PB. After combining chemotherapy and G-CSF, the number of PBSC increases from 5 to 15 times [3–5].
The target quantity of HSC to be collected is dependent on the underlying disease (Non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and the number of transplants. The minimum dose considered to be safe in case of ASCT is 2 × 106 CD34+ cells/kg per transplant; however, the aim of many centers is higher yields of 4–5 × 106 CD34+ cells/kg as it may allow faster neutrophil and platelet (PLT) recovery, reduced hospitalization, blood transfusions, and antibiotic therapy. The ideal dose required for successful transplantation was considered to be 5 × 106 CD34+ cells/kg [6–8]. The choice of a specific chemomobilization approach is based on the patient’s disease characteristics and local clinical practice guidelines. The applications that incorporate both the G-CSF and chemotherapy regimens were shown to mobilize more PBSCs than G-CSF alone [9,10].
The combination of G-CSF and chemotherapy is favored for stem cell mobilization and for tumor burden reduction and especially those who need to harvest a greater count of stem cells. It is an option to utilize mobilization not by splitting chemotherapy apart, however, through more precise, disease definite chemotherapy regimens such as; rituximab dexamethasone cytarabine cisplatin (R-DHAP) or rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) for lymphoma patients [11]. After chemotherapy regimen employment, G-CSF daily dosage for mobilization was recommended as filgrastim 10 μg/kg and lenograstim 150 μg/m2. The G-CSF should be initiated following the fulfillment of chemotherapy instantly when leukocyte nadir is detected, and it should be continued till the ending of leukapheresis. Generally, it is recommended to begin G-CSF in 1–5 days following the completion of chemotherapy. Nonetheless, chemomobilization is not a panacea and has some detrimental aspects such as; therapy-associated toxicity, need for frequent hospitalization, harming bone marrow for forthcoming mobilizations and huge cost [11]. Also, it is known that repeated interventions for mobilization after failures constitute a burden for resource utilization and morbidity [12]. Considering all these factors together, determination of the most appropriate chemotherapy regimen for mobilization gains more importance [13].
The data regarding gemcitabine, dexamethasone, and cisplatin (GDP)/rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) on stem cell mobilization are not widely investigated. This study is particularly designed to determine the results of GDP/R-GDP regimen plus G-CSF on mobilization as salvage therapy in patients with relapsed and refractory lymphoma.
2. Materials and methods
Data of 69 relapsed and refractory HL and NHL patients who received GDP/R-GDP as salvage chemotherapy in our center between July 2014 and January 2020 were retrospectively evaluated. All the patients received GDP/R-GDP as salvage regimen (rituximab 375 mg/m2 on day 0, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, dexamethasone 40 mg/day on days 1, 2, 3 and 4: standard doses without dose modifications). Response assessment was based on imaging results from fluorodeoxyglucose–positron emission tomography-computed tomography (FDG/PET-CT) and computed tomography (CT) scans after treatments. The FDG/PET–CT and CT scans were evaluated by using Lugano criteria to assess FDG/PET–CT in lymphoma response criteria published in 2014 [14]. Fifty-two patients who received GDP/R-GDP had a chemosensitive disease. After GDP was given, it was the nadir for neutrophil to decrease and start to increase again, and G-CSF (2 × 5 g/kg/day) was started. Stem cell mobilization practice for lymphoma patients in our center was to start apheresis when the peripheral blood CD34+ count (PB CD34+) was > 10 cells/L, with a collection target of > 5 × 106 CD34+ cells/kg. Mobilization failure was defined as achieving a total CD34+ yield of < 2 × 106 cells/kg. Stem cell mobilization with GDP/R–GDP was compared in terms of diagnosis of HL and NHL, early and late stage, patients who did not receive RT and those who received RT, and patients under 60 and over 60 years of age.
2.1. Statistical analysis
The SPSS version 21.0 (IBM Corporation, Armonk, NY, USA) was applied to analyses. The categorical variables were presented as frequency tables, and the numerical variables were presented as either mean ± standard deviations or median and minimum-maximum values, where appropriate. Distributions of continuous variables were assessed with graphics and Kolmogorov–Smirnov test. Mann–Whitney U test was implemented to compare the nonparametric continuous variables within the groups. A chi-square test was used to analyze apheresis count frequency between the groups. A P-value ≤ 0.05 was regarded as statistically significant.
3. Results
GDP/R–GDP was given to 69 relapsed and refractory HL and NHL patients as salvage chemotherapy. Of the patients, 42 (60.9%) were males, and 27 (39.1%) were females. 38 (55%) patients had the diagnosis of HL, and 31 (45%) patients had NHL. The mean age of the patients was 43.9 ± 15.2 years. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. After the evaluation of response to GDP or R-GDP regimen, a mobilization with G-CSF was performed for 52 patients who had a chemosensitive disease. On the 15th day, on average (range 11–20), ____ CD34+ stem cells were collected. The G-CSF mean was performed for 5 days (range 3–11). Peripheral CD34+ stem cell count before collection (on the day of collection) was between 11 and 467 cells?/μL, and median number of peak CD34+ stem cells in peripheral blood was 55 cells?/μL. The CD34+ stem cells were collected in 51 of our 52 chemosensitive patients (≈ 98%), and 1 (≈ 2%) patients failed to mobilize. In 51 patients, > 2 × 106 CD34+ stem cells/kg (median 8.68 × 106, range 4.06–41.50) were successfully collected. They were collected with one leukapheresis procedure in 34 patients, with two leukapheresis procedures in 15 patients, and with three leukapheresis procedures in 2 patients. The results of PBPCs collection are summarized in Table 3.
Table 1 Demographic and clinical characteristics of the patients.
Diagnosis HL (n: 38); NHL (n: 31)
Age 17–77 years (range) (mean age: 43.9)
Sex Male (n:42); Female (n:27)
Disease status Relapse (n:40); Refractory (n:29)
Radiotherapy Yes (n:14); no. (n:55)
Previous number of chemotherapies 1 line (n: 60); 2 line (n: 7); 3 line (n: 1); 4line (n: 1)
GDP/R-GDP GDP (n:42); R-GDP (n: 27)
Ann Arbor stage before GDP/R-GDP treatment Stage 1 (n: 4); Stage 2 (n: 13); Stage 3(n: 16); Stage 4 (n: 36)
Bone marrow involvement 3/38 (8%); 8/31 (25.8%)
GDP/R-GDP number of cycles 2 (n: 36); 3 (n: 26); 4 (n: 7)
GDP/R-GDP treatment response Chemorefractory disease n: 17;Chemosensitive disease n: 52
Stem cell mobilization with GDP/R-GDP n: 52 (n: 51, 98% successful; n: 1, 2% unsuccessful)
Table 2 Clinical characteristics of patients.
Clinical characteristics Number of patients (n)
Lymphoma type 69
Hodgkin’s lymphoma 38
Non-Hodgkin’s lymphoma 31
Diffuse large B-cell lymphoma 24
T-cell lymphoma 4
Mantle cell lymphoma 1
Follicular lymphoma 1
Marginal zone lymphoma 1
Previous chemotherapies
Hodgkin’s lymphoma
ABVD 27
ABVD + radiotherapy 11
Non-Hodgkin’s lymphoma
R-CHOP 21
R-CHOP + radiotherapy 3
CHOP 4
R-EPOCH 2
CHOEP 1
Table 3 Results of peripheral blood stem cells collection.
Variable All patients, n: 52
Median CD34+ cell count in peripheral blood (/μL) (range) 55.04 (11.07–467.18)
Median apheresis days (range) 15 (11–20)
Leukapheresis procedure count (n) 1 (n: 34); 2 (n: 15); 3 (n: 2)
Median total CD34+ cells collected (106/kg) (range)Out of target (< 2 × 106 CD34 + cells/kg) (%) 8.68 (4.06–41.50)1 (2)
Above minimum target (> 2×106 CD34 + cells/kg) (%) 51 (98)
Above optimal target (> 5×106 CD34 + cells/kg) (%) 48 (92)
Demographic and clinical characteristics of the patients with successful mobilization are summarized in Table 4. The mean age of the patients with successful mobilization (n: 51) was 44 ± 14.5 years. Twenty-nine (≈ 57%) were males and 22 (≈ 43%) were females. Twenty-four (≈ 47%) patients had the diagnosis of HL, and 27 (≈ 53%) patients had NHL. Of these, 22 were relapsed, 29 were refractory, and 15 had early stage and 36 had an advanced stage disease. The patient with unsuccessful mobilization was a 25-year-old female relapse Stage 3BX HL who had received one-line chemotherapy before and had a history of RT. Her response to GDP was a complete response. After nearly 3 weeks, CD34+ stem cells were collected with a G-CSF plus plerixafor.
Table 4 Demographic and clinical characteristics of successfully mobilized patients.
Variable All patients, n: 51
Median age (range) 44 (18–77)
Sex Male (n: 29); Female (n: 22)
Diagnosis HL (n: 24); NHL (n: 27)
Disease status Relapse (n: 22); Refractory (n: 29)
Stage 1–2, n 15
Stage 3–4, n 36
Patients undergoing radiotherapy, n 11
Median CD34 cell count in peripheral blood (cells?/μL)(range) 55.04 (11.07–467.18)
Previous line of chemotherapy 1 line (n: 45); 2 line (n: 4); 3 line (n: 1); 4 line (n: 1)
Blood parameters at the collection date are shown in Table 5. The PLT count was below 150 × 109 /L in 42 (82%) of 51 patients and below 100 × 109 /L in 34 (67%) of 51 patients. 2 patients (4%) had neutropenia (< 1.500 × 109 /L).
Grade 1–2 toxicity was approximately 5.9% (n: 3), which was ototoxicity, mucositis, and/or nephrotoxicity. Grade 3–4 toxicity was approximately 7.8% (n: 4), which was neutropenia (n: 2), febrile neutropenia (n: 1), infections requiring hospital admission (n: 2) and/or nephrotoxicity (n: 1).
Table 5 Blood parameters at harvest.
Variable Median (range)
Leukocyte count (×109/L) 14 (2.44–53.6)
Hemoglobin level (g/dL) 11.2 (7.57–13.4)
Platelet count (×109/L) 62 (20–181)
Neutrophil count (×109/L) 8.7 (1.05–42.74)
Patients under 60 years of age had a higher number of CD34+ stem cells collected on day 1 than those over 60 years of age (P: 0.03). However, there was no difference in total CD34+ collected. The amount of premobilization PLT, apheresis day PB CD34+, CD34+ on the first day, and CD34+ total in HL patients were higher than in the NHL patients (P: 0.02, P: 0.002, P: 0.006, P: 0.03, respectively). In the early-stage patients, total CD34+ amount, and apheresis day PB CD34+ was found higher than in the late-stage patients (P: 0.02 and P: 0.04, respectively). As shown in Tables 6 and 7, when patients who received RT were compared with those who did not receive RT, no statistically significant difference was found in terms of WBC, PLT, and premobilization PB CD34+ stem cell counts, total number of collected CD34+ stem cells, number of CD34+ stem cells collected on the 1st day, and apheresis procedures.
Table 6 Relationship of mobilization and laboratory parameters with clinical variables.
Age Diagnosis
Median (min-max) Aged < 60 (n: 39) Aged ≥ 60 (n: 12) P value HL (n: 24) NHL (n: 27) P value
WBC 13.7(2.4–53.6) 14(6.6–34.1) 0.85 15.7(3.2–53.6) 10.1(2.4–46.2) 0.12
PLT 65.5(20–181) 52(20–107) 0.51 73(30–134) 46(20–181) 0.02*
PB CD34 73.6(11.1–467.2) 35.2(19.5–213) 0.12 119.3(19.5–467.2) 35.2(11.1–173.8) 0.002*
CD34 (1st) 6.5(2.3–41.5) 3.6(1.7–20) 0.03* 11.5(2.2-34.3) 4.3(1.7–41.5) 0.006*
CD34 (T) 9.5(4.1–41.5) 8.2(5.5–20) 0.31 12.4(4.7–34.3) 8.3(4.1–41.5) 0.03*
Apheresiscount 1(1–3) 2(1–3) 0.12 1(1–2) 2(1–3) 0.11
Table 7 Relationship of mobilization and laboratory parameters with clinical variables.
Stage RT
Median(min-max) Early(n: 15) Late(n: 36) P value RT(n:11) Non-RT(n:40) P value
WBC 17.6(3.2–53.6) 12.5(2.4–46.2) 0.19 14.7(6.6–34.9) 12.5(2.4–53.6) 0.33
PLT 74(24–134) 52(20–181) 0.10 97(36-123) 55(20-181) 0.15
PB CD34 106.7(33.1–337.6) 36.8(11.1–467.2) 0.02* 132.5(29.3–399.1) 50.68(11.1–467.2) 0.90
CD34 (1st) 10.6(3.3–20) 4.9(1.7–41.5) 0.09 6.5(2.0–13.3) 5.95(1.7–41.5) 0.98
CD34 (T) 12.5(4.1–20) 8.3(4.7–41.5) 0.04* 9.5(4.7–17.1) 9.14(4.1–41.5) 0.92
Apheresis count 1(1–2) 1(1–3) 0.33 1(1–2) 1(1–3) 0.71
4. Discussion
Currently, the number of 2 × 106 CD34+ cells/kg is generally considered to be the minimum stem cell count needed for a successful ASCT. Ideally, the optimum value is generally considered to be > 5 × 106 CD34+ cells/kg, and the sum of collected stem cells below < 2 × 106 CD34+ cells/kg is regarded as mobilization failure [6,7,8,15].
Various chemotherapeutic agents are used in conjunction with G-CSF for stem cell mobilization in ASCT. Chemotherapeutic agents should be both effective against the underlying disease and should also facilitate stem cell mobilization; thus, both cytoreduction and mobilization should be provided together. This is the reason why single agents such as cyclophosphamide, etoposide, cytarabine, etc. are used along with G-CSF for both pretransplant cytoreduction and stem cell mobilization; therefore, combined regimens such as GDP, cisplatin, cytosine arabinoside and dexamethasone (DHAP), doxorubicin, methylprednisolone, high-dose cytarabine and cisplatin (ASHAP), Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) and ifosfamide, carboplatin, and etoposide phosphate (ICE) have been used as stem cell mobilizing regimens in hematology units [16–18]. By using salvage chemotherapy in patients with relapsed or refractory HL, failure of 3%, 18%, and 14% mobilization rates were reported for GDP, carmustine cytarabine etoposide melphalan (Mini-BEAM), and ICE, respectively [16,17].
Bozdağ et al. investigated the effect of chemotherapy regimens on mobilization in lymphoma patients [18]. Patients were given chemotherapy protocols such as cyclophosphamide (n: 15), ASHAP (n: 11), and ViGePP (n: 12) [18]. Although no difference was reported between the groups concerning the number of stem cells collected (P: 0.58), mobilization failure was 33% in the cyclophosphamide group (n: 5/15), 9% in the ASHAP group (n: 1/11) and 8% in the ViGePP group (n: 1/12) [18].
Berber et al. evaluated the effectiveness of the DHAP regimen plus filgrastim for mobilization of stem cells in relapsed and/or refractory lymphoma patients [19]. Stem cells from 32 patients (94%) were collected on the 11th day on average and the median CD34+ cell count collected was 9.7 × 106 /kg (range 3.8–41.6) [19]. Mobilization failure in salvage treatments was reported as 10% in diffuse large B-cell lymphoma (DLBCL) (n: 197) patients given R-ICE, and it was 8% in DLBCL (n: 191) patients given R-DHAP [20]. Moccia et al. provided GDP salvage treatment to 235 relapsed and refractory HL and NHL patients in their study [21]. Autologous stem cell transplantation was applied to 126 patients (69 HL and 57 DLBCL) in total [21]. In addition, Moccia AA et al. also reported GDP as an effective out-patient salvage regimen for relapsed and refractory DLBCL and HL. However, in the study, the effectiveness of GDP on PBSC mobilization has not been adequately evaluated [21].
In the current study, we evaluated the efficacy of the GDP/R-GDP regimen plus G-CSF to mobilize PBSCs in relapsed and refractory lymphoma patients. Successful mobilization was achieved in 51 of chemosensitive patients and approximately 98% of patients had stem cells collected over 2 × 106 cells?/kg. Our mobilization failure was nearly 2%, and our mobilization failure seemed to be lower when compared to the reports of Mini-BEAM, ICE, cyclophosphamide, ASHAP, ViGePP, R-ICE, and R-DHAP regimens usage reported previously [15–18]. Besides, our study suggests that GDP mobilization regimen may be more effective in HL patients in comparison to NHL patients in terms of premobilization PLT levels, PB CD34+ stem cell counts, first-day collected stem cell amount of the mobilization, and the total number of CD34+ stem cells collected as shown in Tables 6 and 7.
Plerixafor could be added to G-CSF at a dose of 24 µg/kg when there is a possibility of inadequate mobilization (defined as PB CD34+ stem cell number < 10 cells/L on the first apheresis day planned or target CD34+ stem cell yield on the first day of apheresis < 50%) [23,24]. Tang C et al. used 4% and 18% plerixafor in regimens (CE (cyclophosphamide/etoposide) + G-CSF and GDP + G-CSF), respectively [24]. Besides, they reported the mobilization failure as 1.2% [24]. In our study, mobilization failure was 2% and only 1 patient used G-CSF plus plerixafor. Eventually, GDP regimen seemed not to need very high rates of plerixafor usage.
Patient and disease-related factors predicting mobilization failure are being over 60 years of age, having an underlying advanced disease, having previously received more than one-line chemotherapy, and having low CD34+ cells in peripheral blood before apheresis. However, the low PLT count before mobilization and previous treatments, including fludarabine, melphalan, or lenalidomide are controversial factors in terms of mobilization failure. It is generally accepted that the most influential predictive factor for mobilization failure is the number of CD34+ cells in preapheresis PB [6].
From a total of 145 patients, 52% of whom were diagnosed with lymphoma, participated in a study conducted by Demiriz et al. [25]. The patients were divided into two groups according to successful and unsuccessful mobilization and the groups were compared in terms of the parameters affecting the mobilization success [25]. Among the factors of age, platelet count, LDH, ferritin, CRP, LDL, and triglyceride levels, it was only high platelet count that was shown to be effective in mobilization success in their study (P < 0.05) [25]. On the other hand, due to the high platelet count before mobilization, the number of stem cells collected in HL patients was found to be higher than in NHL patients in this study and it would be an indicator of bone marrow reserve.
Dogu MH et al. showed that age, the number of chemotherapy cycles taken before mobilization, and radiation therapy had no significant effect on the number of final CD34+ stem cell yield (P: 0.492, 0.746, and 0.078, respectively) [26]. On the contrary, in our study, the amounts of CD34+ stem cells collected on the 1st day in patients under 60 years of age and older than that were different; however, total amounts of collected CD34+ stem cells were similar. However, there was no difference in terms of the amount of collected total CD34+ between the patients who received RT and those who did not. In addition, when early stage patients were compared with late stage patients, the total number of collected CD34+ stem cells was found to be significantly higher in the early stage patients.
Tang C et al. examined the efficacy and safety of PBSC mobilization following CE + G-CSF versus GDP + G-CSF [24]. Patients mobilized with CE + G-CSF required fewer days of leukapheresis (median 1 vs. 2 days; P: 0.001) and achieved a higher total CD34+ stem cell yield than patients mobilized with GDP + G-CSF (8.5 × 106 vs. 7.1 × 106 CD34+ cells/kg; P: 0.001) [24]. Frequencies of febrile neutropenia and rates of CD34+ stem cell collection ≥ 5 × 106 CD34+ cells/kg were similar [24]. Furthermore, in our study, GDP/R-GDP regimens provided a median number of 8.68 × 106 cells?/kg of CD34+ stem cells (range 4.06–41.50) PBSCs. Total CD34+ stem cell yield was collected by one leukapheresis procedure in 34 (≈ 66.7%) patients, 2 leukapheresis procedures in 15 patients (≈ 29.4%), and 3 leukapheresis procedures in 2 (≈ 3.9%) patients.
In conclusion, we observed acceptable hematological and nonhematological toxicities with R-GDP/GDP salvage chemotherapies used in relapsed and refractory lymphoma patients. We also showed high rates of successful stem cell mobilization in relapsed and refractory lymphoma patients receiving GDP/R-GDP salvage chemotherapies. Therefore, GDP/R-GDP chemotherapy regimens should also be kept in mind as an alternative for salvage chemotherapy followed by peripheral stem cell mobilization in patients with relapsed and refractory lymphoma. It can also be assumed that a GDP mobilization regimen may be more effective, especially in patients with early-stage disease and also HL patients.
Ethical approval
Local ethics committee approval was obtained. | 375 MG/M2, CYCLIC | DrugDosageText | CC BY | 33237657 | 18,592,629 | 2021-04-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute graft versus host disease'. | The clinical role of the gut microbiome and fecal microbiota transplantation in allogeneic stem cell transplantation.
Outcomes of allogeneic hematopoietic stem cell transplantation (allo- HSCT) have improved in the recent decade; however, infections and graft-versus-host disease remain two leading complications significantly contributing to early transplant-related mortality. In past years, the human intestinal microbial composition (microbiota) has been found to be associated with various disease states, including cancer, response to cancer immunotherapy and to modulate the gut innate and adaptive immune response. In the setting of allo-HSCT, the intestinal microbiota diversity and composition appear to have an impact on infection risk, mortality and overall survival. Microbial metabolites have been shown to contribute to the health and integrity of intestinal epithelial cells during inflammation, thus mitigating graft-versus-host disease in animal models. While the cause-andeffect relationship between the intestinal microbiota and transplant-associated complications has not yet been fully elucidated, the above findings have already resulted in the implementation of various interventions aiming to restore the intestinal microbiota diversity and composition. Among others, these interventions include the administration of fecal microbiota transplantation. The present review, based on published data, is intended to define the role of the latter approach in the setting of allo-HSCT.
Introduction
The past decades have witnessed important advances in the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT),1 mainly attributed to the reduction in non-relapse mortality.2 Yet, the need for further improvement is compelling. Acute graft-versus-host disease (aGvHD) and infections are two of the main causes of early transplant-related mortality (TRM), jointly accounting for 36% and 43% of deaths by day 100 in matched related and matched unrelated transplants, respectively.1
One of the emerging and extensively explored allo-HSCT-associated issues is the change in the gut microbial flora, as well as its effect on the pathogenesis of transplant- related complications and association with transplant outcomes.
The human body hosts a hundred trillion microbial organisms; the majority of them are bacteria, predominantly colonizing the gut, with the lower intestine being most densely colonized (1011-1012 organisms/g of intestinal content).3 The composition of bacteria in the gut is referred to as the intestinal microbiota and their collective genome is termed the “intestinal microbiome”.3 The two main phyla constituting more than 90% of the gut microbiota are the Firmicutes and Bacteroidetes and among less dominant phyla are Proteobacteria, Actinobacteria, and Verrucomicrobia.4 This composition is relatively flexible and can rapidly change in response to different environmental factors, adjusting the metabolic and immunologic performance accordingly.5 Intestinal microbiota has been recently found to have a significant impact on both health and disease states. It appears to be crucial for the maturation and education of the immune system and has a role in intestinal cell proliferation, intestine vascularization and endocrine functions. Moreover, it produces energy, synthesizes vitamins, metabolizes bile acids and even inactivates drugs.6-13 The microbiome has been reported to be associated with a variety of disorders such as obesity, type 2 diabetes, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis.14-17 This association is also suggested to be true for cancer18 and response to cancer immunotherapy.19 The gut microbiota has a close and reciprocal relationship with the host immune system. Intestinal epithelial cells, goblet and paneth cells produce the luminal protective mucosal layer and antimicrobial peptides, allowing the transcellular transport of immunoglobulin A (IgA) antibodies. These functions regulate luminal microbial colonization.20
Homeostasis of the immune response in the gut mucosa is maintained by the balance between pro-inflammatory cells, which include T-helper 1 (Th1) cells producing interferon γ (IFNγ), Th17 cells producing IL-17A and IL-22, diverse innate lymphoid cells with cytokine effector features resembling those of Th2 and Th17 cells, the antiinflammatory Foxp3+ regulatory T-cells (Tregs) and IgAsecreting B-cells. This homeostasis can be modulated by the gut microbiota.21-23 In pre-clinical studies, intestinal microbiota has been shown to regulate the expression of pro-inflammatory cytokines, human leukocyte antigen (HLA) type I and type II molecules and increase T-cell proliferation. 18 Effects of the microbiota on cytokine expression and immune cell subsets are not limited to the gut, and are extended to regional mesenteric and systemic lymph nodes.24 Furthermore, while some bacterial strains can induce pro-inflammatory intestinal Th17 cells,25 others induce anti-inflammatory Tregs26,27 and can thus ameliorate inflammatory colitis.28 Moreover, human host gut microbiota has been shown to correlate with expression pattern of the cytokines secreted from peripheral blood mononuclear cells isolated from the host.29 Microbial metabolites such as the short chain fatty acid (SCFA) butyrate or indole derivatives produced by tryptophan metabolism act to maintain the intestinal epithelial cell health, mucosal barrier, and to promote anti-inflammatory responses.30,31
Currently available molecular techniques allowing rapid and wide genomic sequencing enable extensive exploration of the microbiome. The most commonly used method is the 16S ribosomal RNA sequencing by PCR. Bioinformatics analysis tools assign the sequences to microbial taxon at different taxonomic levels. Other methods include shotgun next-generation metagenomics sequencing enabling massive and deeper genomic sequencing and allowing better identification of taxonomic species and potential functional pathways of the organisms, metatranscriptomics using high throughput RNA sequencing to profile gene expression, metaproteomics capable to provide large-scale characterization of the entire proteins in the environmental sample and metabolomics, identifying and quantifying all metabolites in the tested samples.32,33 The two main microbiome features that have been widely characterized in health and disease are its diversity and the abundance of specific bacteria or bacterial subgroups.34
The revelation of significant relationship between the microbiome, the immune system and disease has led to interventional studies aiming to normalize the microbiome composition and diversity thus ameliorating disease conditions. One of such interventions is the use of fecal microbiota transplantation (FMT), the term referring to the transfer of the fecal microbial content from a healthy individual into the intestine of a diseased individual. FMT, the standard of care for refractory or recurrent Clostridium difficile infection (CDI), proved to be highly effective in this condition. At the same time, mixed results were demonstrated in the studies evaluating the use of FMT for the management of inflammatory bowel disease, irritable bowel syndrome and hepatic encephalopathy. To date, FMT application for indications other than CDI has been limited to the experimental setting only.35,36
The setting of allo-HSCT imposes a significant disruption on the gut microbiome homeostasis through a variety of mechanisms (all part of the transplantation procedure), such as the use of broad-spectrum antibiotics, dietary changes (restriction), gut epithelial damage by conditioning regimens and introduction of a donor immune system.
Data from clinical studies support the association of alterations in the gut microbiome profile, mainly loss of diversity and change in composition during allo-HSCT, with patient outcomes such as aGvHD, GvHD-related mortality, non-relapse mortality (NRM) and overall survival (OS).37-40 Moreover, the gut microbial composition is reported to have an impact on infection risk, including CDI and blood stream infections (BSI), in this clinical setting. 38,41 Findings of these associations have led to a preponderance of research in this field,42 and although the causeand- effect relationship between the microbiome and transplant complications has not been unequivocally established, many ongoing clinical trials are implementing various interventions aiming to maintain microbiome diversity, thus potentially preventing transplant-related complications and treating aGvHD. These interventions include the use of probiotics,43 prebiotics,44 change in antibiotic prophylaxis45 and administration of FMT.46 This review appraises the currently available evidence on the association of gut microbiota and allo-HSCT and analyzes a potential role of FMT in allo-HSCT, by presenting two illustrative clinical cases, where effects on the gut microbiota composition could be employed either as a prophylactic or therapeutic measure.
Case 1
A 54-year old male, with mutated FLT3-ITD acute myeloid leukemia (AML) in complete remission (CR) after induction and re-induction chemotherapies, during which he acquired gut colonization with carbapenemresistant Klebsiella pneumoniae. He underwent an allo- HSCT from a mismatched 9/10 unrelated female donor with myeloablative conditioning (busulfan, fludarabine) and received levofloxacin for infection prophylaxis. During the transplantation period, he had a BSI event with extended spectrum β lactamase Escherichia coli (E. coli) treated with meropenem for 10 days, followed by a CDI event treated with oral vancomycin. His neutrophils engrafted on day +15 and on day +33 he developed diarrhea and was diagnosed with grade 3 acute lower gastrointestinal (GI) GvHD that was steroid refractory.
This case raises a number of important questions related to the role of gut flora in allo-HSCT.
Is the microbiome already disrupted prior to allogeneic hematopoietic stem cell transplantation conditioning?
There is ample evidence suggesting that the pre-transplant patient microbiome is already disrupted. The insult to the microbiome starts with preceding chemotherapy and antibiotic exposure. Galloway-Pena et al.47 analyzed 487 stool samples from 30 AML patients and found that their pre-induction microbiome diversity was not significantly different from that of healthy volunteers participating in the Human Microbiome Project (HMP). However, following neutrophil recovery, patient microbiome composition changed, with a significant decrease in diversity. Importantly, this reduction in diversity was associated with an increased risk of infections. The use of carbapenem antibiotics for more than 3 days during induction elevated the risk for a subsequent loss of diversity.47Moreover, exposure to anti-anaerobic antibiotics, like piperacillin-tazobactam, ticarcillin, meropenem, clindamycin and metronidazole, within the 3 months preceding allo-HSCT was associated with a significant decrease in pre-transplant microbiome diversity.38 With more courses of intensive chemotherapy, such as re-induction or salvage, the microbiome disruption was shown to enhance, leading to ecosystem instability and outgrowth of pathogenic bacteria like Enterococcus.48 This disruption in patient microbiome continued up to the time of allo-HSCT, as shown in the largest to date inter-center effort, where 8,767 sequential stool samples were collected from 1,362 patients prior to and throughout the transplantation period and analyzed using 16S ribosomal RNA sequencing. The pre-transplant microbiome of patients obtained on days -30 to -6 (n=606), was compared to that of healthy volunteers (n=246), demonstrating a significant reduction in diversity in patient microbiome.37 Additionally, evidence from another recently published study showed that the pre-transplant microbiome and the one derived from healthy controls differed in composition, displaying decreased abundance of beneficial bacteria of genera Bifidobacterium and butyrate producing genera such as Faecalibacterium and Lachnospiraceae in the former case.49 To conclude, pre-transplant microbiome disruption is clearly evident.
What is the microbiome status during the transplantation period and at time of recovery?
Data from several studies demonstrate that during the transplantation course, the microbiome diversity significantly decreases and its composition changes.37,50 The lower-diversity microbiome is reported to be characterized by abundance of pathogenic bacteria such as Enterococcus, Klebsiella, Escherichia, Staphylococcus and Streptococcus. The single taxonomic unit domination (abundance ≥30%) peaks at 1 week post-transplant, which is followed by a subsequent moderate decrease. The most common dominating taxonomic groups belong to the genera Enterococcus and Streptococcus.37 Along the same lines, other studies have found the Enterococcus genus to be more prolific during the first month posttransplant, with significantly higher abundance in patients with active or subsequent aGvHD.51,52 Following allo-HSCT, the microbiome recovery appears to be prolonged and incomplete. In a large cohort of patients (n=753), the post-transplant recovery of the gut microbiota has been reported to start around day +50, but even by day +100 the composition and bacterial abundance observed pre-transplant have not been fully achieved.53 Moreover, in some patients, microbiota has remained disrupted even 1 year after HSCT, this being particularly the case with butyrate-producing bacteria and Bifidobacterium.54 Eventually, the effect of environmental insult on the intestinal microbiota during allo-HSCT can be so severe that its recovery may require a long time.
Is the disrupted microbiome in allogeneic hematopoietic stem cell transplantation recipients clinically significant?
In the above-mentioned study by Peled et al., reduced microbiome diversity both pre-transplant (days -30 to -6) and peri-engraftment (days +7 to 21), was shown to be significantly associated with lower 2-year OS, while a persistent decrease of this parameter in the latter period was also associated with higher 2-year treatment-related mortality (TRM). Moreover, lower peri-engraftment microbiome diversity in T-cell replete allo-HSCT corresponded to increased GvHD-related mortality, which was not observed in T-cell depleted transplantations. This difference suggests a connection between the microbiota and T-cell alloreactivity.37 Liu et al. revealed a similar association of pre-transplant diversity with mortality as well as a correlation between post-transplant microbiome disruption and acute GI GvHD risk.55 Furthermore, in a study of 66 patients whose stool specimens were analyzed weekly during the transplantation period up to day +100, Golob et al. found a trend of association between near-engraftment low microbiome diversity and the risk for grade 3-4 aGvHD.56 Likewise, Mancini et al. evaluating a cohort of 100 patients, observed a significant connection between low microbiome diversity by day +10 and an increased risk for early (within 30 days) aGvHD.38
A number of studies also reported an impact of pre- or post-transplant bacterial abundance on patient outcomes (Table 1). Results of a two-cohort study (a total of 115 adult patients) conducted at the Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated that increased abundance of the genus Blautia, including anaerobic commensal bacteria, observed 12 days post-transplant, was associated with reduced GvHD-related mortality and improved OS. At the same time, the use of antibiotics with anti-anaerobic activity and total parenteral nutrition (TPN) correlated with loss of Blautia.57 In the pediatric setting, Biagi et al. reported an association of pre-transplant high abundance of Blautia and low abundance of Fusobacterium with diminished risk for grade 2-4 acute GI GvHD.58 Additionally, pre-transplant Enterobacteriaceae abundance of >5% was associated with an increased risk of BSI and Lachnospiraceae abundance of ≤10% appeared to correspond to increased mortality.38 In a large study from the MSKCC, very high abundance of a bacterial group, mainly composed of Eubacterium limosum, in pretransplant samples or the presence of this group in periengraftment samples was found to correspond to a decreased relapse risk,59 once again emphasizing the association of the microbiome and T-cell immunity. Furthermore, in the study from the Osaka University,54 Enterococcus relative abundance of ≥1% at 1 month posttransplant appeared to be indicative of poor OS, with a 2- year survival of 83.9% for patients with relative abundance of Enterococcus <1% versus 47.6% for those in whom this parameter was ≥1%. It is noteworthy that none of the surviving patients at 1 year post-transplant displayed Enterococcus abundance higher than 1%, suggesting that this cutoff could serve as a prognosticator of a long-term outcome in this clinical setting.54 The above evidence suggests that the microbiota changes before and during allo-HSCT are significantly associated with transplant complications and outcomes and might even serve as a predictive marker in this setting.
Table 1. Intestine microbial changes in diversity and abundance during pre-transplant and peri-engraftment periods, associated with outcomes of allogeneic hematopoietic stem cell transplantation
Can prophylactic fecal microbiota transplantation reduce the risk of infections during allogeneic hematopoietic stem cell transplantation?
In allo-HSCT recipients, curtailment of infection risk is crucial for reducing TRM, particularly due to increased frequency of BSI with multidrug resistant (MDR) bacteria. MDR colonization is established to range between 16% for gram-negative bacteria and 39% for vancomycin- resistant Enterococcus (VRE). While BSI have been reported in 16-41% of patients colonized with MDR bacteria, findings regarding a possible association of such colonization with TRM or infection-related mortality are inconclusive.60-62 In addition, MDR gram-negative colonization has neither been found to correspond to an increased risk for sepsis.38,63 In the lack of clear evidence, proof-of-concept studies are becoming of increasing importance. Battipaglia et al.64 have evaluated four patients colonized with MDR bacteria who had received FMT on days -46 to -9 before transplant with an aim to limit the risk for infectious complications during HSCT. All the four patients responded with decolonization of the MDR bacteria. One patient developed grade 3 acute gut GvHD on day +30 after transplant (day +51 after FMT) and two others developed bacteremia with sensitive bacteria. Notably, despite receiving broad-spectrum antibiotics during the transplantation period, none of the patients had recolonization of the gut with MDR bacteria. 64 Similar results were reported in a 63-year old HSCT recipient.65
The ongoing ODYSSEE trial (clinicaltrials gov. Identifier: 02928523) is aimed at reducing complications that may arise as a result of a loss of microbiota diversity, including infectious complications, poor nutritional status, prolonged hospitalization, as well as therapy discontinuation due to induction treatment-related toxicity in AML patients. Twenty newly diagnosed patients collected pre-induction autologous stools. This autologous FMT was later administered as enema after neutrophil recovery and prior to consolidation chemotherapy. Preliminary results demonstrated safety of this approach, with evidence of stool diversity restoration 10 days after FMT and reduction in antibiotic resistant gene copy count by 43%. Yet, clinical efficacy of this method still needs to be confirmed. 66
An important pathogen to consider for intervention with FMT is Clostridium difficile. The incidence of CDI during allo-HSCT varies between 13% and 30%, mostly in the first month after transplant.67-69 The disease is usually of mild-to-moderate severity, with good response to treatment; there is no association with TRM, and its possible correlation to subsequent acute GI GvHD is indefinite. 68-70 Given these facts, and the paucity of data on potential efficacy of prophylactic FMT in reducing the risk of CDI among Clostridium difficile carriers, FMT prophylaxis may not be required for this indication.
As for the treatment of recurrent CDI, results of three small studies demonstrate safety of FMT administration to a total of 16 patients with recurrent CDI after allo- HSCT, with only three patients recurring after the procedure. 71-73
Currently available data are insufficient to definitively conclude that prophylactic FMT will reduce the infection rate in the allo-HSCT setting.
Can prophylactic fecal microbiota transplantation reduce the risk of acute graft-versus-host disease or transplant-related mortality?
The incidence of clinically significant aGvHD ranges between 22% in allo-HSCT from a matched related donor to 29% in case of a mismatched unrelated donor, with grade 3-4 disease incidence being 8.6% and 12%, respectively.24 Whether any intervention that restores the microbiome composition could also decrease aGvHD rates is yet to be revealed. Hitherto, only two small studies have reported results of using prophylactic FMT in the post-engraftment period. In the study by Defillip et al.,25 aiming to evaluate safety and feasibility of early restoration of the gut microbiome, frozen capsules of FMT derived from unrelated donors were administered to 13 allo-HSCT recipients 4 weeks after neutrophil engraftment. No FMT-related bacteremia events occurred and two cases of acute GI GvHD were registered. Analysis of stool composition indicated improvement in intestinal microbiome diversity after FMT that was mainly attributed to operational taxonomic units (OTU) originating from the FMT donor.25 In the study by Taur et al.,53 within 3-28 days of engraftment, patients not receiving broadspectrum antibiotics, not critically ill and with low abundance of Bacteroides (<0.1% of the total 16S sequencing) at that time period, were randomized to either receive autologous FMT (n=14) or to a control group (n=11).
Solely the FMT group was found to reconstitute their microbiome diversity and composition to the pre-transplant state. Of note, the use of autologous FMT raises concern for disrupted microbiota due to prior antibiotic exposure.53
These data suggest feasibility and safety of prophylactic FMT; however, its clinical benefit has not been demonstrated yet.
Should additional interventions along with fecal microbiota transplantation aiming to attenuate mircobiome disruption be considered?
Given that a variety of factors could affect the microbiome diversity and composition during the transplantation course, their adequate control might potentially preclude such microbiome changes. The question remains whether FMT alone is sufficient enough or it should be combined with other interventions to provide the required control.
Transplant conditioning
Conditioning chemotherapy itself has a disruptive effect on the microbiome, as found by Montassier et al.26 who evaluated eight lymphoma patients undergoing autologous HSCT with the BEAM (carmustine, etoposide, cytarabine arabine, melphalan) protocol. Since none of the patients received nasogastric tube nutrition, total parenteral nutrition, ciprofloxacin prophylaxis or systemic antibiotic treatment, only the chemotherapy effect on the microbiome was measured. Compared to pretransplant samples, those drawn at 1 week post-conditioning demonstrated significantly reduced diversity, decreased abundance of Firmicutes and Actinobacteria and increased presence in bacteroides and proteobacteria, indicating chemotherapy-induced disruption of the intestinal microbiota.26 Of note, this disruptive effect might be related to etoposide, which has bacterial inhibitory activity. 27,28 Remarkably, the post-transplant decrease in microbiome diversity appeared to be more profound when more intensive conditioning was applied.74 However, reducing the conditioning intensity was not shown to consistently decrease the rate of aGvHD.75 Moreover, it might increase the relapse rate and decrease long-term OS.76,77 Therefore, changing the conditioning regimen in an attempt to attenuate the insult on the microbiome is not currently recommended.
Diet
Dietary interventions such as TPN, prebiotics and probiotics could potentially influence the microbiome composition before or during the transplantation course. TPN administration was reported to be associated with decreased recovery of post-transplant (up to day +120) diversity compared to enteral nutrition. In addition, SCFA levels in the gut content were found to be lower in the TPN group.78 Iyama et al. retrospectively compared a group of patients whose diet was supplemented with prebiotics, i.e., glutamine, fiber and oligosaccharides (GFO) with a group that did not receive such supplementation. GFO was started 7 days before conditioning and continued up to day +28. In the GFO group, duration of diarrhea, mucositis and TPN requirement was shorter and the weight loss was also less prominent.44 An ongoing prospective trial (clinicaltrials gov. Identifier: 02763033) is evaluating the efficacy of resistant potato starch supplementation between day -7 and day +100 in HSCT recipients. This starch is a non-absorbable carbohydrate that is metabolized by the anaerobic commensal bacteria to produce the SCFA butyrate,79 shown to reduce the severity of acute GI GvHD in an experimental model.31 Preliminary results demonstrate the feasibility of this approach in terms of patient compliance, increase in intestinal butyrate levels and abundance of butyrate producing bacteria. 80 As for probiotic supplementation, the available data do not suggest its influence on the microbiome composition or clinical outcomes. It is worth mentioning that the products used in the studies contained only one bacterial strain and not a diversity of bacteria,43,81 and safety of probiotic administration is of concern in immunocompromised patients.82
The loss of diversity during the transplantation course is accompanied with microbiome domination by single taxonomic units such as Enterococcus.37 This enterococcal expansion has been found to be most prominent in patients developing acute GI GvHD.52 Stein-Thoeringer et al. have shown in a gnotobiotic mouse model of allo- HSCT that enterococcal expansion in the gut depends on lactose and its depletion decreases the enterococcal abundance and thus attenuates GvHD severity. Furthermore, in patients with a lactose malabsorption genotype, Enterococcus abundance appears to be higher than in patients without this genotype.83 This finding may give rise to a new approach to dietary intervention during HSCT. Interestingly, in the study by Khandelwal et al., where pediatric allo-HSCT patients under the age of 5 were treated with ready to eat human milk and breast feeding (n=24) or formula (n=14), plasma levels of IL6, IL10, and Reg3α were significantly lower in the group receiving human milk. The microbiome composition also differed between the two groups, with an increase in pathogenic species such as E. coli in the formula-receiving group. Despite the fact that human milk oligosaccharides are metabolized to SCFA by the commensal bacteria, butyrate levels in the stool were similar in both groups. Moreover, no significant difference in the rate of grade 2-4 acute GI GvHD between the groups was revealed. However, the limited size of this study calls for cautious interpretation of these encouraging results.84 Overall, dietary interventions emerge as a promising way to shape the intestinal microbiota during allo-HSCT. However, results are too preliminary and more research is required before implementing any of these methods.
Antibiotic treatment
The antibiotic treatment applied during the transplantation course is the main factor affecting the microbiome. Quinolone prophylaxis during afebrile neutropenia and systemic broad-spectrum antibiotic treatment with piperacillin-tazobactam or meropenem are widely accepted. 85-87 However, data demonstrate that the use of other antibiotics can better preserve gut beneficial commensals and is associated with improved outcomes.
The study from the University of Regensburg in Germany employed the non-absorbable antibiotic rifaximin and compared it to ciprofloxacin and metronidazole used in a historic cohort of patients for infection prophylaxis during allo-HSCT.45 Antibiotics were given from day -8 up to engraftment. The urine 3-indoxyl sulfate (3-IS) level was measured as a marker of microbiome diversity.88 In the rifaximin cohort, the pre-engraftment 3-IS levels were significantly higher without an increase in the sepsis rate or colonization with pathogenic bacteria. This group had significantly lower TRM, prolonged OS and the acute GI GvHD rate tended to be lower in these patients. The observed advantage remained evident even in patients who later received systemic antibiotics for neutropenic fever. 45
Given the major role of microbiome diversity preservation during allo-HSCT and an association of impaired diversity with acute GI GvHD and adverse patient outcome, Weber et al. further compared the effects of various prophylactic and systemic antibiotics in an attempt to identify the ones that could spare commensal bacteria.89 At 10 days post-transplant, the patient groups receiving rifaximin without systemic antibiotics or rifaximin with systemic antibiotics maintained their microbiome diversity and Clostridia abundance and had higher 3-IS levels compared to patients treated with ciprofloxacin/metronidazole ± systemic antibiotics. These results suggest that rifaximin could better preserve microbiome diversity even when systemic broad-spectrum antibiotics are administered during transplantation. Moreover, in the study conducted in two Canadian hospitals and assessing the effect of antibiotic prophylaxis or treatment given before day 0 on frequency of aGvHD and mortality, the authors compared the outcome of a cohort of patients exposed to antibiotics (n=239) to those who did not receive this therapy (n=261).90 The antibiotic-receiving group demonstrated a significantly higher incidence of grade 2-4 aGvHD and significantly shorter OS at 1, 2 and 10 years posttransplant, indicating an association between the deleterious effect of such treatment on intestinal bacteria and inferior patient outcome.
Importantly, early start of systemic antibiotics (before engraftment) was found to be associated with a lower 3- IS urine level and decreased Clostridia abundance in the stool. Furthermore, the TRM rate in such cases was higher than in patients who did not require systemic antibiotics during HSCT or started them after engraftment.91
Similarly, systemic treatment with piperacillin-tazobactam and meropenem was reported to correlate with decreased microbiome diversity during the transplantation37 and significant loss of commensal anaerobic bacteria. 92 In pediatric patients, Simms-Waldrip et al.93 found that higher load of anti-anaerobic antibiotics was associated with a significant decrease in anti-inflammatory Clostridia (AIC) abundance, and in patients with aGvHD the abundance decrease was severe (10-log fold) compared to patients without GvHD. In a mouse allo-HSCT model, clindamycin administration was associated with AIC decrease and more severe GvHD, while re-administration of AIC increased its levels in the gut and improved survival.93 Additionally, Lee et al.94 compared patients who did not require any systemic antibiotic treatment during the transplantation course with those who received cefepime and those who were treated with carbapenem antibiotics. The carbapenem group displayed a significant loss of microbial diversity at engraftment and an increased rate of acute GI GvHD (32.1%) compared to the noantibiotics group (11.6%). Interestingly, the cefepime group retained a diverse microbiome, demonstrating only a trend to a higher GI GvHD rate (26.4%).
Furthermore, a large multicenter study retrospectively evaluating 857 patients revealed that the use of piperacillin-tazobactam and imipenem-cilastatin was associated with increased 5-year GvHD-related mortality, 95 while this was not observed in patients receiving cefepime and aztreonam. The former antibiotics caused a significant decrease in abundance of Bacteroidetes and Lactobacillus compared to the latter ones. These results suggest that some antibiotics may be more beneficial than others in the setting of allo-HSCT, and that this beneficial effect is related to the antibiotic ability to be less detrimental to intestinal commensal bacteria.95 Findings in the pediatric setting were consistent with these data, and exposure to anti-anaerobic antibiotics was reported to result in a significant decrease in butyrate-producing bacteria and the butyrate level in luminal content by day +14. Pediatric patients who later developed aGvHD had a significantly lower butyrate level at that time point than patients without GvHD.96
It was also demonstrated that specific antibiotic use during allo-HSCT could change the abundance of specific taxa which was associated with BSI risk. In a cohort of 94 patients, Taur Y et al.50 found that domination of the gut microbiome (abundance ≥30%) by single bacterial taxa Enterococcus and Streptococcus occurred at the peri-engraftment period (days +10 to +20) in two thirds of the patients. However, treatment with metronidazole increased the risk for enterococcal domination by 3-fold, and this domination elevated the risk for VRE bacteremia by 9-fold. Altogether, these data establish an essential role of antibiotics in disrupting or preserving the intestinal microbiota during allo-HSCT.
Case 1: conclusions
Several issues should be considered in decision-making regarding the appropriate management of this case. This patient has pre-transplant intestinal microbiota disruption and assumed colonization by MDR bacteria and probably by Clostridium difficile. His risk for aGvHD is high, since he has undergone allo-HSCT from a mismatched unrelated donor. Quinolone prophylaxis and meropenem treatment for BSI have further disrupted his intestinal microbiota. The existence of pre-transplant microbiota disruption, mainly attributed to the use of broad-spectrum antibiotics during intensive chemotherapy, is associated with increased TRM, shorter OS and GvHD-related mortality. Pre-transplant FMT can potentially enrich the microbiome diversity and eradicate MDR bacteria or Clostridium difficile; however, without controlling such factors as antibiotic prophylaxis and the type of systemic antibiotic therapy employed, the intervention by FMT may not completely achieve its goals.
Table 2. Clinical trials of fecal microbiota transplant in allogeneic hematopoietic stem cell transplantation.
So far, no data are available regarding a clinical benefit of prophylactic pre-transplant FMT.
While an association between peri-engraftment microbiome low diversity and patient outcome is established, implying potential feasibility of FMT use at that stage, data regarding FMT application before engraftment are not available, and for safety reasons this approach will probably not be attempted. Results of several small-scale studies suggest safety and feasibility of post-engraftment FMT in restoring microbiome diversity (Table 2); however, it remains unknown if this strategy could decrease the risk for aGvHD-related mortality and TRM.
As for dietary interventions at this period, their efficacy is still under investigation. Choosing a different antibiotic prophylaxis, such as rifaximin and systemic antibiotics such as cefepime, looks promising. Nevertheless, new strategies need to be tested to prove their non-inferiority in OS85 and to establish less disruption for the microbiome (clinicaltrials gov. Identifier: 03078010), especially since fourth-generation cephalosporins have been found in one study to be associated with an increased risk for aGvHD.97
Case 1: recommendations
In this case, based on the currently available data, we do not recommend prophylactic administration of pretransplant or post-engraftment FMT.
Case 2
A 25-year old female with intermediate-risk AML in CR underwent an allo-HSCT with BuCy myeloablative conditioning from her matched sibling. Her neutrophils engrafted by day +14. On day +34 she developed grade 3 aGvHD of the lower GI tract which was steroid refractory (SR). She did not respond to the addition of budesonide, extracorporeal photopheresis (ECP), mofetil mycophenolate or infliximab.
Can fecal microbiota transplantation mitigate prevailing acute gastrointestinal graft-versushost disease?
The current data regarding the use of FMT for the treatment of acute GI GvHD are limited to case reports and small case series (Table 2). A total of 58 described patients were treated with FMT for SR GI grade 2-4 aGvHD. The FMT source was an unrelated donor in 36 cases, a related donor – in six cases and in eight cases a commercial pooled highly diverse FMT was used. FMT was processed and either given fresh within a few hours of collection or it was frozen and later thawed before administration. FMT was administered orally as packed capsules, through a nasogastric/ nasoduodenal tube or an enema. Of 58 patients, 28 received FMT after two or more therapy lines, while 19 received it as second-line therapy right after steroid failure. Response was observed in 74% (43 of 58) of patients, with complete response in 57% (33 of 58) and partial response in 17% (10 of 58). Complete response was observed in 73% of patients receiving FMT as second-line therapy. Ten of the responding patients relapsed and 29 patients were alive at the last follow-up (54%; 29 of 54 patients with available data).
Response to treatment was seen within a median of 14 days (range: 3-28), with a median of two FMT (range: 1-7), and a median of 7 days between treatments (range: 2-60).46,98-106
Infectious complications occurred in 11 patients. Two had sepsis with bacteria not originating from FMT,102 and one patient developed diarrhea due to Norovirus that was traced to FMT.106 Other infections were attributed to the severe immunocompromised state of patients. However, a possible association with FMT could not be ruled out. In responding patients in whom the stool microbiome was sequenced post-FMT, it was found to be significantly more diverse and enriched with Bacteroides, Lactobacillus, Bifidobacterium and Faecalibacterium compared to pre-FMT microbiome.46,98-101 Notably, the diversity increased only upon discontinuation of anti-anaerobic systemic antibiotic treatment, such as piperacillin-tazobactam. However, continuous use or re-initiating treatment with cefepime did not reduce FMT efficiency.46,98,99
These results are highly encouraging and support FMT therapy to be relatively safe and effective in SR GI aGvHD.
Case 2: conclusions
Available data suggest a potentially beneficial effect of FMT in acute lower GI GvHD. It should probably be used earlier rather than later, so that patients' response will not be overcome by infectious complications related to extensive immunosuppressive therapy. Discontinuation of antibiotic treatment prior to FMT administration appears to be an important factor contributing to successful response. If antibiotic treatment is required, using cefepime may allow attenuating microbiome insult while maintaining clinical response.
Current information is based on case reports and small series with a wide variability in patient selection, FMT preparation and mode of administration. However, the reported feasibility, safety and clinical benefit appear to be similar across the studies, implying that intestinal microbiota can be recovered with FMT, irrespective of its administration method. Safety remains a concern,107 especially in advanced GI aGvHD, and if an infectious complication occurs post-FMT, the pathogen should be sequenced and traced to find out if it originates from the FMT.
Case 2: recommendations
Currently, ruxolitinib is the only FDA-approved drug for the treatment of SR aGvHD, while other modalities are also commonly used in this scenario (e.g., extracorporeal photopheresis). Thus, FMT could be recommended for patients with grade 2-4 steroid refractory or dependent aGVHD of the lower GI tract, albeit in the context of a clinical study only.108-110 Other treatment approaches could also be considered, such as adding it to steroids as part of the first-line therapy (clinicaltrials gov. Identifier: 04269850).
Although clinical trials are still ongoing, given the grave prognosis of SR aGvHD with more than 50% mortality,111 and the high rate of response to FMT, we recommend considering FMT as a therapeutic option in this setting.
Practical considerations for fecal microbiota transplantation treatment
As FMT has become the standard of care in recurrent and refractory CDI,112,113 more and more centers are gaining access to FMT programs through either establishing their own stool banks or acquiring FMT from universal stool banks.114,115
One of the limiting factors to wider application of stool banks and FMT programs is the lack or variance of regulatory standards. In different countries, FMT is regulated as a drug, tissue or a combined product composed of both human cells and non-human components (microbial DNA and metabolites). Stool banks are recommended to operate under the designated authority in each country. In the absence of local directives, the scientific committee should be responsible for establishing regulatory protocols.114
FMT donor screening should follow national regulations and international recommendations.114 Screening should include medical history related to the risk for transmitting infections, as well as medical conditions and treatments associated with perturbed microbiome (Table 3). Special considerations are to be applied when planning FMT use in allo-HSCT patients, such as testing the donor for Cytomegalovirus and Epstein-Barr virus IgG and IgM, and administering FMT from seronegative donors to seronegative patients. However, when weighing suitability of an FMT donor, one should be cognizant of the fact that no data are available to support the advantage of a particular donor (a family member, an unrelated donor, or pooled stool from several unrelated donors).
As for autologous FMT, it has not been tested in the setting of aGvHD treatment. Since the microbiota composition of a patient is already disrupted prior to HSCT, using such stool in FMT preparation to be applied for diversity restoration may not be effective. In order to circumvent this problem, in AML patients, we recommend freezing self-stool before the beginning of induction chemotherapy.
In CDI, both fresh and frozen FMT have been shown to be efficient116 as have been the two delivery routes − colonoscopy and oral capsules.117 While there are no data pointing to the superiority of either method of preparation or administration for aGvHD treatment, frozen samples from a stool bank allow FMT to be readily available for immediate use without the need to wait for donor screening and FMT collection.
The basic principles of FMT preparation include weighing the sample, suspension in sterile solution (saline), adding glycerol in case the FMT is planned for freezing and storing, homogenization, filtering and aliquoting the suspension for fresh use or freezing (Table 3). The FMT product should be registered and labeled.114
Based on the available data (Table 2) we suggest evaluating clinical response at 7-14 days after FMT administration. If no response or only partial response is achieved, we recommend administering a second dose of FMT. Whether in such cases the use of FMT from another donor could provide a superior outcome is yet to be determined. In general, in order to consider FMT as an efficacious therapeutic approach for SR GI aGvHD management, an overall response rate of around 60-70%, with a complete response rate of 30-50% should be a desired target, as these rates are achieved with the use of the approved ruxolitinib treatment and in non-randomized FMT studies.46,98-106,110
As for the antibiotic treatment peri-FMT, if feasible, 24-48 hours prior to FMT, systemic antibiotics should be stopped or replaced by one with less anti-anaerobic activity such as rifaximin for prophylaxis or cefepime for febrile neutropenic treatment.46,98,99
Microbiome sequencing of donor and patient samples could help interpreting clinical outcomes. It could also be valuable in distinguishing between the donor and the recipient as the source of post-FMT infection. However, currently there are no data suggesting that patient stool sequencing prior to FMT could guide its administration or affect the outcome. Therefore, given that the primary outcome should be the clinical response to treatment we recommend treating SR GI aGvHD patients with FMT even if the microbiome analysis is not available. Nonetheless, we do suggest storing stool samples from the donor and the patient (before and after FMT) for later sequencing if it becomes available.
Table 3. Practical aspects of fecal microbiota transplantation.
Further accumulation of data on FMT for SR GI aGvHD will allow wider and more efficient application of this treatment approach.
Open challenges and future directions
Disruption of the intestinal microbiome during allo- HSCT is a multifaceted process with a cause-and-effect relationship between multiple factors such as conditioning, diet and antibiotic treatment. Lately, FMT has emerged as an intervention that can facilitate microbiome recovery and potentially intervene with the above interplay (Figure 1). The intestinal microbial disruption before and during allo-HSCT is clearly associated with transplant-related outcomes, mainly acute GvHD and mortality, and pre-clinical data demonstrate the key role of the intestinal microbiota in protecting the gut from inflammatory damage and in regulating the innate immune system to maintain a more tolerant state.118 While the addition of beneficial bacteria or their metabolites has been shown to ameliorate acute GvHD in animal allo-HSCT models, many challenges remain concerning the role of the intestinal microbiota in allo-HSCT in humans. A substantial amount of basic research is being conducted aiming to better understand the place of microbiome changes in the pathogenesis of acute GvHD. In addition, a large population microbiome analysis is ongoing attempting to delineate the interplay between other factors, such as antibiotics and diet, and the microbiota disruption, and to determine the optimal strategy allowing to preserve the microbiota intact.119 However, while these issues are still under investigation, clinical trials evaluating the efficacy of FMT and other abovementioned interventions in the HSCT setting are underway (Table 2). Joint efforts to further explore biological, correlative and recovery functions of the intestinal microbiota could ultimately lead to decreased transplantrelated mortality, and even pave the way to personalized therapeutic strategies in HSCT.
Figure 1. The multifactorial interplay between environmental factors, intestinal microbiota and tissue damage affects transplant-related outcomes. During allogeneic hematopoietic stem cell transplantation (allo-HSCT), conditioning chemotherapy causes damage to the intestinal mucosa cells such as intestinal epithelial cells, intestinal stem cells, paneth cells and mucus producing goblet cells. Gut microbiota is already disrupted before allo-HSCT and due to prophylactic and systemic antibiotic therapy the microbiota disruption worsens with loss of butyrate producing bacteria and other beneficial commensals, along with increase in pathogenic bacteria such as Enterococcus. Depletion of bacterial metabolites postpones epithelial cell repair and restoration of the mucus barrier. Pathogenic bacteria can disseminate through the damaged mucosa and cause blood stream infections, which will necessitate the administration of systemic antibiotics further disrupting the intestinal microbiota. This vicious cycle is associated with graft-versus-host disease (GvHD), increased mortality and diminished overall survival. The question remains whether fecal microbiota transplantation (FMT) and other interventions such as prebiotics and the use of antibiotics with less anti-anaerobic activity could eventually break the cycle and improve outcomes. IEC:– intestinal epithelial cells; ISC: intestinal stem cells.
Supplementary Material
Disclosures and Contributions
Acknowledgements
The authors wish to thank Sonia Kamenetsky for her assistance in the preparation of this manuscript. | BUSULFAN, FLUDARABINE PHOSPHATE, LEVOFLOXACIN, MEROPENEM | DrugsGivenReaction | CC BY-NC | 33241674 | 19,317,760 | 2021-04-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Clostridium difficile infection'. | The clinical role of the gut microbiome and fecal microbiota transplantation in allogeneic stem cell transplantation.
Outcomes of allogeneic hematopoietic stem cell transplantation (allo- HSCT) have improved in the recent decade; however, infections and graft-versus-host disease remain two leading complications significantly contributing to early transplant-related mortality. In past years, the human intestinal microbial composition (microbiota) has been found to be associated with various disease states, including cancer, response to cancer immunotherapy and to modulate the gut innate and adaptive immune response. In the setting of allo-HSCT, the intestinal microbiota diversity and composition appear to have an impact on infection risk, mortality and overall survival. Microbial metabolites have been shown to contribute to the health and integrity of intestinal epithelial cells during inflammation, thus mitigating graft-versus-host disease in animal models. While the cause-andeffect relationship between the intestinal microbiota and transplant-associated complications has not yet been fully elucidated, the above findings have already resulted in the implementation of various interventions aiming to restore the intestinal microbiota diversity and composition. Among others, these interventions include the administration of fecal microbiota transplantation. The present review, based on published data, is intended to define the role of the latter approach in the setting of allo-HSCT.
Introduction
The past decades have witnessed important advances in the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT),1 mainly attributed to the reduction in non-relapse mortality.2 Yet, the need for further improvement is compelling. Acute graft-versus-host disease (aGvHD) and infections are two of the main causes of early transplant-related mortality (TRM), jointly accounting for 36% and 43% of deaths by day 100 in matched related and matched unrelated transplants, respectively.1
One of the emerging and extensively explored allo-HSCT-associated issues is the change in the gut microbial flora, as well as its effect on the pathogenesis of transplant- related complications and association with transplant outcomes.
The human body hosts a hundred trillion microbial organisms; the majority of them are bacteria, predominantly colonizing the gut, with the lower intestine being most densely colonized (1011-1012 organisms/g of intestinal content).3 The composition of bacteria in the gut is referred to as the intestinal microbiota and their collective genome is termed the “intestinal microbiome”.3 The two main phyla constituting more than 90% of the gut microbiota are the Firmicutes and Bacteroidetes and among less dominant phyla are Proteobacteria, Actinobacteria, and Verrucomicrobia.4 This composition is relatively flexible and can rapidly change in response to different environmental factors, adjusting the metabolic and immunologic performance accordingly.5 Intestinal microbiota has been recently found to have a significant impact on both health and disease states. It appears to be crucial for the maturation and education of the immune system and has a role in intestinal cell proliferation, intestine vascularization and endocrine functions. Moreover, it produces energy, synthesizes vitamins, metabolizes bile acids and even inactivates drugs.6-13 The microbiome has been reported to be associated with a variety of disorders such as obesity, type 2 diabetes, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis.14-17 This association is also suggested to be true for cancer18 and response to cancer immunotherapy.19 The gut microbiota has a close and reciprocal relationship with the host immune system. Intestinal epithelial cells, goblet and paneth cells produce the luminal protective mucosal layer and antimicrobial peptides, allowing the transcellular transport of immunoglobulin A (IgA) antibodies. These functions regulate luminal microbial colonization.20
Homeostasis of the immune response in the gut mucosa is maintained by the balance between pro-inflammatory cells, which include T-helper 1 (Th1) cells producing interferon γ (IFNγ), Th17 cells producing IL-17A and IL-22, diverse innate lymphoid cells with cytokine effector features resembling those of Th2 and Th17 cells, the antiinflammatory Foxp3+ regulatory T-cells (Tregs) and IgAsecreting B-cells. This homeostasis can be modulated by the gut microbiota.21-23 In pre-clinical studies, intestinal microbiota has been shown to regulate the expression of pro-inflammatory cytokines, human leukocyte antigen (HLA) type I and type II molecules and increase T-cell proliferation. 18 Effects of the microbiota on cytokine expression and immune cell subsets are not limited to the gut, and are extended to regional mesenteric and systemic lymph nodes.24 Furthermore, while some bacterial strains can induce pro-inflammatory intestinal Th17 cells,25 others induce anti-inflammatory Tregs26,27 and can thus ameliorate inflammatory colitis.28 Moreover, human host gut microbiota has been shown to correlate with expression pattern of the cytokines secreted from peripheral blood mononuclear cells isolated from the host.29 Microbial metabolites such as the short chain fatty acid (SCFA) butyrate or indole derivatives produced by tryptophan metabolism act to maintain the intestinal epithelial cell health, mucosal barrier, and to promote anti-inflammatory responses.30,31
Currently available molecular techniques allowing rapid and wide genomic sequencing enable extensive exploration of the microbiome. The most commonly used method is the 16S ribosomal RNA sequencing by PCR. Bioinformatics analysis tools assign the sequences to microbial taxon at different taxonomic levels. Other methods include shotgun next-generation metagenomics sequencing enabling massive and deeper genomic sequencing and allowing better identification of taxonomic species and potential functional pathways of the organisms, metatranscriptomics using high throughput RNA sequencing to profile gene expression, metaproteomics capable to provide large-scale characterization of the entire proteins in the environmental sample and metabolomics, identifying and quantifying all metabolites in the tested samples.32,33 The two main microbiome features that have been widely characterized in health and disease are its diversity and the abundance of specific bacteria or bacterial subgroups.34
The revelation of significant relationship between the microbiome, the immune system and disease has led to interventional studies aiming to normalize the microbiome composition and diversity thus ameliorating disease conditions. One of such interventions is the use of fecal microbiota transplantation (FMT), the term referring to the transfer of the fecal microbial content from a healthy individual into the intestine of a diseased individual. FMT, the standard of care for refractory or recurrent Clostridium difficile infection (CDI), proved to be highly effective in this condition. At the same time, mixed results were demonstrated in the studies evaluating the use of FMT for the management of inflammatory bowel disease, irritable bowel syndrome and hepatic encephalopathy. To date, FMT application for indications other than CDI has been limited to the experimental setting only.35,36
The setting of allo-HSCT imposes a significant disruption on the gut microbiome homeostasis through a variety of mechanisms (all part of the transplantation procedure), such as the use of broad-spectrum antibiotics, dietary changes (restriction), gut epithelial damage by conditioning regimens and introduction of a donor immune system.
Data from clinical studies support the association of alterations in the gut microbiome profile, mainly loss of diversity and change in composition during allo-HSCT, with patient outcomes such as aGvHD, GvHD-related mortality, non-relapse mortality (NRM) and overall survival (OS).37-40 Moreover, the gut microbial composition is reported to have an impact on infection risk, including CDI and blood stream infections (BSI), in this clinical setting. 38,41 Findings of these associations have led to a preponderance of research in this field,42 and although the causeand- effect relationship between the microbiome and transplant complications has not been unequivocally established, many ongoing clinical trials are implementing various interventions aiming to maintain microbiome diversity, thus potentially preventing transplant-related complications and treating aGvHD. These interventions include the use of probiotics,43 prebiotics,44 change in antibiotic prophylaxis45 and administration of FMT.46 This review appraises the currently available evidence on the association of gut microbiota and allo-HSCT and analyzes a potential role of FMT in allo-HSCT, by presenting two illustrative clinical cases, where effects on the gut microbiota composition could be employed either as a prophylactic or therapeutic measure.
Case 1
A 54-year old male, with mutated FLT3-ITD acute myeloid leukemia (AML) in complete remission (CR) after induction and re-induction chemotherapies, during which he acquired gut colonization with carbapenemresistant Klebsiella pneumoniae. He underwent an allo- HSCT from a mismatched 9/10 unrelated female donor with myeloablative conditioning (busulfan, fludarabine) and received levofloxacin for infection prophylaxis. During the transplantation period, he had a BSI event with extended spectrum β lactamase Escherichia coli (E. coli) treated with meropenem for 10 days, followed by a CDI event treated with oral vancomycin. His neutrophils engrafted on day +15 and on day +33 he developed diarrhea and was diagnosed with grade 3 acute lower gastrointestinal (GI) GvHD that was steroid refractory.
This case raises a number of important questions related to the role of gut flora in allo-HSCT.
Is the microbiome already disrupted prior to allogeneic hematopoietic stem cell transplantation conditioning?
There is ample evidence suggesting that the pre-transplant patient microbiome is already disrupted. The insult to the microbiome starts with preceding chemotherapy and antibiotic exposure. Galloway-Pena et al.47 analyzed 487 stool samples from 30 AML patients and found that their pre-induction microbiome diversity was not significantly different from that of healthy volunteers participating in the Human Microbiome Project (HMP). However, following neutrophil recovery, patient microbiome composition changed, with a significant decrease in diversity. Importantly, this reduction in diversity was associated with an increased risk of infections. The use of carbapenem antibiotics for more than 3 days during induction elevated the risk for a subsequent loss of diversity.47Moreover, exposure to anti-anaerobic antibiotics, like piperacillin-tazobactam, ticarcillin, meropenem, clindamycin and metronidazole, within the 3 months preceding allo-HSCT was associated with a significant decrease in pre-transplant microbiome diversity.38 With more courses of intensive chemotherapy, such as re-induction or salvage, the microbiome disruption was shown to enhance, leading to ecosystem instability and outgrowth of pathogenic bacteria like Enterococcus.48 This disruption in patient microbiome continued up to the time of allo-HSCT, as shown in the largest to date inter-center effort, where 8,767 sequential stool samples were collected from 1,362 patients prior to and throughout the transplantation period and analyzed using 16S ribosomal RNA sequencing. The pre-transplant microbiome of patients obtained on days -30 to -6 (n=606), was compared to that of healthy volunteers (n=246), demonstrating a significant reduction in diversity in patient microbiome.37 Additionally, evidence from another recently published study showed that the pre-transplant microbiome and the one derived from healthy controls differed in composition, displaying decreased abundance of beneficial bacteria of genera Bifidobacterium and butyrate producing genera such as Faecalibacterium and Lachnospiraceae in the former case.49 To conclude, pre-transplant microbiome disruption is clearly evident.
What is the microbiome status during the transplantation period and at time of recovery?
Data from several studies demonstrate that during the transplantation course, the microbiome diversity significantly decreases and its composition changes.37,50 The lower-diversity microbiome is reported to be characterized by abundance of pathogenic bacteria such as Enterococcus, Klebsiella, Escherichia, Staphylococcus and Streptococcus. The single taxonomic unit domination (abundance ≥30%) peaks at 1 week post-transplant, which is followed by a subsequent moderate decrease. The most common dominating taxonomic groups belong to the genera Enterococcus and Streptococcus.37 Along the same lines, other studies have found the Enterococcus genus to be more prolific during the first month posttransplant, with significantly higher abundance in patients with active or subsequent aGvHD.51,52 Following allo-HSCT, the microbiome recovery appears to be prolonged and incomplete. In a large cohort of patients (n=753), the post-transplant recovery of the gut microbiota has been reported to start around day +50, but even by day +100 the composition and bacterial abundance observed pre-transplant have not been fully achieved.53 Moreover, in some patients, microbiota has remained disrupted even 1 year after HSCT, this being particularly the case with butyrate-producing bacteria and Bifidobacterium.54 Eventually, the effect of environmental insult on the intestinal microbiota during allo-HSCT can be so severe that its recovery may require a long time.
Is the disrupted microbiome in allogeneic hematopoietic stem cell transplantation recipients clinically significant?
In the above-mentioned study by Peled et al., reduced microbiome diversity both pre-transplant (days -30 to -6) and peri-engraftment (days +7 to 21), was shown to be significantly associated with lower 2-year OS, while a persistent decrease of this parameter in the latter period was also associated with higher 2-year treatment-related mortality (TRM). Moreover, lower peri-engraftment microbiome diversity in T-cell replete allo-HSCT corresponded to increased GvHD-related mortality, which was not observed in T-cell depleted transplantations. This difference suggests a connection between the microbiota and T-cell alloreactivity.37 Liu et al. revealed a similar association of pre-transplant diversity with mortality as well as a correlation between post-transplant microbiome disruption and acute GI GvHD risk.55 Furthermore, in a study of 66 patients whose stool specimens were analyzed weekly during the transplantation period up to day +100, Golob et al. found a trend of association between near-engraftment low microbiome diversity and the risk for grade 3-4 aGvHD.56 Likewise, Mancini et al. evaluating a cohort of 100 patients, observed a significant connection between low microbiome diversity by day +10 and an increased risk for early (within 30 days) aGvHD.38
A number of studies also reported an impact of pre- or post-transplant bacterial abundance on patient outcomes (Table 1). Results of a two-cohort study (a total of 115 adult patients) conducted at the Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated that increased abundance of the genus Blautia, including anaerobic commensal bacteria, observed 12 days post-transplant, was associated with reduced GvHD-related mortality and improved OS. At the same time, the use of antibiotics with anti-anaerobic activity and total parenteral nutrition (TPN) correlated with loss of Blautia.57 In the pediatric setting, Biagi et al. reported an association of pre-transplant high abundance of Blautia and low abundance of Fusobacterium with diminished risk for grade 2-4 acute GI GvHD.58 Additionally, pre-transplant Enterobacteriaceae abundance of >5% was associated with an increased risk of BSI and Lachnospiraceae abundance of ≤10% appeared to correspond to increased mortality.38 In a large study from the MSKCC, very high abundance of a bacterial group, mainly composed of Eubacterium limosum, in pretransplant samples or the presence of this group in periengraftment samples was found to correspond to a decreased relapse risk,59 once again emphasizing the association of the microbiome and T-cell immunity. Furthermore, in the study from the Osaka University,54 Enterococcus relative abundance of ≥1% at 1 month posttransplant appeared to be indicative of poor OS, with a 2- year survival of 83.9% for patients with relative abundance of Enterococcus <1% versus 47.6% for those in whom this parameter was ≥1%. It is noteworthy that none of the surviving patients at 1 year post-transplant displayed Enterococcus abundance higher than 1%, suggesting that this cutoff could serve as a prognosticator of a long-term outcome in this clinical setting.54 The above evidence suggests that the microbiota changes before and during allo-HSCT are significantly associated with transplant complications and outcomes and might even serve as a predictive marker in this setting.
Table 1. Intestine microbial changes in diversity and abundance during pre-transplant and peri-engraftment periods, associated with outcomes of allogeneic hematopoietic stem cell transplantation
Can prophylactic fecal microbiota transplantation reduce the risk of infections during allogeneic hematopoietic stem cell transplantation?
In allo-HSCT recipients, curtailment of infection risk is crucial for reducing TRM, particularly due to increased frequency of BSI with multidrug resistant (MDR) bacteria. MDR colonization is established to range between 16% for gram-negative bacteria and 39% for vancomycin- resistant Enterococcus (VRE). While BSI have been reported in 16-41% of patients colonized with MDR bacteria, findings regarding a possible association of such colonization with TRM or infection-related mortality are inconclusive.60-62 In addition, MDR gram-negative colonization has neither been found to correspond to an increased risk for sepsis.38,63 In the lack of clear evidence, proof-of-concept studies are becoming of increasing importance. Battipaglia et al.64 have evaluated four patients colonized with MDR bacteria who had received FMT on days -46 to -9 before transplant with an aim to limit the risk for infectious complications during HSCT. All the four patients responded with decolonization of the MDR bacteria. One patient developed grade 3 acute gut GvHD on day +30 after transplant (day +51 after FMT) and two others developed bacteremia with sensitive bacteria. Notably, despite receiving broad-spectrum antibiotics during the transplantation period, none of the patients had recolonization of the gut with MDR bacteria. 64 Similar results were reported in a 63-year old HSCT recipient.65
The ongoing ODYSSEE trial (clinicaltrials gov. Identifier: 02928523) is aimed at reducing complications that may arise as a result of a loss of microbiota diversity, including infectious complications, poor nutritional status, prolonged hospitalization, as well as therapy discontinuation due to induction treatment-related toxicity in AML patients. Twenty newly diagnosed patients collected pre-induction autologous stools. This autologous FMT was later administered as enema after neutrophil recovery and prior to consolidation chemotherapy. Preliminary results demonstrated safety of this approach, with evidence of stool diversity restoration 10 days after FMT and reduction in antibiotic resistant gene copy count by 43%. Yet, clinical efficacy of this method still needs to be confirmed. 66
An important pathogen to consider for intervention with FMT is Clostridium difficile. The incidence of CDI during allo-HSCT varies between 13% and 30%, mostly in the first month after transplant.67-69 The disease is usually of mild-to-moderate severity, with good response to treatment; there is no association with TRM, and its possible correlation to subsequent acute GI GvHD is indefinite. 68-70 Given these facts, and the paucity of data on potential efficacy of prophylactic FMT in reducing the risk of CDI among Clostridium difficile carriers, FMT prophylaxis may not be required for this indication.
As for the treatment of recurrent CDI, results of three small studies demonstrate safety of FMT administration to a total of 16 patients with recurrent CDI after allo- HSCT, with only three patients recurring after the procedure. 71-73
Currently available data are insufficient to definitively conclude that prophylactic FMT will reduce the infection rate in the allo-HSCT setting.
Can prophylactic fecal microbiota transplantation reduce the risk of acute graft-versus-host disease or transplant-related mortality?
The incidence of clinically significant aGvHD ranges between 22% in allo-HSCT from a matched related donor to 29% in case of a mismatched unrelated donor, with grade 3-4 disease incidence being 8.6% and 12%, respectively.24 Whether any intervention that restores the microbiome composition could also decrease aGvHD rates is yet to be revealed. Hitherto, only two small studies have reported results of using prophylactic FMT in the post-engraftment period. In the study by Defillip et al.,25 aiming to evaluate safety and feasibility of early restoration of the gut microbiome, frozen capsules of FMT derived from unrelated donors were administered to 13 allo-HSCT recipients 4 weeks after neutrophil engraftment. No FMT-related bacteremia events occurred and two cases of acute GI GvHD were registered. Analysis of stool composition indicated improvement in intestinal microbiome diversity after FMT that was mainly attributed to operational taxonomic units (OTU) originating from the FMT donor.25 In the study by Taur et al.,53 within 3-28 days of engraftment, patients not receiving broadspectrum antibiotics, not critically ill and with low abundance of Bacteroides (<0.1% of the total 16S sequencing) at that time period, were randomized to either receive autologous FMT (n=14) or to a control group (n=11).
Solely the FMT group was found to reconstitute their microbiome diversity and composition to the pre-transplant state. Of note, the use of autologous FMT raises concern for disrupted microbiota due to prior antibiotic exposure.53
These data suggest feasibility and safety of prophylactic FMT; however, its clinical benefit has not been demonstrated yet.
Should additional interventions along with fecal microbiota transplantation aiming to attenuate mircobiome disruption be considered?
Given that a variety of factors could affect the microbiome diversity and composition during the transplantation course, their adequate control might potentially preclude such microbiome changes. The question remains whether FMT alone is sufficient enough or it should be combined with other interventions to provide the required control.
Transplant conditioning
Conditioning chemotherapy itself has a disruptive effect on the microbiome, as found by Montassier et al.26 who evaluated eight lymphoma patients undergoing autologous HSCT with the BEAM (carmustine, etoposide, cytarabine arabine, melphalan) protocol. Since none of the patients received nasogastric tube nutrition, total parenteral nutrition, ciprofloxacin prophylaxis or systemic antibiotic treatment, only the chemotherapy effect on the microbiome was measured. Compared to pretransplant samples, those drawn at 1 week post-conditioning demonstrated significantly reduced diversity, decreased abundance of Firmicutes and Actinobacteria and increased presence in bacteroides and proteobacteria, indicating chemotherapy-induced disruption of the intestinal microbiota.26 Of note, this disruptive effect might be related to etoposide, which has bacterial inhibitory activity. 27,28 Remarkably, the post-transplant decrease in microbiome diversity appeared to be more profound when more intensive conditioning was applied.74 However, reducing the conditioning intensity was not shown to consistently decrease the rate of aGvHD.75 Moreover, it might increase the relapse rate and decrease long-term OS.76,77 Therefore, changing the conditioning regimen in an attempt to attenuate the insult on the microbiome is not currently recommended.
Diet
Dietary interventions such as TPN, prebiotics and probiotics could potentially influence the microbiome composition before or during the transplantation course. TPN administration was reported to be associated with decreased recovery of post-transplant (up to day +120) diversity compared to enteral nutrition. In addition, SCFA levels in the gut content were found to be lower in the TPN group.78 Iyama et al. retrospectively compared a group of patients whose diet was supplemented with prebiotics, i.e., glutamine, fiber and oligosaccharides (GFO) with a group that did not receive such supplementation. GFO was started 7 days before conditioning and continued up to day +28. In the GFO group, duration of diarrhea, mucositis and TPN requirement was shorter and the weight loss was also less prominent.44 An ongoing prospective trial (clinicaltrials gov. Identifier: 02763033) is evaluating the efficacy of resistant potato starch supplementation between day -7 and day +100 in HSCT recipients. This starch is a non-absorbable carbohydrate that is metabolized by the anaerobic commensal bacteria to produce the SCFA butyrate,79 shown to reduce the severity of acute GI GvHD in an experimental model.31 Preliminary results demonstrate the feasibility of this approach in terms of patient compliance, increase in intestinal butyrate levels and abundance of butyrate producing bacteria. 80 As for probiotic supplementation, the available data do not suggest its influence on the microbiome composition or clinical outcomes. It is worth mentioning that the products used in the studies contained only one bacterial strain and not a diversity of bacteria,43,81 and safety of probiotic administration is of concern in immunocompromised patients.82
The loss of diversity during the transplantation course is accompanied with microbiome domination by single taxonomic units such as Enterococcus.37 This enterococcal expansion has been found to be most prominent in patients developing acute GI GvHD.52 Stein-Thoeringer et al. have shown in a gnotobiotic mouse model of allo- HSCT that enterococcal expansion in the gut depends on lactose and its depletion decreases the enterococcal abundance and thus attenuates GvHD severity. Furthermore, in patients with a lactose malabsorption genotype, Enterococcus abundance appears to be higher than in patients without this genotype.83 This finding may give rise to a new approach to dietary intervention during HSCT. Interestingly, in the study by Khandelwal et al., where pediatric allo-HSCT patients under the age of 5 were treated with ready to eat human milk and breast feeding (n=24) or formula (n=14), plasma levels of IL6, IL10, and Reg3α were significantly lower in the group receiving human milk. The microbiome composition also differed between the two groups, with an increase in pathogenic species such as E. coli in the formula-receiving group. Despite the fact that human milk oligosaccharides are metabolized to SCFA by the commensal bacteria, butyrate levels in the stool were similar in both groups. Moreover, no significant difference in the rate of grade 2-4 acute GI GvHD between the groups was revealed. However, the limited size of this study calls for cautious interpretation of these encouraging results.84 Overall, dietary interventions emerge as a promising way to shape the intestinal microbiota during allo-HSCT. However, results are too preliminary and more research is required before implementing any of these methods.
Antibiotic treatment
The antibiotic treatment applied during the transplantation course is the main factor affecting the microbiome. Quinolone prophylaxis during afebrile neutropenia and systemic broad-spectrum antibiotic treatment with piperacillin-tazobactam or meropenem are widely accepted. 85-87 However, data demonstrate that the use of other antibiotics can better preserve gut beneficial commensals and is associated with improved outcomes.
The study from the University of Regensburg in Germany employed the non-absorbable antibiotic rifaximin and compared it to ciprofloxacin and metronidazole used in a historic cohort of patients for infection prophylaxis during allo-HSCT.45 Antibiotics were given from day -8 up to engraftment. The urine 3-indoxyl sulfate (3-IS) level was measured as a marker of microbiome diversity.88 In the rifaximin cohort, the pre-engraftment 3-IS levels were significantly higher without an increase in the sepsis rate or colonization with pathogenic bacteria. This group had significantly lower TRM, prolonged OS and the acute GI GvHD rate tended to be lower in these patients. The observed advantage remained evident even in patients who later received systemic antibiotics for neutropenic fever. 45
Given the major role of microbiome diversity preservation during allo-HSCT and an association of impaired diversity with acute GI GvHD and adverse patient outcome, Weber et al. further compared the effects of various prophylactic and systemic antibiotics in an attempt to identify the ones that could spare commensal bacteria.89 At 10 days post-transplant, the patient groups receiving rifaximin without systemic antibiotics or rifaximin with systemic antibiotics maintained their microbiome diversity and Clostridia abundance and had higher 3-IS levels compared to patients treated with ciprofloxacin/metronidazole ± systemic antibiotics. These results suggest that rifaximin could better preserve microbiome diversity even when systemic broad-spectrum antibiotics are administered during transplantation. Moreover, in the study conducted in two Canadian hospitals and assessing the effect of antibiotic prophylaxis or treatment given before day 0 on frequency of aGvHD and mortality, the authors compared the outcome of a cohort of patients exposed to antibiotics (n=239) to those who did not receive this therapy (n=261).90 The antibiotic-receiving group demonstrated a significantly higher incidence of grade 2-4 aGvHD and significantly shorter OS at 1, 2 and 10 years posttransplant, indicating an association between the deleterious effect of such treatment on intestinal bacteria and inferior patient outcome.
Importantly, early start of systemic antibiotics (before engraftment) was found to be associated with a lower 3- IS urine level and decreased Clostridia abundance in the stool. Furthermore, the TRM rate in such cases was higher than in patients who did not require systemic antibiotics during HSCT or started them after engraftment.91
Similarly, systemic treatment with piperacillin-tazobactam and meropenem was reported to correlate with decreased microbiome diversity during the transplantation37 and significant loss of commensal anaerobic bacteria. 92 In pediatric patients, Simms-Waldrip et al.93 found that higher load of anti-anaerobic antibiotics was associated with a significant decrease in anti-inflammatory Clostridia (AIC) abundance, and in patients with aGvHD the abundance decrease was severe (10-log fold) compared to patients without GvHD. In a mouse allo-HSCT model, clindamycin administration was associated with AIC decrease and more severe GvHD, while re-administration of AIC increased its levels in the gut and improved survival.93 Additionally, Lee et al.94 compared patients who did not require any systemic antibiotic treatment during the transplantation course with those who received cefepime and those who were treated with carbapenem antibiotics. The carbapenem group displayed a significant loss of microbial diversity at engraftment and an increased rate of acute GI GvHD (32.1%) compared to the noantibiotics group (11.6%). Interestingly, the cefepime group retained a diverse microbiome, demonstrating only a trend to a higher GI GvHD rate (26.4%).
Furthermore, a large multicenter study retrospectively evaluating 857 patients revealed that the use of piperacillin-tazobactam and imipenem-cilastatin was associated with increased 5-year GvHD-related mortality, 95 while this was not observed in patients receiving cefepime and aztreonam. The former antibiotics caused a significant decrease in abundance of Bacteroidetes and Lactobacillus compared to the latter ones. These results suggest that some antibiotics may be more beneficial than others in the setting of allo-HSCT, and that this beneficial effect is related to the antibiotic ability to be less detrimental to intestinal commensal bacteria.95 Findings in the pediatric setting were consistent with these data, and exposure to anti-anaerobic antibiotics was reported to result in a significant decrease in butyrate-producing bacteria and the butyrate level in luminal content by day +14. Pediatric patients who later developed aGvHD had a significantly lower butyrate level at that time point than patients without GvHD.96
It was also demonstrated that specific antibiotic use during allo-HSCT could change the abundance of specific taxa which was associated with BSI risk. In a cohort of 94 patients, Taur Y et al.50 found that domination of the gut microbiome (abundance ≥30%) by single bacterial taxa Enterococcus and Streptococcus occurred at the peri-engraftment period (days +10 to +20) in two thirds of the patients. However, treatment with metronidazole increased the risk for enterococcal domination by 3-fold, and this domination elevated the risk for VRE bacteremia by 9-fold. Altogether, these data establish an essential role of antibiotics in disrupting or preserving the intestinal microbiota during allo-HSCT.
Case 1: conclusions
Several issues should be considered in decision-making regarding the appropriate management of this case. This patient has pre-transplant intestinal microbiota disruption and assumed colonization by MDR bacteria and probably by Clostridium difficile. His risk for aGvHD is high, since he has undergone allo-HSCT from a mismatched unrelated donor. Quinolone prophylaxis and meropenem treatment for BSI have further disrupted his intestinal microbiota. The existence of pre-transplant microbiota disruption, mainly attributed to the use of broad-spectrum antibiotics during intensive chemotherapy, is associated with increased TRM, shorter OS and GvHD-related mortality. Pre-transplant FMT can potentially enrich the microbiome diversity and eradicate MDR bacteria or Clostridium difficile; however, without controlling such factors as antibiotic prophylaxis and the type of systemic antibiotic therapy employed, the intervention by FMT may not completely achieve its goals.
Table 2. Clinical trials of fecal microbiota transplant in allogeneic hematopoietic stem cell transplantation.
So far, no data are available regarding a clinical benefit of prophylactic pre-transplant FMT.
While an association between peri-engraftment microbiome low diversity and patient outcome is established, implying potential feasibility of FMT use at that stage, data regarding FMT application before engraftment are not available, and for safety reasons this approach will probably not be attempted. Results of several small-scale studies suggest safety and feasibility of post-engraftment FMT in restoring microbiome diversity (Table 2); however, it remains unknown if this strategy could decrease the risk for aGvHD-related mortality and TRM.
As for dietary interventions at this period, their efficacy is still under investigation. Choosing a different antibiotic prophylaxis, such as rifaximin and systemic antibiotics such as cefepime, looks promising. Nevertheless, new strategies need to be tested to prove their non-inferiority in OS85 and to establish less disruption for the microbiome (clinicaltrials gov. Identifier: 03078010), especially since fourth-generation cephalosporins have been found in one study to be associated with an increased risk for aGvHD.97
Case 1: recommendations
In this case, based on the currently available data, we do not recommend prophylactic administration of pretransplant or post-engraftment FMT.
Case 2
A 25-year old female with intermediate-risk AML in CR underwent an allo-HSCT with BuCy myeloablative conditioning from her matched sibling. Her neutrophils engrafted by day +14. On day +34 she developed grade 3 aGvHD of the lower GI tract which was steroid refractory (SR). She did not respond to the addition of budesonide, extracorporeal photopheresis (ECP), mofetil mycophenolate or infliximab.
Can fecal microbiota transplantation mitigate prevailing acute gastrointestinal graft-versushost disease?
The current data regarding the use of FMT for the treatment of acute GI GvHD are limited to case reports and small case series (Table 2). A total of 58 described patients were treated with FMT for SR GI grade 2-4 aGvHD. The FMT source was an unrelated donor in 36 cases, a related donor – in six cases and in eight cases a commercial pooled highly diverse FMT was used. FMT was processed and either given fresh within a few hours of collection or it was frozen and later thawed before administration. FMT was administered orally as packed capsules, through a nasogastric/ nasoduodenal tube or an enema. Of 58 patients, 28 received FMT after two or more therapy lines, while 19 received it as second-line therapy right after steroid failure. Response was observed in 74% (43 of 58) of patients, with complete response in 57% (33 of 58) and partial response in 17% (10 of 58). Complete response was observed in 73% of patients receiving FMT as second-line therapy. Ten of the responding patients relapsed and 29 patients were alive at the last follow-up (54%; 29 of 54 patients with available data).
Response to treatment was seen within a median of 14 days (range: 3-28), with a median of two FMT (range: 1-7), and a median of 7 days between treatments (range: 2-60).46,98-106
Infectious complications occurred in 11 patients. Two had sepsis with bacteria not originating from FMT,102 and one patient developed diarrhea due to Norovirus that was traced to FMT.106 Other infections were attributed to the severe immunocompromised state of patients. However, a possible association with FMT could not be ruled out. In responding patients in whom the stool microbiome was sequenced post-FMT, it was found to be significantly more diverse and enriched with Bacteroides, Lactobacillus, Bifidobacterium and Faecalibacterium compared to pre-FMT microbiome.46,98-101 Notably, the diversity increased only upon discontinuation of anti-anaerobic systemic antibiotic treatment, such as piperacillin-tazobactam. However, continuous use or re-initiating treatment with cefepime did not reduce FMT efficiency.46,98,99
These results are highly encouraging and support FMT therapy to be relatively safe and effective in SR GI aGvHD.
Case 2: conclusions
Available data suggest a potentially beneficial effect of FMT in acute lower GI GvHD. It should probably be used earlier rather than later, so that patients' response will not be overcome by infectious complications related to extensive immunosuppressive therapy. Discontinuation of antibiotic treatment prior to FMT administration appears to be an important factor contributing to successful response. If antibiotic treatment is required, using cefepime may allow attenuating microbiome insult while maintaining clinical response.
Current information is based on case reports and small series with a wide variability in patient selection, FMT preparation and mode of administration. However, the reported feasibility, safety and clinical benefit appear to be similar across the studies, implying that intestinal microbiota can be recovered with FMT, irrespective of its administration method. Safety remains a concern,107 especially in advanced GI aGvHD, and if an infectious complication occurs post-FMT, the pathogen should be sequenced and traced to find out if it originates from the FMT.
Case 2: recommendations
Currently, ruxolitinib is the only FDA-approved drug for the treatment of SR aGvHD, while other modalities are also commonly used in this scenario (e.g., extracorporeal photopheresis). Thus, FMT could be recommended for patients with grade 2-4 steroid refractory or dependent aGVHD of the lower GI tract, albeit in the context of a clinical study only.108-110 Other treatment approaches could also be considered, such as adding it to steroids as part of the first-line therapy (clinicaltrials gov. Identifier: 04269850).
Although clinical trials are still ongoing, given the grave prognosis of SR aGvHD with more than 50% mortality,111 and the high rate of response to FMT, we recommend considering FMT as a therapeutic option in this setting.
Practical considerations for fecal microbiota transplantation treatment
As FMT has become the standard of care in recurrent and refractory CDI,112,113 more and more centers are gaining access to FMT programs through either establishing their own stool banks or acquiring FMT from universal stool banks.114,115
One of the limiting factors to wider application of stool banks and FMT programs is the lack or variance of regulatory standards. In different countries, FMT is regulated as a drug, tissue or a combined product composed of both human cells and non-human components (microbial DNA and metabolites). Stool banks are recommended to operate under the designated authority in each country. In the absence of local directives, the scientific committee should be responsible for establishing regulatory protocols.114
FMT donor screening should follow national regulations and international recommendations.114 Screening should include medical history related to the risk for transmitting infections, as well as medical conditions and treatments associated with perturbed microbiome (Table 3). Special considerations are to be applied when planning FMT use in allo-HSCT patients, such as testing the donor for Cytomegalovirus and Epstein-Barr virus IgG and IgM, and administering FMT from seronegative donors to seronegative patients. However, when weighing suitability of an FMT donor, one should be cognizant of the fact that no data are available to support the advantage of a particular donor (a family member, an unrelated donor, or pooled stool from several unrelated donors).
As for autologous FMT, it has not been tested in the setting of aGvHD treatment. Since the microbiota composition of a patient is already disrupted prior to HSCT, using such stool in FMT preparation to be applied for diversity restoration may not be effective. In order to circumvent this problem, in AML patients, we recommend freezing self-stool before the beginning of induction chemotherapy.
In CDI, both fresh and frozen FMT have been shown to be efficient116 as have been the two delivery routes − colonoscopy and oral capsules.117 While there are no data pointing to the superiority of either method of preparation or administration for aGvHD treatment, frozen samples from a stool bank allow FMT to be readily available for immediate use without the need to wait for donor screening and FMT collection.
The basic principles of FMT preparation include weighing the sample, suspension in sterile solution (saline), adding glycerol in case the FMT is planned for freezing and storing, homogenization, filtering and aliquoting the suspension for fresh use or freezing (Table 3). The FMT product should be registered and labeled.114
Based on the available data (Table 2) we suggest evaluating clinical response at 7-14 days after FMT administration. If no response or only partial response is achieved, we recommend administering a second dose of FMT. Whether in such cases the use of FMT from another donor could provide a superior outcome is yet to be determined. In general, in order to consider FMT as an efficacious therapeutic approach for SR GI aGvHD management, an overall response rate of around 60-70%, with a complete response rate of 30-50% should be a desired target, as these rates are achieved with the use of the approved ruxolitinib treatment and in non-randomized FMT studies.46,98-106,110
As for the antibiotic treatment peri-FMT, if feasible, 24-48 hours prior to FMT, systemic antibiotics should be stopped or replaced by one with less anti-anaerobic activity such as rifaximin for prophylaxis or cefepime for febrile neutropenic treatment.46,98,99
Microbiome sequencing of donor and patient samples could help interpreting clinical outcomes. It could also be valuable in distinguishing between the donor and the recipient as the source of post-FMT infection. However, currently there are no data suggesting that patient stool sequencing prior to FMT could guide its administration or affect the outcome. Therefore, given that the primary outcome should be the clinical response to treatment we recommend treating SR GI aGvHD patients with FMT even if the microbiome analysis is not available. Nonetheless, we do suggest storing stool samples from the donor and the patient (before and after FMT) for later sequencing if it becomes available.
Table 3. Practical aspects of fecal microbiota transplantation.
Further accumulation of data on FMT for SR GI aGvHD will allow wider and more efficient application of this treatment approach.
Open challenges and future directions
Disruption of the intestinal microbiome during allo- HSCT is a multifaceted process with a cause-and-effect relationship between multiple factors such as conditioning, diet and antibiotic treatment. Lately, FMT has emerged as an intervention that can facilitate microbiome recovery and potentially intervene with the above interplay (Figure 1). The intestinal microbial disruption before and during allo-HSCT is clearly associated with transplant-related outcomes, mainly acute GvHD and mortality, and pre-clinical data demonstrate the key role of the intestinal microbiota in protecting the gut from inflammatory damage and in regulating the innate immune system to maintain a more tolerant state.118 While the addition of beneficial bacteria or their metabolites has been shown to ameliorate acute GvHD in animal allo-HSCT models, many challenges remain concerning the role of the intestinal microbiota in allo-HSCT in humans. A substantial amount of basic research is being conducted aiming to better understand the place of microbiome changes in the pathogenesis of acute GvHD. In addition, a large population microbiome analysis is ongoing attempting to delineate the interplay between other factors, such as antibiotics and diet, and the microbiota disruption, and to determine the optimal strategy allowing to preserve the microbiota intact.119 However, while these issues are still under investigation, clinical trials evaluating the efficacy of FMT and other abovementioned interventions in the HSCT setting are underway (Table 2). Joint efforts to further explore biological, correlative and recovery functions of the intestinal microbiota could ultimately lead to decreased transplantrelated mortality, and even pave the way to personalized therapeutic strategies in HSCT.
Figure 1. The multifactorial interplay between environmental factors, intestinal microbiota and tissue damage affects transplant-related outcomes. During allogeneic hematopoietic stem cell transplantation (allo-HSCT), conditioning chemotherapy causes damage to the intestinal mucosa cells such as intestinal epithelial cells, intestinal stem cells, paneth cells and mucus producing goblet cells. Gut microbiota is already disrupted before allo-HSCT and due to prophylactic and systemic antibiotic therapy the microbiota disruption worsens with loss of butyrate producing bacteria and other beneficial commensals, along with increase in pathogenic bacteria such as Enterococcus. Depletion of bacterial metabolites postpones epithelial cell repair and restoration of the mucus barrier. Pathogenic bacteria can disseminate through the damaged mucosa and cause blood stream infections, which will necessitate the administration of systemic antibiotics further disrupting the intestinal microbiota. This vicious cycle is associated with graft-versus-host disease (GvHD), increased mortality and diminished overall survival. The question remains whether fecal microbiota transplantation (FMT) and other interventions such as prebiotics and the use of antibiotics with less anti-anaerobic activity could eventually break the cycle and improve outcomes. IEC:– intestinal epithelial cells; ISC: intestinal stem cells.
Supplementary Material
Disclosures and Contributions
Acknowledgements
The authors wish to thank Sonia Kamenetsky for her assistance in the preparation of this manuscript. | BUSULFAN, FLUDARABINE PHOSPHATE, LEVOFLOXACIN, MEROPENEM | DrugsGivenReaction | CC BY-NC | 33241674 | 19,317,760 | 2021-04-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | The clinical role of the gut microbiome and fecal microbiota transplantation in allogeneic stem cell transplantation.
Outcomes of allogeneic hematopoietic stem cell transplantation (allo- HSCT) have improved in the recent decade; however, infections and graft-versus-host disease remain two leading complications significantly contributing to early transplant-related mortality. In past years, the human intestinal microbial composition (microbiota) has been found to be associated with various disease states, including cancer, response to cancer immunotherapy and to modulate the gut innate and adaptive immune response. In the setting of allo-HSCT, the intestinal microbiota diversity and composition appear to have an impact on infection risk, mortality and overall survival. Microbial metabolites have been shown to contribute to the health and integrity of intestinal epithelial cells during inflammation, thus mitigating graft-versus-host disease in animal models. While the cause-andeffect relationship between the intestinal microbiota and transplant-associated complications has not yet been fully elucidated, the above findings have already resulted in the implementation of various interventions aiming to restore the intestinal microbiota diversity and composition. Among others, these interventions include the administration of fecal microbiota transplantation. The present review, based on published data, is intended to define the role of the latter approach in the setting of allo-HSCT.
Introduction
The past decades have witnessed important advances in the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT),1 mainly attributed to the reduction in non-relapse mortality.2 Yet, the need for further improvement is compelling. Acute graft-versus-host disease (aGvHD) and infections are two of the main causes of early transplant-related mortality (TRM), jointly accounting for 36% and 43% of deaths by day 100 in matched related and matched unrelated transplants, respectively.1
One of the emerging and extensively explored allo-HSCT-associated issues is the change in the gut microbial flora, as well as its effect on the pathogenesis of transplant- related complications and association with transplant outcomes.
The human body hosts a hundred trillion microbial organisms; the majority of them are bacteria, predominantly colonizing the gut, with the lower intestine being most densely colonized (1011-1012 organisms/g of intestinal content).3 The composition of bacteria in the gut is referred to as the intestinal microbiota and their collective genome is termed the “intestinal microbiome”.3 The two main phyla constituting more than 90% of the gut microbiota are the Firmicutes and Bacteroidetes and among less dominant phyla are Proteobacteria, Actinobacteria, and Verrucomicrobia.4 This composition is relatively flexible and can rapidly change in response to different environmental factors, adjusting the metabolic and immunologic performance accordingly.5 Intestinal microbiota has been recently found to have a significant impact on both health and disease states. It appears to be crucial for the maturation and education of the immune system and has a role in intestinal cell proliferation, intestine vascularization and endocrine functions. Moreover, it produces energy, synthesizes vitamins, metabolizes bile acids and even inactivates drugs.6-13 The microbiome has been reported to be associated with a variety of disorders such as obesity, type 2 diabetes, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis.14-17 This association is also suggested to be true for cancer18 and response to cancer immunotherapy.19 The gut microbiota has a close and reciprocal relationship with the host immune system. Intestinal epithelial cells, goblet and paneth cells produce the luminal protective mucosal layer and antimicrobial peptides, allowing the transcellular transport of immunoglobulin A (IgA) antibodies. These functions regulate luminal microbial colonization.20
Homeostasis of the immune response in the gut mucosa is maintained by the balance between pro-inflammatory cells, which include T-helper 1 (Th1) cells producing interferon γ (IFNγ), Th17 cells producing IL-17A and IL-22, diverse innate lymphoid cells with cytokine effector features resembling those of Th2 and Th17 cells, the antiinflammatory Foxp3+ regulatory T-cells (Tregs) and IgAsecreting B-cells. This homeostasis can be modulated by the gut microbiota.21-23 In pre-clinical studies, intestinal microbiota has been shown to regulate the expression of pro-inflammatory cytokines, human leukocyte antigen (HLA) type I and type II molecules and increase T-cell proliferation. 18 Effects of the microbiota on cytokine expression and immune cell subsets are not limited to the gut, and are extended to regional mesenteric and systemic lymph nodes.24 Furthermore, while some bacterial strains can induce pro-inflammatory intestinal Th17 cells,25 others induce anti-inflammatory Tregs26,27 and can thus ameliorate inflammatory colitis.28 Moreover, human host gut microbiota has been shown to correlate with expression pattern of the cytokines secreted from peripheral blood mononuclear cells isolated from the host.29 Microbial metabolites such as the short chain fatty acid (SCFA) butyrate or indole derivatives produced by tryptophan metabolism act to maintain the intestinal epithelial cell health, mucosal barrier, and to promote anti-inflammatory responses.30,31
Currently available molecular techniques allowing rapid and wide genomic sequencing enable extensive exploration of the microbiome. The most commonly used method is the 16S ribosomal RNA sequencing by PCR. Bioinformatics analysis tools assign the sequences to microbial taxon at different taxonomic levels. Other methods include shotgun next-generation metagenomics sequencing enabling massive and deeper genomic sequencing and allowing better identification of taxonomic species and potential functional pathways of the organisms, metatranscriptomics using high throughput RNA sequencing to profile gene expression, metaproteomics capable to provide large-scale characterization of the entire proteins in the environmental sample and metabolomics, identifying and quantifying all metabolites in the tested samples.32,33 The two main microbiome features that have been widely characterized in health and disease are its diversity and the abundance of specific bacteria or bacterial subgroups.34
The revelation of significant relationship between the microbiome, the immune system and disease has led to interventional studies aiming to normalize the microbiome composition and diversity thus ameliorating disease conditions. One of such interventions is the use of fecal microbiota transplantation (FMT), the term referring to the transfer of the fecal microbial content from a healthy individual into the intestine of a diseased individual. FMT, the standard of care for refractory or recurrent Clostridium difficile infection (CDI), proved to be highly effective in this condition. At the same time, mixed results were demonstrated in the studies evaluating the use of FMT for the management of inflammatory bowel disease, irritable bowel syndrome and hepatic encephalopathy. To date, FMT application for indications other than CDI has been limited to the experimental setting only.35,36
The setting of allo-HSCT imposes a significant disruption on the gut microbiome homeostasis through a variety of mechanisms (all part of the transplantation procedure), such as the use of broad-spectrum antibiotics, dietary changes (restriction), gut epithelial damage by conditioning regimens and introduction of a donor immune system.
Data from clinical studies support the association of alterations in the gut microbiome profile, mainly loss of diversity and change in composition during allo-HSCT, with patient outcomes such as aGvHD, GvHD-related mortality, non-relapse mortality (NRM) and overall survival (OS).37-40 Moreover, the gut microbial composition is reported to have an impact on infection risk, including CDI and blood stream infections (BSI), in this clinical setting. 38,41 Findings of these associations have led to a preponderance of research in this field,42 and although the causeand- effect relationship between the microbiome and transplant complications has not been unequivocally established, many ongoing clinical trials are implementing various interventions aiming to maintain microbiome diversity, thus potentially preventing transplant-related complications and treating aGvHD. These interventions include the use of probiotics,43 prebiotics,44 change in antibiotic prophylaxis45 and administration of FMT.46 This review appraises the currently available evidence on the association of gut microbiota and allo-HSCT and analyzes a potential role of FMT in allo-HSCT, by presenting two illustrative clinical cases, where effects on the gut microbiota composition could be employed either as a prophylactic or therapeutic measure.
Case 1
A 54-year old male, with mutated FLT3-ITD acute myeloid leukemia (AML) in complete remission (CR) after induction and re-induction chemotherapies, during which he acquired gut colonization with carbapenemresistant Klebsiella pneumoniae. He underwent an allo- HSCT from a mismatched 9/10 unrelated female donor with myeloablative conditioning (busulfan, fludarabine) and received levofloxacin for infection prophylaxis. During the transplantation period, he had a BSI event with extended spectrum β lactamase Escherichia coli (E. coli) treated with meropenem for 10 days, followed by a CDI event treated with oral vancomycin. His neutrophils engrafted on day +15 and on day +33 he developed diarrhea and was diagnosed with grade 3 acute lower gastrointestinal (GI) GvHD that was steroid refractory.
This case raises a number of important questions related to the role of gut flora in allo-HSCT.
Is the microbiome already disrupted prior to allogeneic hematopoietic stem cell transplantation conditioning?
There is ample evidence suggesting that the pre-transplant patient microbiome is already disrupted. The insult to the microbiome starts with preceding chemotherapy and antibiotic exposure. Galloway-Pena et al.47 analyzed 487 stool samples from 30 AML patients and found that their pre-induction microbiome diversity was not significantly different from that of healthy volunteers participating in the Human Microbiome Project (HMP). However, following neutrophil recovery, patient microbiome composition changed, with a significant decrease in diversity. Importantly, this reduction in diversity was associated with an increased risk of infections. The use of carbapenem antibiotics for more than 3 days during induction elevated the risk for a subsequent loss of diversity.47Moreover, exposure to anti-anaerobic antibiotics, like piperacillin-tazobactam, ticarcillin, meropenem, clindamycin and metronidazole, within the 3 months preceding allo-HSCT was associated with a significant decrease in pre-transplant microbiome diversity.38 With more courses of intensive chemotherapy, such as re-induction or salvage, the microbiome disruption was shown to enhance, leading to ecosystem instability and outgrowth of pathogenic bacteria like Enterococcus.48 This disruption in patient microbiome continued up to the time of allo-HSCT, as shown in the largest to date inter-center effort, where 8,767 sequential stool samples were collected from 1,362 patients prior to and throughout the transplantation period and analyzed using 16S ribosomal RNA sequencing. The pre-transplant microbiome of patients obtained on days -30 to -6 (n=606), was compared to that of healthy volunteers (n=246), demonstrating a significant reduction in diversity in patient microbiome.37 Additionally, evidence from another recently published study showed that the pre-transplant microbiome and the one derived from healthy controls differed in composition, displaying decreased abundance of beneficial bacteria of genera Bifidobacterium and butyrate producing genera such as Faecalibacterium and Lachnospiraceae in the former case.49 To conclude, pre-transplant microbiome disruption is clearly evident.
What is the microbiome status during the transplantation period and at time of recovery?
Data from several studies demonstrate that during the transplantation course, the microbiome diversity significantly decreases and its composition changes.37,50 The lower-diversity microbiome is reported to be characterized by abundance of pathogenic bacteria such as Enterococcus, Klebsiella, Escherichia, Staphylococcus and Streptococcus. The single taxonomic unit domination (abundance ≥30%) peaks at 1 week post-transplant, which is followed by a subsequent moderate decrease. The most common dominating taxonomic groups belong to the genera Enterococcus and Streptococcus.37 Along the same lines, other studies have found the Enterococcus genus to be more prolific during the first month posttransplant, with significantly higher abundance in patients with active or subsequent aGvHD.51,52 Following allo-HSCT, the microbiome recovery appears to be prolonged and incomplete. In a large cohort of patients (n=753), the post-transplant recovery of the gut microbiota has been reported to start around day +50, but even by day +100 the composition and bacterial abundance observed pre-transplant have not been fully achieved.53 Moreover, in some patients, microbiota has remained disrupted even 1 year after HSCT, this being particularly the case with butyrate-producing bacteria and Bifidobacterium.54 Eventually, the effect of environmental insult on the intestinal microbiota during allo-HSCT can be so severe that its recovery may require a long time.
Is the disrupted microbiome in allogeneic hematopoietic stem cell transplantation recipients clinically significant?
In the above-mentioned study by Peled et al., reduced microbiome diversity both pre-transplant (days -30 to -6) and peri-engraftment (days +7 to 21), was shown to be significantly associated with lower 2-year OS, while a persistent decrease of this parameter in the latter period was also associated with higher 2-year treatment-related mortality (TRM). Moreover, lower peri-engraftment microbiome diversity in T-cell replete allo-HSCT corresponded to increased GvHD-related mortality, which was not observed in T-cell depleted transplantations. This difference suggests a connection between the microbiota and T-cell alloreactivity.37 Liu et al. revealed a similar association of pre-transplant diversity with mortality as well as a correlation between post-transplant microbiome disruption and acute GI GvHD risk.55 Furthermore, in a study of 66 patients whose stool specimens were analyzed weekly during the transplantation period up to day +100, Golob et al. found a trend of association between near-engraftment low microbiome diversity and the risk for grade 3-4 aGvHD.56 Likewise, Mancini et al. evaluating a cohort of 100 patients, observed a significant connection between low microbiome diversity by day +10 and an increased risk for early (within 30 days) aGvHD.38
A number of studies also reported an impact of pre- or post-transplant bacterial abundance on patient outcomes (Table 1). Results of a two-cohort study (a total of 115 adult patients) conducted at the Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated that increased abundance of the genus Blautia, including anaerobic commensal bacteria, observed 12 days post-transplant, was associated with reduced GvHD-related mortality and improved OS. At the same time, the use of antibiotics with anti-anaerobic activity and total parenteral nutrition (TPN) correlated with loss of Blautia.57 In the pediatric setting, Biagi et al. reported an association of pre-transplant high abundance of Blautia and low abundance of Fusobacterium with diminished risk for grade 2-4 acute GI GvHD.58 Additionally, pre-transplant Enterobacteriaceae abundance of >5% was associated with an increased risk of BSI and Lachnospiraceae abundance of ≤10% appeared to correspond to increased mortality.38 In a large study from the MSKCC, very high abundance of a bacterial group, mainly composed of Eubacterium limosum, in pretransplant samples or the presence of this group in periengraftment samples was found to correspond to a decreased relapse risk,59 once again emphasizing the association of the microbiome and T-cell immunity. Furthermore, in the study from the Osaka University,54 Enterococcus relative abundance of ≥1% at 1 month posttransplant appeared to be indicative of poor OS, with a 2- year survival of 83.9% for patients with relative abundance of Enterococcus <1% versus 47.6% for those in whom this parameter was ≥1%. It is noteworthy that none of the surviving patients at 1 year post-transplant displayed Enterococcus abundance higher than 1%, suggesting that this cutoff could serve as a prognosticator of a long-term outcome in this clinical setting.54 The above evidence suggests that the microbiota changes before and during allo-HSCT are significantly associated with transplant complications and outcomes and might even serve as a predictive marker in this setting.
Table 1. Intestine microbial changes in diversity and abundance during pre-transplant and peri-engraftment periods, associated with outcomes of allogeneic hematopoietic stem cell transplantation
Can prophylactic fecal microbiota transplantation reduce the risk of infections during allogeneic hematopoietic stem cell transplantation?
In allo-HSCT recipients, curtailment of infection risk is crucial for reducing TRM, particularly due to increased frequency of BSI with multidrug resistant (MDR) bacteria. MDR colonization is established to range between 16% for gram-negative bacteria and 39% for vancomycin- resistant Enterococcus (VRE). While BSI have been reported in 16-41% of patients colonized with MDR bacteria, findings regarding a possible association of such colonization with TRM or infection-related mortality are inconclusive.60-62 In addition, MDR gram-negative colonization has neither been found to correspond to an increased risk for sepsis.38,63 In the lack of clear evidence, proof-of-concept studies are becoming of increasing importance. Battipaglia et al.64 have evaluated four patients colonized with MDR bacteria who had received FMT on days -46 to -9 before transplant with an aim to limit the risk for infectious complications during HSCT. All the four patients responded with decolonization of the MDR bacteria. One patient developed grade 3 acute gut GvHD on day +30 after transplant (day +51 after FMT) and two others developed bacteremia with sensitive bacteria. Notably, despite receiving broad-spectrum antibiotics during the transplantation period, none of the patients had recolonization of the gut with MDR bacteria. 64 Similar results were reported in a 63-year old HSCT recipient.65
The ongoing ODYSSEE trial (clinicaltrials gov. Identifier: 02928523) is aimed at reducing complications that may arise as a result of a loss of microbiota diversity, including infectious complications, poor nutritional status, prolonged hospitalization, as well as therapy discontinuation due to induction treatment-related toxicity in AML patients. Twenty newly diagnosed patients collected pre-induction autologous stools. This autologous FMT was later administered as enema after neutrophil recovery and prior to consolidation chemotherapy. Preliminary results demonstrated safety of this approach, with evidence of stool diversity restoration 10 days after FMT and reduction in antibiotic resistant gene copy count by 43%. Yet, clinical efficacy of this method still needs to be confirmed. 66
An important pathogen to consider for intervention with FMT is Clostridium difficile. The incidence of CDI during allo-HSCT varies between 13% and 30%, mostly in the first month after transplant.67-69 The disease is usually of mild-to-moderate severity, with good response to treatment; there is no association with TRM, and its possible correlation to subsequent acute GI GvHD is indefinite. 68-70 Given these facts, and the paucity of data on potential efficacy of prophylactic FMT in reducing the risk of CDI among Clostridium difficile carriers, FMT prophylaxis may not be required for this indication.
As for the treatment of recurrent CDI, results of three small studies demonstrate safety of FMT administration to a total of 16 patients with recurrent CDI after allo- HSCT, with only three patients recurring after the procedure. 71-73
Currently available data are insufficient to definitively conclude that prophylactic FMT will reduce the infection rate in the allo-HSCT setting.
Can prophylactic fecal microbiota transplantation reduce the risk of acute graft-versus-host disease or transplant-related mortality?
The incidence of clinically significant aGvHD ranges between 22% in allo-HSCT from a matched related donor to 29% in case of a mismatched unrelated donor, with grade 3-4 disease incidence being 8.6% and 12%, respectively.24 Whether any intervention that restores the microbiome composition could also decrease aGvHD rates is yet to be revealed. Hitherto, only two small studies have reported results of using prophylactic FMT in the post-engraftment period. In the study by Defillip et al.,25 aiming to evaluate safety and feasibility of early restoration of the gut microbiome, frozen capsules of FMT derived from unrelated donors were administered to 13 allo-HSCT recipients 4 weeks after neutrophil engraftment. No FMT-related bacteremia events occurred and two cases of acute GI GvHD were registered. Analysis of stool composition indicated improvement in intestinal microbiome diversity after FMT that was mainly attributed to operational taxonomic units (OTU) originating from the FMT donor.25 In the study by Taur et al.,53 within 3-28 days of engraftment, patients not receiving broadspectrum antibiotics, not critically ill and with low abundance of Bacteroides (<0.1% of the total 16S sequencing) at that time period, were randomized to either receive autologous FMT (n=14) or to a control group (n=11).
Solely the FMT group was found to reconstitute their microbiome diversity and composition to the pre-transplant state. Of note, the use of autologous FMT raises concern for disrupted microbiota due to prior antibiotic exposure.53
These data suggest feasibility and safety of prophylactic FMT; however, its clinical benefit has not been demonstrated yet.
Should additional interventions along with fecal microbiota transplantation aiming to attenuate mircobiome disruption be considered?
Given that a variety of factors could affect the microbiome diversity and composition during the transplantation course, their adequate control might potentially preclude such microbiome changes. The question remains whether FMT alone is sufficient enough or it should be combined with other interventions to provide the required control.
Transplant conditioning
Conditioning chemotherapy itself has a disruptive effect on the microbiome, as found by Montassier et al.26 who evaluated eight lymphoma patients undergoing autologous HSCT with the BEAM (carmustine, etoposide, cytarabine arabine, melphalan) protocol. Since none of the patients received nasogastric tube nutrition, total parenteral nutrition, ciprofloxacin prophylaxis or systemic antibiotic treatment, only the chemotherapy effect on the microbiome was measured. Compared to pretransplant samples, those drawn at 1 week post-conditioning demonstrated significantly reduced diversity, decreased abundance of Firmicutes and Actinobacteria and increased presence in bacteroides and proteobacteria, indicating chemotherapy-induced disruption of the intestinal microbiota.26 Of note, this disruptive effect might be related to etoposide, which has bacterial inhibitory activity. 27,28 Remarkably, the post-transplant decrease in microbiome diversity appeared to be more profound when more intensive conditioning was applied.74 However, reducing the conditioning intensity was not shown to consistently decrease the rate of aGvHD.75 Moreover, it might increase the relapse rate and decrease long-term OS.76,77 Therefore, changing the conditioning regimen in an attempt to attenuate the insult on the microbiome is not currently recommended.
Diet
Dietary interventions such as TPN, prebiotics and probiotics could potentially influence the microbiome composition before or during the transplantation course. TPN administration was reported to be associated with decreased recovery of post-transplant (up to day +120) diversity compared to enteral nutrition. In addition, SCFA levels in the gut content were found to be lower in the TPN group.78 Iyama et al. retrospectively compared a group of patients whose diet was supplemented with prebiotics, i.e., glutamine, fiber and oligosaccharides (GFO) with a group that did not receive such supplementation. GFO was started 7 days before conditioning and continued up to day +28. In the GFO group, duration of diarrhea, mucositis and TPN requirement was shorter and the weight loss was also less prominent.44 An ongoing prospective trial (clinicaltrials gov. Identifier: 02763033) is evaluating the efficacy of resistant potato starch supplementation between day -7 and day +100 in HSCT recipients. This starch is a non-absorbable carbohydrate that is metabolized by the anaerobic commensal bacteria to produce the SCFA butyrate,79 shown to reduce the severity of acute GI GvHD in an experimental model.31 Preliminary results demonstrate the feasibility of this approach in terms of patient compliance, increase in intestinal butyrate levels and abundance of butyrate producing bacteria. 80 As for probiotic supplementation, the available data do not suggest its influence on the microbiome composition or clinical outcomes. It is worth mentioning that the products used in the studies contained only one bacterial strain and not a diversity of bacteria,43,81 and safety of probiotic administration is of concern in immunocompromised patients.82
The loss of diversity during the transplantation course is accompanied with microbiome domination by single taxonomic units such as Enterococcus.37 This enterococcal expansion has been found to be most prominent in patients developing acute GI GvHD.52 Stein-Thoeringer et al. have shown in a gnotobiotic mouse model of allo- HSCT that enterococcal expansion in the gut depends on lactose and its depletion decreases the enterococcal abundance and thus attenuates GvHD severity. Furthermore, in patients with a lactose malabsorption genotype, Enterococcus abundance appears to be higher than in patients without this genotype.83 This finding may give rise to a new approach to dietary intervention during HSCT. Interestingly, in the study by Khandelwal et al., where pediatric allo-HSCT patients under the age of 5 were treated with ready to eat human milk and breast feeding (n=24) or formula (n=14), plasma levels of IL6, IL10, and Reg3α were significantly lower in the group receiving human milk. The microbiome composition also differed between the two groups, with an increase in pathogenic species such as E. coli in the formula-receiving group. Despite the fact that human milk oligosaccharides are metabolized to SCFA by the commensal bacteria, butyrate levels in the stool were similar in both groups. Moreover, no significant difference in the rate of grade 2-4 acute GI GvHD between the groups was revealed. However, the limited size of this study calls for cautious interpretation of these encouraging results.84 Overall, dietary interventions emerge as a promising way to shape the intestinal microbiota during allo-HSCT. However, results are too preliminary and more research is required before implementing any of these methods.
Antibiotic treatment
The antibiotic treatment applied during the transplantation course is the main factor affecting the microbiome. Quinolone prophylaxis during afebrile neutropenia and systemic broad-spectrum antibiotic treatment with piperacillin-tazobactam or meropenem are widely accepted. 85-87 However, data demonstrate that the use of other antibiotics can better preserve gut beneficial commensals and is associated with improved outcomes.
The study from the University of Regensburg in Germany employed the non-absorbable antibiotic rifaximin and compared it to ciprofloxacin and metronidazole used in a historic cohort of patients for infection prophylaxis during allo-HSCT.45 Antibiotics were given from day -8 up to engraftment. The urine 3-indoxyl sulfate (3-IS) level was measured as a marker of microbiome diversity.88 In the rifaximin cohort, the pre-engraftment 3-IS levels were significantly higher without an increase in the sepsis rate or colonization with pathogenic bacteria. This group had significantly lower TRM, prolonged OS and the acute GI GvHD rate tended to be lower in these patients. The observed advantage remained evident even in patients who later received systemic antibiotics for neutropenic fever. 45
Given the major role of microbiome diversity preservation during allo-HSCT and an association of impaired diversity with acute GI GvHD and adverse patient outcome, Weber et al. further compared the effects of various prophylactic and systemic antibiotics in an attempt to identify the ones that could spare commensal bacteria.89 At 10 days post-transplant, the patient groups receiving rifaximin without systemic antibiotics or rifaximin with systemic antibiotics maintained their microbiome diversity and Clostridia abundance and had higher 3-IS levels compared to patients treated with ciprofloxacin/metronidazole ± systemic antibiotics. These results suggest that rifaximin could better preserve microbiome diversity even when systemic broad-spectrum antibiotics are administered during transplantation. Moreover, in the study conducted in two Canadian hospitals and assessing the effect of antibiotic prophylaxis or treatment given before day 0 on frequency of aGvHD and mortality, the authors compared the outcome of a cohort of patients exposed to antibiotics (n=239) to those who did not receive this therapy (n=261).90 The antibiotic-receiving group demonstrated a significantly higher incidence of grade 2-4 aGvHD and significantly shorter OS at 1, 2 and 10 years posttransplant, indicating an association between the deleterious effect of such treatment on intestinal bacteria and inferior patient outcome.
Importantly, early start of systemic antibiotics (before engraftment) was found to be associated with a lower 3- IS urine level and decreased Clostridia abundance in the stool. Furthermore, the TRM rate in such cases was higher than in patients who did not require systemic antibiotics during HSCT or started them after engraftment.91
Similarly, systemic treatment with piperacillin-tazobactam and meropenem was reported to correlate with decreased microbiome diversity during the transplantation37 and significant loss of commensal anaerobic bacteria. 92 In pediatric patients, Simms-Waldrip et al.93 found that higher load of anti-anaerobic antibiotics was associated with a significant decrease in anti-inflammatory Clostridia (AIC) abundance, and in patients with aGvHD the abundance decrease was severe (10-log fold) compared to patients without GvHD. In a mouse allo-HSCT model, clindamycin administration was associated with AIC decrease and more severe GvHD, while re-administration of AIC increased its levels in the gut and improved survival.93 Additionally, Lee et al.94 compared patients who did not require any systemic antibiotic treatment during the transplantation course with those who received cefepime and those who were treated with carbapenem antibiotics. The carbapenem group displayed a significant loss of microbial diversity at engraftment and an increased rate of acute GI GvHD (32.1%) compared to the noantibiotics group (11.6%). Interestingly, the cefepime group retained a diverse microbiome, demonstrating only a trend to a higher GI GvHD rate (26.4%).
Furthermore, a large multicenter study retrospectively evaluating 857 patients revealed that the use of piperacillin-tazobactam and imipenem-cilastatin was associated with increased 5-year GvHD-related mortality, 95 while this was not observed in patients receiving cefepime and aztreonam. The former antibiotics caused a significant decrease in abundance of Bacteroidetes and Lactobacillus compared to the latter ones. These results suggest that some antibiotics may be more beneficial than others in the setting of allo-HSCT, and that this beneficial effect is related to the antibiotic ability to be less detrimental to intestinal commensal bacteria.95 Findings in the pediatric setting were consistent with these data, and exposure to anti-anaerobic antibiotics was reported to result in a significant decrease in butyrate-producing bacteria and the butyrate level in luminal content by day +14. Pediatric patients who later developed aGvHD had a significantly lower butyrate level at that time point than patients without GvHD.96
It was also demonstrated that specific antibiotic use during allo-HSCT could change the abundance of specific taxa which was associated with BSI risk. In a cohort of 94 patients, Taur Y et al.50 found that domination of the gut microbiome (abundance ≥30%) by single bacterial taxa Enterococcus and Streptococcus occurred at the peri-engraftment period (days +10 to +20) in two thirds of the patients. However, treatment with metronidazole increased the risk for enterococcal domination by 3-fold, and this domination elevated the risk for VRE bacteremia by 9-fold. Altogether, these data establish an essential role of antibiotics in disrupting or preserving the intestinal microbiota during allo-HSCT.
Case 1: conclusions
Several issues should be considered in decision-making regarding the appropriate management of this case. This patient has pre-transplant intestinal microbiota disruption and assumed colonization by MDR bacteria and probably by Clostridium difficile. His risk for aGvHD is high, since he has undergone allo-HSCT from a mismatched unrelated donor. Quinolone prophylaxis and meropenem treatment for BSI have further disrupted his intestinal microbiota. The existence of pre-transplant microbiota disruption, mainly attributed to the use of broad-spectrum antibiotics during intensive chemotherapy, is associated with increased TRM, shorter OS and GvHD-related mortality. Pre-transplant FMT can potentially enrich the microbiome diversity and eradicate MDR bacteria or Clostridium difficile; however, without controlling such factors as antibiotic prophylaxis and the type of systemic antibiotic therapy employed, the intervention by FMT may not completely achieve its goals.
Table 2. Clinical trials of fecal microbiota transplant in allogeneic hematopoietic stem cell transplantation.
So far, no data are available regarding a clinical benefit of prophylactic pre-transplant FMT.
While an association between peri-engraftment microbiome low diversity and patient outcome is established, implying potential feasibility of FMT use at that stage, data regarding FMT application before engraftment are not available, and for safety reasons this approach will probably not be attempted. Results of several small-scale studies suggest safety and feasibility of post-engraftment FMT in restoring microbiome diversity (Table 2); however, it remains unknown if this strategy could decrease the risk for aGvHD-related mortality and TRM.
As for dietary interventions at this period, their efficacy is still under investigation. Choosing a different antibiotic prophylaxis, such as rifaximin and systemic antibiotics such as cefepime, looks promising. Nevertheless, new strategies need to be tested to prove their non-inferiority in OS85 and to establish less disruption for the microbiome (clinicaltrials gov. Identifier: 03078010), especially since fourth-generation cephalosporins have been found in one study to be associated with an increased risk for aGvHD.97
Case 1: recommendations
In this case, based on the currently available data, we do not recommend prophylactic administration of pretransplant or post-engraftment FMT.
Case 2
A 25-year old female with intermediate-risk AML in CR underwent an allo-HSCT with BuCy myeloablative conditioning from her matched sibling. Her neutrophils engrafted by day +14. On day +34 she developed grade 3 aGvHD of the lower GI tract which was steroid refractory (SR). She did not respond to the addition of budesonide, extracorporeal photopheresis (ECP), mofetil mycophenolate or infliximab.
Can fecal microbiota transplantation mitigate prevailing acute gastrointestinal graft-versushost disease?
The current data regarding the use of FMT for the treatment of acute GI GvHD are limited to case reports and small case series (Table 2). A total of 58 described patients were treated with FMT for SR GI grade 2-4 aGvHD. The FMT source was an unrelated donor in 36 cases, a related donor – in six cases and in eight cases a commercial pooled highly diverse FMT was used. FMT was processed and either given fresh within a few hours of collection or it was frozen and later thawed before administration. FMT was administered orally as packed capsules, through a nasogastric/ nasoduodenal tube or an enema. Of 58 patients, 28 received FMT after two or more therapy lines, while 19 received it as second-line therapy right after steroid failure. Response was observed in 74% (43 of 58) of patients, with complete response in 57% (33 of 58) and partial response in 17% (10 of 58). Complete response was observed in 73% of patients receiving FMT as second-line therapy. Ten of the responding patients relapsed and 29 patients were alive at the last follow-up (54%; 29 of 54 patients with available data).
Response to treatment was seen within a median of 14 days (range: 3-28), with a median of two FMT (range: 1-7), and a median of 7 days between treatments (range: 2-60).46,98-106
Infectious complications occurred in 11 patients. Two had sepsis with bacteria not originating from FMT,102 and one patient developed diarrhea due to Norovirus that was traced to FMT.106 Other infections were attributed to the severe immunocompromised state of patients. However, a possible association with FMT could not be ruled out. In responding patients in whom the stool microbiome was sequenced post-FMT, it was found to be significantly more diverse and enriched with Bacteroides, Lactobacillus, Bifidobacterium and Faecalibacterium compared to pre-FMT microbiome.46,98-101 Notably, the diversity increased only upon discontinuation of anti-anaerobic systemic antibiotic treatment, such as piperacillin-tazobactam. However, continuous use or re-initiating treatment with cefepime did not reduce FMT efficiency.46,98,99
These results are highly encouraging and support FMT therapy to be relatively safe and effective in SR GI aGvHD.
Case 2: conclusions
Available data suggest a potentially beneficial effect of FMT in acute lower GI GvHD. It should probably be used earlier rather than later, so that patients' response will not be overcome by infectious complications related to extensive immunosuppressive therapy. Discontinuation of antibiotic treatment prior to FMT administration appears to be an important factor contributing to successful response. If antibiotic treatment is required, using cefepime may allow attenuating microbiome insult while maintaining clinical response.
Current information is based on case reports and small series with a wide variability in patient selection, FMT preparation and mode of administration. However, the reported feasibility, safety and clinical benefit appear to be similar across the studies, implying that intestinal microbiota can be recovered with FMT, irrespective of its administration method. Safety remains a concern,107 especially in advanced GI aGvHD, and if an infectious complication occurs post-FMT, the pathogen should be sequenced and traced to find out if it originates from the FMT.
Case 2: recommendations
Currently, ruxolitinib is the only FDA-approved drug for the treatment of SR aGvHD, while other modalities are also commonly used in this scenario (e.g., extracorporeal photopheresis). Thus, FMT could be recommended for patients with grade 2-4 steroid refractory or dependent aGVHD of the lower GI tract, albeit in the context of a clinical study only.108-110 Other treatment approaches could also be considered, such as adding it to steroids as part of the first-line therapy (clinicaltrials gov. Identifier: 04269850).
Although clinical trials are still ongoing, given the grave prognosis of SR aGvHD with more than 50% mortality,111 and the high rate of response to FMT, we recommend considering FMT as a therapeutic option in this setting.
Practical considerations for fecal microbiota transplantation treatment
As FMT has become the standard of care in recurrent and refractory CDI,112,113 more and more centers are gaining access to FMT programs through either establishing their own stool banks or acquiring FMT from universal stool banks.114,115
One of the limiting factors to wider application of stool banks and FMT programs is the lack or variance of regulatory standards. In different countries, FMT is regulated as a drug, tissue or a combined product composed of both human cells and non-human components (microbial DNA and metabolites). Stool banks are recommended to operate under the designated authority in each country. In the absence of local directives, the scientific committee should be responsible for establishing regulatory protocols.114
FMT donor screening should follow national regulations and international recommendations.114 Screening should include medical history related to the risk for transmitting infections, as well as medical conditions and treatments associated with perturbed microbiome (Table 3). Special considerations are to be applied when planning FMT use in allo-HSCT patients, such as testing the donor for Cytomegalovirus and Epstein-Barr virus IgG and IgM, and administering FMT from seronegative donors to seronegative patients. However, when weighing suitability of an FMT donor, one should be cognizant of the fact that no data are available to support the advantage of a particular donor (a family member, an unrelated donor, or pooled stool from several unrelated donors).
As for autologous FMT, it has not been tested in the setting of aGvHD treatment. Since the microbiota composition of a patient is already disrupted prior to HSCT, using such stool in FMT preparation to be applied for diversity restoration may not be effective. In order to circumvent this problem, in AML patients, we recommend freezing self-stool before the beginning of induction chemotherapy.
In CDI, both fresh and frozen FMT have been shown to be efficient116 as have been the two delivery routes − colonoscopy and oral capsules.117 While there are no data pointing to the superiority of either method of preparation or administration for aGvHD treatment, frozen samples from a stool bank allow FMT to be readily available for immediate use without the need to wait for donor screening and FMT collection.
The basic principles of FMT preparation include weighing the sample, suspension in sterile solution (saline), adding glycerol in case the FMT is planned for freezing and storing, homogenization, filtering and aliquoting the suspension for fresh use or freezing (Table 3). The FMT product should be registered and labeled.114
Based on the available data (Table 2) we suggest evaluating clinical response at 7-14 days after FMT administration. If no response or only partial response is achieved, we recommend administering a second dose of FMT. Whether in such cases the use of FMT from another donor could provide a superior outcome is yet to be determined. In general, in order to consider FMT as an efficacious therapeutic approach for SR GI aGvHD management, an overall response rate of around 60-70%, with a complete response rate of 30-50% should be a desired target, as these rates are achieved with the use of the approved ruxolitinib treatment and in non-randomized FMT studies.46,98-106,110
As for the antibiotic treatment peri-FMT, if feasible, 24-48 hours prior to FMT, systemic antibiotics should be stopped or replaced by one with less anti-anaerobic activity such as rifaximin for prophylaxis or cefepime for febrile neutropenic treatment.46,98,99
Microbiome sequencing of donor and patient samples could help interpreting clinical outcomes. It could also be valuable in distinguishing between the donor and the recipient as the source of post-FMT infection. However, currently there are no data suggesting that patient stool sequencing prior to FMT could guide its administration or affect the outcome. Therefore, given that the primary outcome should be the clinical response to treatment we recommend treating SR GI aGvHD patients with FMT even if the microbiome analysis is not available. Nonetheless, we do suggest storing stool samples from the donor and the patient (before and after FMT) for later sequencing if it becomes available.
Table 3. Practical aspects of fecal microbiota transplantation.
Further accumulation of data on FMT for SR GI aGvHD will allow wider and more efficient application of this treatment approach.
Open challenges and future directions
Disruption of the intestinal microbiome during allo- HSCT is a multifaceted process with a cause-and-effect relationship between multiple factors such as conditioning, diet and antibiotic treatment. Lately, FMT has emerged as an intervention that can facilitate microbiome recovery and potentially intervene with the above interplay (Figure 1). The intestinal microbial disruption before and during allo-HSCT is clearly associated with transplant-related outcomes, mainly acute GvHD and mortality, and pre-clinical data demonstrate the key role of the intestinal microbiota in protecting the gut from inflammatory damage and in regulating the innate immune system to maintain a more tolerant state.118 While the addition of beneficial bacteria or their metabolites has been shown to ameliorate acute GvHD in animal allo-HSCT models, many challenges remain concerning the role of the intestinal microbiota in allo-HSCT in humans. A substantial amount of basic research is being conducted aiming to better understand the place of microbiome changes in the pathogenesis of acute GvHD. In addition, a large population microbiome analysis is ongoing attempting to delineate the interplay between other factors, such as antibiotics and diet, and the microbiota disruption, and to determine the optimal strategy allowing to preserve the microbiota intact.119 However, while these issues are still under investigation, clinical trials evaluating the efficacy of FMT and other abovementioned interventions in the HSCT setting are underway (Table 2). Joint efforts to further explore biological, correlative and recovery functions of the intestinal microbiota could ultimately lead to decreased transplantrelated mortality, and even pave the way to personalized therapeutic strategies in HSCT.
Figure 1. The multifactorial interplay between environmental factors, intestinal microbiota and tissue damage affects transplant-related outcomes. During allogeneic hematopoietic stem cell transplantation (allo-HSCT), conditioning chemotherapy causes damage to the intestinal mucosa cells such as intestinal epithelial cells, intestinal stem cells, paneth cells and mucus producing goblet cells. Gut microbiota is already disrupted before allo-HSCT and due to prophylactic and systemic antibiotic therapy the microbiota disruption worsens with loss of butyrate producing bacteria and other beneficial commensals, along with increase in pathogenic bacteria such as Enterococcus. Depletion of bacterial metabolites postpones epithelial cell repair and restoration of the mucus barrier. Pathogenic bacteria can disseminate through the damaged mucosa and cause blood stream infections, which will necessitate the administration of systemic antibiotics further disrupting the intestinal microbiota. This vicious cycle is associated with graft-versus-host disease (GvHD), increased mortality and diminished overall survival. The question remains whether fecal microbiota transplantation (FMT) and other interventions such as prebiotics and the use of antibiotics with less anti-anaerobic activity could eventually break the cycle and improve outcomes. IEC:– intestinal epithelial cells; ISC: intestinal stem cells.
Supplementary Material
Disclosures and Contributions
Acknowledgements
The authors wish to thank Sonia Kamenetsky for her assistance in the preparation of this manuscript. | BUSULFAN, FLUDARABINE PHOSPHATE, LEVOFLOXACIN, MEROPENEM | DrugsGivenReaction | CC BY-NC | 33241674 | 19,317,760 | 2021-04-01 |
What was the administration route of drug 'VANCOMYCIN'? | The clinical role of the gut microbiome and fecal microbiota transplantation in allogeneic stem cell transplantation.
Outcomes of allogeneic hematopoietic stem cell transplantation (allo- HSCT) have improved in the recent decade; however, infections and graft-versus-host disease remain two leading complications significantly contributing to early transplant-related mortality. In past years, the human intestinal microbial composition (microbiota) has been found to be associated with various disease states, including cancer, response to cancer immunotherapy and to modulate the gut innate and adaptive immune response. In the setting of allo-HSCT, the intestinal microbiota diversity and composition appear to have an impact on infection risk, mortality and overall survival. Microbial metabolites have been shown to contribute to the health and integrity of intestinal epithelial cells during inflammation, thus mitigating graft-versus-host disease in animal models. While the cause-andeffect relationship between the intestinal microbiota and transplant-associated complications has not yet been fully elucidated, the above findings have already resulted in the implementation of various interventions aiming to restore the intestinal microbiota diversity and composition. Among others, these interventions include the administration of fecal microbiota transplantation. The present review, based on published data, is intended to define the role of the latter approach in the setting of allo-HSCT.
Introduction
The past decades have witnessed important advances in the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT),1 mainly attributed to the reduction in non-relapse mortality.2 Yet, the need for further improvement is compelling. Acute graft-versus-host disease (aGvHD) and infections are two of the main causes of early transplant-related mortality (TRM), jointly accounting for 36% and 43% of deaths by day 100 in matched related and matched unrelated transplants, respectively.1
One of the emerging and extensively explored allo-HSCT-associated issues is the change in the gut microbial flora, as well as its effect on the pathogenesis of transplant- related complications and association with transplant outcomes.
The human body hosts a hundred trillion microbial organisms; the majority of them are bacteria, predominantly colonizing the gut, with the lower intestine being most densely colonized (1011-1012 organisms/g of intestinal content).3 The composition of bacteria in the gut is referred to as the intestinal microbiota and their collective genome is termed the “intestinal microbiome”.3 The two main phyla constituting more than 90% of the gut microbiota are the Firmicutes and Bacteroidetes and among less dominant phyla are Proteobacteria, Actinobacteria, and Verrucomicrobia.4 This composition is relatively flexible and can rapidly change in response to different environmental factors, adjusting the metabolic and immunologic performance accordingly.5 Intestinal microbiota has been recently found to have a significant impact on both health and disease states. It appears to be crucial for the maturation and education of the immune system and has a role in intestinal cell proliferation, intestine vascularization and endocrine functions. Moreover, it produces energy, synthesizes vitamins, metabolizes bile acids and even inactivates drugs.6-13 The microbiome has been reported to be associated with a variety of disorders such as obesity, type 2 diabetes, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis.14-17 This association is also suggested to be true for cancer18 and response to cancer immunotherapy.19 The gut microbiota has a close and reciprocal relationship with the host immune system. Intestinal epithelial cells, goblet and paneth cells produce the luminal protective mucosal layer and antimicrobial peptides, allowing the transcellular transport of immunoglobulin A (IgA) antibodies. These functions regulate luminal microbial colonization.20
Homeostasis of the immune response in the gut mucosa is maintained by the balance between pro-inflammatory cells, which include T-helper 1 (Th1) cells producing interferon γ (IFNγ), Th17 cells producing IL-17A and IL-22, diverse innate lymphoid cells with cytokine effector features resembling those of Th2 and Th17 cells, the antiinflammatory Foxp3+ regulatory T-cells (Tregs) and IgAsecreting B-cells. This homeostasis can be modulated by the gut microbiota.21-23 In pre-clinical studies, intestinal microbiota has been shown to regulate the expression of pro-inflammatory cytokines, human leukocyte antigen (HLA) type I and type II molecules and increase T-cell proliferation. 18 Effects of the microbiota on cytokine expression and immune cell subsets are not limited to the gut, and are extended to regional mesenteric and systemic lymph nodes.24 Furthermore, while some bacterial strains can induce pro-inflammatory intestinal Th17 cells,25 others induce anti-inflammatory Tregs26,27 and can thus ameliorate inflammatory colitis.28 Moreover, human host gut microbiota has been shown to correlate with expression pattern of the cytokines secreted from peripheral blood mononuclear cells isolated from the host.29 Microbial metabolites such as the short chain fatty acid (SCFA) butyrate or indole derivatives produced by tryptophan metabolism act to maintain the intestinal epithelial cell health, mucosal barrier, and to promote anti-inflammatory responses.30,31
Currently available molecular techniques allowing rapid and wide genomic sequencing enable extensive exploration of the microbiome. The most commonly used method is the 16S ribosomal RNA sequencing by PCR. Bioinformatics analysis tools assign the sequences to microbial taxon at different taxonomic levels. Other methods include shotgun next-generation metagenomics sequencing enabling massive and deeper genomic sequencing and allowing better identification of taxonomic species and potential functional pathways of the organisms, metatranscriptomics using high throughput RNA sequencing to profile gene expression, metaproteomics capable to provide large-scale characterization of the entire proteins in the environmental sample and metabolomics, identifying and quantifying all metabolites in the tested samples.32,33 The two main microbiome features that have been widely characterized in health and disease are its diversity and the abundance of specific bacteria or bacterial subgroups.34
The revelation of significant relationship between the microbiome, the immune system and disease has led to interventional studies aiming to normalize the microbiome composition and diversity thus ameliorating disease conditions. One of such interventions is the use of fecal microbiota transplantation (FMT), the term referring to the transfer of the fecal microbial content from a healthy individual into the intestine of a diseased individual. FMT, the standard of care for refractory or recurrent Clostridium difficile infection (CDI), proved to be highly effective in this condition. At the same time, mixed results were demonstrated in the studies evaluating the use of FMT for the management of inflammatory bowel disease, irritable bowel syndrome and hepatic encephalopathy. To date, FMT application for indications other than CDI has been limited to the experimental setting only.35,36
The setting of allo-HSCT imposes a significant disruption on the gut microbiome homeostasis through a variety of mechanisms (all part of the transplantation procedure), such as the use of broad-spectrum antibiotics, dietary changes (restriction), gut epithelial damage by conditioning regimens and introduction of a donor immune system.
Data from clinical studies support the association of alterations in the gut microbiome profile, mainly loss of diversity and change in composition during allo-HSCT, with patient outcomes such as aGvHD, GvHD-related mortality, non-relapse mortality (NRM) and overall survival (OS).37-40 Moreover, the gut microbial composition is reported to have an impact on infection risk, including CDI and blood stream infections (BSI), in this clinical setting. 38,41 Findings of these associations have led to a preponderance of research in this field,42 and although the causeand- effect relationship between the microbiome and transplant complications has not been unequivocally established, many ongoing clinical trials are implementing various interventions aiming to maintain microbiome diversity, thus potentially preventing transplant-related complications and treating aGvHD. These interventions include the use of probiotics,43 prebiotics,44 change in antibiotic prophylaxis45 and administration of FMT.46 This review appraises the currently available evidence on the association of gut microbiota and allo-HSCT and analyzes a potential role of FMT in allo-HSCT, by presenting two illustrative clinical cases, where effects on the gut microbiota composition could be employed either as a prophylactic or therapeutic measure.
Case 1
A 54-year old male, with mutated FLT3-ITD acute myeloid leukemia (AML) in complete remission (CR) after induction and re-induction chemotherapies, during which he acquired gut colonization with carbapenemresistant Klebsiella pneumoniae. He underwent an allo- HSCT from a mismatched 9/10 unrelated female donor with myeloablative conditioning (busulfan, fludarabine) and received levofloxacin for infection prophylaxis. During the transplantation period, he had a BSI event with extended spectrum β lactamase Escherichia coli (E. coli) treated with meropenem for 10 days, followed by a CDI event treated with oral vancomycin. His neutrophils engrafted on day +15 and on day +33 he developed diarrhea and was diagnosed with grade 3 acute lower gastrointestinal (GI) GvHD that was steroid refractory.
This case raises a number of important questions related to the role of gut flora in allo-HSCT.
Is the microbiome already disrupted prior to allogeneic hematopoietic stem cell transplantation conditioning?
There is ample evidence suggesting that the pre-transplant patient microbiome is already disrupted. The insult to the microbiome starts with preceding chemotherapy and antibiotic exposure. Galloway-Pena et al.47 analyzed 487 stool samples from 30 AML patients and found that their pre-induction microbiome diversity was not significantly different from that of healthy volunteers participating in the Human Microbiome Project (HMP). However, following neutrophil recovery, patient microbiome composition changed, with a significant decrease in diversity. Importantly, this reduction in diversity was associated with an increased risk of infections. The use of carbapenem antibiotics for more than 3 days during induction elevated the risk for a subsequent loss of diversity.47Moreover, exposure to anti-anaerobic antibiotics, like piperacillin-tazobactam, ticarcillin, meropenem, clindamycin and metronidazole, within the 3 months preceding allo-HSCT was associated with a significant decrease in pre-transplant microbiome diversity.38 With more courses of intensive chemotherapy, such as re-induction or salvage, the microbiome disruption was shown to enhance, leading to ecosystem instability and outgrowth of pathogenic bacteria like Enterococcus.48 This disruption in patient microbiome continued up to the time of allo-HSCT, as shown in the largest to date inter-center effort, where 8,767 sequential stool samples were collected from 1,362 patients prior to and throughout the transplantation period and analyzed using 16S ribosomal RNA sequencing. The pre-transplant microbiome of patients obtained on days -30 to -6 (n=606), was compared to that of healthy volunteers (n=246), demonstrating a significant reduction in diversity in patient microbiome.37 Additionally, evidence from another recently published study showed that the pre-transplant microbiome and the one derived from healthy controls differed in composition, displaying decreased abundance of beneficial bacteria of genera Bifidobacterium and butyrate producing genera such as Faecalibacterium and Lachnospiraceae in the former case.49 To conclude, pre-transplant microbiome disruption is clearly evident.
What is the microbiome status during the transplantation period and at time of recovery?
Data from several studies demonstrate that during the transplantation course, the microbiome diversity significantly decreases and its composition changes.37,50 The lower-diversity microbiome is reported to be characterized by abundance of pathogenic bacteria such as Enterococcus, Klebsiella, Escherichia, Staphylococcus and Streptococcus. The single taxonomic unit domination (abundance ≥30%) peaks at 1 week post-transplant, which is followed by a subsequent moderate decrease. The most common dominating taxonomic groups belong to the genera Enterococcus and Streptococcus.37 Along the same lines, other studies have found the Enterococcus genus to be more prolific during the first month posttransplant, with significantly higher abundance in patients with active or subsequent aGvHD.51,52 Following allo-HSCT, the microbiome recovery appears to be prolonged and incomplete. In a large cohort of patients (n=753), the post-transplant recovery of the gut microbiota has been reported to start around day +50, but even by day +100 the composition and bacterial abundance observed pre-transplant have not been fully achieved.53 Moreover, in some patients, microbiota has remained disrupted even 1 year after HSCT, this being particularly the case with butyrate-producing bacteria and Bifidobacterium.54 Eventually, the effect of environmental insult on the intestinal microbiota during allo-HSCT can be so severe that its recovery may require a long time.
Is the disrupted microbiome in allogeneic hematopoietic stem cell transplantation recipients clinically significant?
In the above-mentioned study by Peled et al., reduced microbiome diversity both pre-transplant (days -30 to -6) and peri-engraftment (days +7 to 21), was shown to be significantly associated with lower 2-year OS, while a persistent decrease of this parameter in the latter period was also associated with higher 2-year treatment-related mortality (TRM). Moreover, lower peri-engraftment microbiome diversity in T-cell replete allo-HSCT corresponded to increased GvHD-related mortality, which was not observed in T-cell depleted transplantations. This difference suggests a connection between the microbiota and T-cell alloreactivity.37 Liu et al. revealed a similar association of pre-transplant diversity with mortality as well as a correlation between post-transplant microbiome disruption and acute GI GvHD risk.55 Furthermore, in a study of 66 patients whose stool specimens were analyzed weekly during the transplantation period up to day +100, Golob et al. found a trend of association between near-engraftment low microbiome diversity and the risk for grade 3-4 aGvHD.56 Likewise, Mancini et al. evaluating a cohort of 100 patients, observed a significant connection between low microbiome diversity by day +10 and an increased risk for early (within 30 days) aGvHD.38
A number of studies also reported an impact of pre- or post-transplant bacterial abundance on patient outcomes (Table 1). Results of a two-cohort study (a total of 115 adult patients) conducted at the Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated that increased abundance of the genus Blautia, including anaerobic commensal bacteria, observed 12 days post-transplant, was associated with reduced GvHD-related mortality and improved OS. At the same time, the use of antibiotics with anti-anaerobic activity and total parenteral nutrition (TPN) correlated with loss of Blautia.57 In the pediatric setting, Biagi et al. reported an association of pre-transplant high abundance of Blautia and low abundance of Fusobacterium with diminished risk for grade 2-4 acute GI GvHD.58 Additionally, pre-transplant Enterobacteriaceae abundance of >5% was associated with an increased risk of BSI and Lachnospiraceae abundance of ≤10% appeared to correspond to increased mortality.38 In a large study from the MSKCC, very high abundance of a bacterial group, mainly composed of Eubacterium limosum, in pretransplant samples or the presence of this group in periengraftment samples was found to correspond to a decreased relapse risk,59 once again emphasizing the association of the microbiome and T-cell immunity. Furthermore, in the study from the Osaka University,54 Enterococcus relative abundance of ≥1% at 1 month posttransplant appeared to be indicative of poor OS, with a 2- year survival of 83.9% for patients with relative abundance of Enterococcus <1% versus 47.6% for those in whom this parameter was ≥1%. It is noteworthy that none of the surviving patients at 1 year post-transplant displayed Enterococcus abundance higher than 1%, suggesting that this cutoff could serve as a prognosticator of a long-term outcome in this clinical setting.54 The above evidence suggests that the microbiota changes before and during allo-HSCT are significantly associated with transplant complications and outcomes and might even serve as a predictive marker in this setting.
Table 1. Intestine microbial changes in diversity and abundance during pre-transplant and peri-engraftment periods, associated with outcomes of allogeneic hematopoietic stem cell transplantation
Can prophylactic fecal microbiota transplantation reduce the risk of infections during allogeneic hematopoietic stem cell transplantation?
In allo-HSCT recipients, curtailment of infection risk is crucial for reducing TRM, particularly due to increased frequency of BSI with multidrug resistant (MDR) bacteria. MDR colonization is established to range between 16% for gram-negative bacteria and 39% for vancomycin- resistant Enterococcus (VRE). While BSI have been reported in 16-41% of patients colonized with MDR bacteria, findings regarding a possible association of such colonization with TRM or infection-related mortality are inconclusive.60-62 In addition, MDR gram-negative colonization has neither been found to correspond to an increased risk for sepsis.38,63 In the lack of clear evidence, proof-of-concept studies are becoming of increasing importance. Battipaglia et al.64 have evaluated four patients colonized with MDR bacteria who had received FMT on days -46 to -9 before transplant with an aim to limit the risk for infectious complications during HSCT. All the four patients responded with decolonization of the MDR bacteria. One patient developed grade 3 acute gut GvHD on day +30 after transplant (day +51 after FMT) and two others developed bacteremia with sensitive bacteria. Notably, despite receiving broad-spectrum antibiotics during the transplantation period, none of the patients had recolonization of the gut with MDR bacteria. 64 Similar results were reported in a 63-year old HSCT recipient.65
The ongoing ODYSSEE trial (clinicaltrials gov. Identifier: 02928523) is aimed at reducing complications that may arise as a result of a loss of microbiota diversity, including infectious complications, poor nutritional status, prolonged hospitalization, as well as therapy discontinuation due to induction treatment-related toxicity in AML patients. Twenty newly diagnosed patients collected pre-induction autologous stools. This autologous FMT was later administered as enema after neutrophil recovery and prior to consolidation chemotherapy. Preliminary results demonstrated safety of this approach, with evidence of stool diversity restoration 10 days after FMT and reduction in antibiotic resistant gene copy count by 43%. Yet, clinical efficacy of this method still needs to be confirmed. 66
An important pathogen to consider for intervention with FMT is Clostridium difficile. The incidence of CDI during allo-HSCT varies between 13% and 30%, mostly in the first month after transplant.67-69 The disease is usually of mild-to-moderate severity, with good response to treatment; there is no association with TRM, and its possible correlation to subsequent acute GI GvHD is indefinite. 68-70 Given these facts, and the paucity of data on potential efficacy of prophylactic FMT in reducing the risk of CDI among Clostridium difficile carriers, FMT prophylaxis may not be required for this indication.
As for the treatment of recurrent CDI, results of three small studies demonstrate safety of FMT administration to a total of 16 patients with recurrent CDI after allo- HSCT, with only three patients recurring after the procedure. 71-73
Currently available data are insufficient to definitively conclude that prophylactic FMT will reduce the infection rate in the allo-HSCT setting.
Can prophylactic fecal microbiota transplantation reduce the risk of acute graft-versus-host disease or transplant-related mortality?
The incidence of clinically significant aGvHD ranges between 22% in allo-HSCT from a matched related donor to 29% in case of a mismatched unrelated donor, with grade 3-4 disease incidence being 8.6% and 12%, respectively.24 Whether any intervention that restores the microbiome composition could also decrease aGvHD rates is yet to be revealed. Hitherto, only two small studies have reported results of using prophylactic FMT in the post-engraftment period. In the study by Defillip et al.,25 aiming to evaluate safety and feasibility of early restoration of the gut microbiome, frozen capsules of FMT derived from unrelated donors were administered to 13 allo-HSCT recipients 4 weeks after neutrophil engraftment. No FMT-related bacteremia events occurred and two cases of acute GI GvHD were registered. Analysis of stool composition indicated improvement in intestinal microbiome diversity after FMT that was mainly attributed to operational taxonomic units (OTU) originating from the FMT donor.25 In the study by Taur et al.,53 within 3-28 days of engraftment, patients not receiving broadspectrum antibiotics, not critically ill and with low abundance of Bacteroides (<0.1% of the total 16S sequencing) at that time period, were randomized to either receive autologous FMT (n=14) or to a control group (n=11).
Solely the FMT group was found to reconstitute their microbiome diversity and composition to the pre-transplant state. Of note, the use of autologous FMT raises concern for disrupted microbiota due to prior antibiotic exposure.53
These data suggest feasibility and safety of prophylactic FMT; however, its clinical benefit has not been demonstrated yet.
Should additional interventions along with fecal microbiota transplantation aiming to attenuate mircobiome disruption be considered?
Given that a variety of factors could affect the microbiome diversity and composition during the transplantation course, their adequate control might potentially preclude such microbiome changes. The question remains whether FMT alone is sufficient enough or it should be combined with other interventions to provide the required control.
Transplant conditioning
Conditioning chemotherapy itself has a disruptive effect on the microbiome, as found by Montassier et al.26 who evaluated eight lymphoma patients undergoing autologous HSCT with the BEAM (carmustine, etoposide, cytarabine arabine, melphalan) protocol. Since none of the patients received nasogastric tube nutrition, total parenteral nutrition, ciprofloxacin prophylaxis or systemic antibiotic treatment, only the chemotherapy effect on the microbiome was measured. Compared to pretransplant samples, those drawn at 1 week post-conditioning demonstrated significantly reduced diversity, decreased abundance of Firmicutes and Actinobacteria and increased presence in bacteroides and proteobacteria, indicating chemotherapy-induced disruption of the intestinal microbiota.26 Of note, this disruptive effect might be related to etoposide, which has bacterial inhibitory activity. 27,28 Remarkably, the post-transplant decrease in microbiome diversity appeared to be more profound when more intensive conditioning was applied.74 However, reducing the conditioning intensity was not shown to consistently decrease the rate of aGvHD.75 Moreover, it might increase the relapse rate and decrease long-term OS.76,77 Therefore, changing the conditioning regimen in an attempt to attenuate the insult on the microbiome is not currently recommended.
Diet
Dietary interventions such as TPN, prebiotics and probiotics could potentially influence the microbiome composition before or during the transplantation course. TPN administration was reported to be associated with decreased recovery of post-transplant (up to day +120) diversity compared to enteral nutrition. In addition, SCFA levels in the gut content were found to be lower in the TPN group.78 Iyama et al. retrospectively compared a group of patients whose diet was supplemented with prebiotics, i.e., glutamine, fiber and oligosaccharides (GFO) with a group that did not receive such supplementation. GFO was started 7 days before conditioning and continued up to day +28. In the GFO group, duration of diarrhea, mucositis and TPN requirement was shorter and the weight loss was also less prominent.44 An ongoing prospective trial (clinicaltrials gov. Identifier: 02763033) is evaluating the efficacy of resistant potato starch supplementation between day -7 and day +100 in HSCT recipients. This starch is a non-absorbable carbohydrate that is metabolized by the anaerobic commensal bacteria to produce the SCFA butyrate,79 shown to reduce the severity of acute GI GvHD in an experimental model.31 Preliminary results demonstrate the feasibility of this approach in terms of patient compliance, increase in intestinal butyrate levels and abundance of butyrate producing bacteria. 80 As for probiotic supplementation, the available data do not suggest its influence on the microbiome composition or clinical outcomes. It is worth mentioning that the products used in the studies contained only one bacterial strain and not a diversity of bacteria,43,81 and safety of probiotic administration is of concern in immunocompromised patients.82
The loss of diversity during the transplantation course is accompanied with microbiome domination by single taxonomic units such as Enterococcus.37 This enterococcal expansion has been found to be most prominent in patients developing acute GI GvHD.52 Stein-Thoeringer et al. have shown in a gnotobiotic mouse model of allo- HSCT that enterococcal expansion in the gut depends on lactose and its depletion decreases the enterococcal abundance and thus attenuates GvHD severity. Furthermore, in patients with a lactose malabsorption genotype, Enterococcus abundance appears to be higher than in patients without this genotype.83 This finding may give rise to a new approach to dietary intervention during HSCT. Interestingly, in the study by Khandelwal et al., where pediatric allo-HSCT patients under the age of 5 were treated with ready to eat human milk and breast feeding (n=24) or formula (n=14), plasma levels of IL6, IL10, and Reg3α were significantly lower in the group receiving human milk. The microbiome composition also differed between the two groups, with an increase in pathogenic species such as E. coli in the formula-receiving group. Despite the fact that human milk oligosaccharides are metabolized to SCFA by the commensal bacteria, butyrate levels in the stool were similar in both groups. Moreover, no significant difference in the rate of grade 2-4 acute GI GvHD between the groups was revealed. However, the limited size of this study calls for cautious interpretation of these encouraging results.84 Overall, dietary interventions emerge as a promising way to shape the intestinal microbiota during allo-HSCT. However, results are too preliminary and more research is required before implementing any of these methods.
Antibiotic treatment
The antibiotic treatment applied during the transplantation course is the main factor affecting the microbiome. Quinolone prophylaxis during afebrile neutropenia and systemic broad-spectrum antibiotic treatment with piperacillin-tazobactam or meropenem are widely accepted. 85-87 However, data demonstrate that the use of other antibiotics can better preserve gut beneficial commensals and is associated with improved outcomes.
The study from the University of Regensburg in Germany employed the non-absorbable antibiotic rifaximin and compared it to ciprofloxacin and metronidazole used in a historic cohort of patients for infection prophylaxis during allo-HSCT.45 Antibiotics were given from day -8 up to engraftment. The urine 3-indoxyl sulfate (3-IS) level was measured as a marker of microbiome diversity.88 In the rifaximin cohort, the pre-engraftment 3-IS levels were significantly higher without an increase in the sepsis rate or colonization with pathogenic bacteria. This group had significantly lower TRM, prolonged OS and the acute GI GvHD rate tended to be lower in these patients. The observed advantage remained evident even in patients who later received systemic antibiotics for neutropenic fever. 45
Given the major role of microbiome diversity preservation during allo-HSCT and an association of impaired diversity with acute GI GvHD and adverse patient outcome, Weber et al. further compared the effects of various prophylactic and systemic antibiotics in an attempt to identify the ones that could spare commensal bacteria.89 At 10 days post-transplant, the patient groups receiving rifaximin without systemic antibiotics or rifaximin with systemic antibiotics maintained their microbiome diversity and Clostridia abundance and had higher 3-IS levels compared to patients treated with ciprofloxacin/metronidazole ± systemic antibiotics. These results suggest that rifaximin could better preserve microbiome diversity even when systemic broad-spectrum antibiotics are administered during transplantation. Moreover, in the study conducted in two Canadian hospitals and assessing the effect of antibiotic prophylaxis or treatment given before day 0 on frequency of aGvHD and mortality, the authors compared the outcome of a cohort of patients exposed to antibiotics (n=239) to those who did not receive this therapy (n=261).90 The antibiotic-receiving group demonstrated a significantly higher incidence of grade 2-4 aGvHD and significantly shorter OS at 1, 2 and 10 years posttransplant, indicating an association between the deleterious effect of such treatment on intestinal bacteria and inferior patient outcome.
Importantly, early start of systemic antibiotics (before engraftment) was found to be associated with a lower 3- IS urine level and decreased Clostridia abundance in the stool. Furthermore, the TRM rate in such cases was higher than in patients who did not require systemic antibiotics during HSCT or started them after engraftment.91
Similarly, systemic treatment with piperacillin-tazobactam and meropenem was reported to correlate with decreased microbiome diversity during the transplantation37 and significant loss of commensal anaerobic bacteria. 92 In pediatric patients, Simms-Waldrip et al.93 found that higher load of anti-anaerobic antibiotics was associated with a significant decrease in anti-inflammatory Clostridia (AIC) abundance, and in patients with aGvHD the abundance decrease was severe (10-log fold) compared to patients without GvHD. In a mouse allo-HSCT model, clindamycin administration was associated with AIC decrease and more severe GvHD, while re-administration of AIC increased its levels in the gut and improved survival.93 Additionally, Lee et al.94 compared patients who did not require any systemic antibiotic treatment during the transplantation course with those who received cefepime and those who were treated with carbapenem antibiotics. The carbapenem group displayed a significant loss of microbial diversity at engraftment and an increased rate of acute GI GvHD (32.1%) compared to the noantibiotics group (11.6%). Interestingly, the cefepime group retained a diverse microbiome, demonstrating only a trend to a higher GI GvHD rate (26.4%).
Furthermore, a large multicenter study retrospectively evaluating 857 patients revealed that the use of piperacillin-tazobactam and imipenem-cilastatin was associated with increased 5-year GvHD-related mortality, 95 while this was not observed in patients receiving cefepime and aztreonam. The former antibiotics caused a significant decrease in abundance of Bacteroidetes and Lactobacillus compared to the latter ones. These results suggest that some antibiotics may be more beneficial than others in the setting of allo-HSCT, and that this beneficial effect is related to the antibiotic ability to be less detrimental to intestinal commensal bacteria.95 Findings in the pediatric setting were consistent with these data, and exposure to anti-anaerobic antibiotics was reported to result in a significant decrease in butyrate-producing bacteria and the butyrate level in luminal content by day +14. Pediatric patients who later developed aGvHD had a significantly lower butyrate level at that time point than patients without GvHD.96
It was also demonstrated that specific antibiotic use during allo-HSCT could change the abundance of specific taxa which was associated with BSI risk. In a cohort of 94 patients, Taur Y et al.50 found that domination of the gut microbiome (abundance ≥30%) by single bacterial taxa Enterococcus and Streptococcus occurred at the peri-engraftment period (days +10 to +20) in two thirds of the patients. However, treatment with metronidazole increased the risk for enterococcal domination by 3-fold, and this domination elevated the risk for VRE bacteremia by 9-fold. Altogether, these data establish an essential role of antibiotics in disrupting or preserving the intestinal microbiota during allo-HSCT.
Case 1: conclusions
Several issues should be considered in decision-making regarding the appropriate management of this case. This patient has pre-transplant intestinal microbiota disruption and assumed colonization by MDR bacteria and probably by Clostridium difficile. His risk for aGvHD is high, since he has undergone allo-HSCT from a mismatched unrelated donor. Quinolone prophylaxis and meropenem treatment for BSI have further disrupted his intestinal microbiota. The existence of pre-transplant microbiota disruption, mainly attributed to the use of broad-spectrum antibiotics during intensive chemotherapy, is associated with increased TRM, shorter OS and GvHD-related mortality. Pre-transplant FMT can potentially enrich the microbiome diversity and eradicate MDR bacteria or Clostridium difficile; however, without controlling such factors as antibiotic prophylaxis and the type of systemic antibiotic therapy employed, the intervention by FMT may not completely achieve its goals.
Table 2. Clinical trials of fecal microbiota transplant in allogeneic hematopoietic stem cell transplantation.
So far, no data are available regarding a clinical benefit of prophylactic pre-transplant FMT.
While an association between peri-engraftment microbiome low diversity and patient outcome is established, implying potential feasibility of FMT use at that stage, data regarding FMT application before engraftment are not available, and for safety reasons this approach will probably not be attempted. Results of several small-scale studies suggest safety and feasibility of post-engraftment FMT in restoring microbiome diversity (Table 2); however, it remains unknown if this strategy could decrease the risk for aGvHD-related mortality and TRM.
As for dietary interventions at this period, their efficacy is still under investigation. Choosing a different antibiotic prophylaxis, such as rifaximin and systemic antibiotics such as cefepime, looks promising. Nevertheless, new strategies need to be tested to prove their non-inferiority in OS85 and to establish less disruption for the microbiome (clinicaltrials gov. Identifier: 03078010), especially since fourth-generation cephalosporins have been found in one study to be associated with an increased risk for aGvHD.97
Case 1: recommendations
In this case, based on the currently available data, we do not recommend prophylactic administration of pretransplant or post-engraftment FMT.
Case 2
A 25-year old female with intermediate-risk AML in CR underwent an allo-HSCT with BuCy myeloablative conditioning from her matched sibling. Her neutrophils engrafted by day +14. On day +34 she developed grade 3 aGvHD of the lower GI tract which was steroid refractory (SR). She did not respond to the addition of budesonide, extracorporeal photopheresis (ECP), mofetil mycophenolate or infliximab.
Can fecal microbiota transplantation mitigate prevailing acute gastrointestinal graft-versushost disease?
The current data regarding the use of FMT for the treatment of acute GI GvHD are limited to case reports and small case series (Table 2). A total of 58 described patients were treated with FMT for SR GI grade 2-4 aGvHD. The FMT source was an unrelated donor in 36 cases, a related donor – in six cases and in eight cases a commercial pooled highly diverse FMT was used. FMT was processed and either given fresh within a few hours of collection or it was frozen and later thawed before administration. FMT was administered orally as packed capsules, through a nasogastric/ nasoduodenal tube or an enema. Of 58 patients, 28 received FMT after two or more therapy lines, while 19 received it as second-line therapy right after steroid failure. Response was observed in 74% (43 of 58) of patients, with complete response in 57% (33 of 58) and partial response in 17% (10 of 58). Complete response was observed in 73% of patients receiving FMT as second-line therapy. Ten of the responding patients relapsed and 29 patients were alive at the last follow-up (54%; 29 of 54 patients with available data).
Response to treatment was seen within a median of 14 days (range: 3-28), with a median of two FMT (range: 1-7), and a median of 7 days between treatments (range: 2-60).46,98-106
Infectious complications occurred in 11 patients. Two had sepsis with bacteria not originating from FMT,102 and one patient developed diarrhea due to Norovirus that was traced to FMT.106 Other infections were attributed to the severe immunocompromised state of patients. However, a possible association with FMT could not be ruled out. In responding patients in whom the stool microbiome was sequenced post-FMT, it was found to be significantly more diverse and enriched with Bacteroides, Lactobacillus, Bifidobacterium and Faecalibacterium compared to pre-FMT microbiome.46,98-101 Notably, the diversity increased only upon discontinuation of anti-anaerobic systemic antibiotic treatment, such as piperacillin-tazobactam. However, continuous use or re-initiating treatment with cefepime did not reduce FMT efficiency.46,98,99
These results are highly encouraging and support FMT therapy to be relatively safe and effective in SR GI aGvHD.
Case 2: conclusions
Available data suggest a potentially beneficial effect of FMT in acute lower GI GvHD. It should probably be used earlier rather than later, so that patients' response will not be overcome by infectious complications related to extensive immunosuppressive therapy. Discontinuation of antibiotic treatment prior to FMT administration appears to be an important factor contributing to successful response. If antibiotic treatment is required, using cefepime may allow attenuating microbiome insult while maintaining clinical response.
Current information is based on case reports and small series with a wide variability in patient selection, FMT preparation and mode of administration. However, the reported feasibility, safety and clinical benefit appear to be similar across the studies, implying that intestinal microbiota can be recovered with FMT, irrespective of its administration method. Safety remains a concern,107 especially in advanced GI aGvHD, and if an infectious complication occurs post-FMT, the pathogen should be sequenced and traced to find out if it originates from the FMT.
Case 2: recommendations
Currently, ruxolitinib is the only FDA-approved drug for the treatment of SR aGvHD, while other modalities are also commonly used in this scenario (e.g., extracorporeal photopheresis). Thus, FMT could be recommended for patients with grade 2-4 steroid refractory or dependent aGVHD of the lower GI tract, albeit in the context of a clinical study only.108-110 Other treatment approaches could also be considered, such as adding it to steroids as part of the first-line therapy (clinicaltrials gov. Identifier: 04269850).
Although clinical trials are still ongoing, given the grave prognosis of SR aGvHD with more than 50% mortality,111 and the high rate of response to FMT, we recommend considering FMT as a therapeutic option in this setting.
Practical considerations for fecal microbiota transplantation treatment
As FMT has become the standard of care in recurrent and refractory CDI,112,113 more and more centers are gaining access to FMT programs through either establishing their own stool banks or acquiring FMT from universal stool banks.114,115
One of the limiting factors to wider application of stool banks and FMT programs is the lack or variance of regulatory standards. In different countries, FMT is regulated as a drug, tissue or a combined product composed of both human cells and non-human components (microbial DNA and metabolites). Stool banks are recommended to operate under the designated authority in each country. In the absence of local directives, the scientific committee should be responsible for establishing regulatory protocols.114
FMT donor screening should follow national regulations and international recommendations.114 Screening should include medical history related to the risk for transmitting infections, as well as medical conditions and treatments associated with perturbed microbiome (Table 3). Special considerations are to be applied when planning FMT use in allo-HSCT patients, such as testing the donor for Cytomegalovirus and Epstein-Barr virus IgG and IgM, and administering FMT from seronegative donors to seronegative patients. However, when weighing suitability of an FMT donor, one should be cognizant of the fact that no data are available to support the advantage of a particular donor (a family member, an unrelated donor, or pooled stool from several unrelated donors).
As for autologous FMT, it has not been tested in the setting of aGvHD treatment. Since the microbiota composition of a patient is already disrupted prior to HSCT, using such stool in FMT preparation to be applied for diversity restoration may not be effective. In order to circumvent this problem, in AML patients, we recommend freezing self-stool before the beginning of induction chemotherapy.
In CDI, both fresh and frozen FMT have been shown to be efficient116 as have been the two delivery routes − colonoscopy and oral capsules.117 While there are no data pointing to the superiority of either method of preparation or administration for aGvHD treatment, frozen samples from a stool bank allow FMT to be readily available for immediate use without the need to wait for donor screening and FMT collection.
The basic principles of FMT preparation include weighing the sample, suspension in sterile solution (saline), adding glycerol in case the FMT is planned for freezing and storing, homogenization, filtering and aliquoting the suspension for fresh use or freezing (Table 3). The FMT product should be registered and labeled.114
Based on the available data (Table 2) we suggest evaluating clinical response at 7-14 days after FMT administration. If no response or only partial response is achieved, we recommend administering a second dose of FMT. Whether in such cases the use of FMT from another donor could provide a superior outcome is yet to be determined. In general, in order to consider FMT as an efficacious therapeutic approach for SR GI aGvHD management, an overall response rate of around 60-70%, with a complete response rate of 30-50% should be a desired target, as these rates are achieved with the use of the approved ruxolitinib treatment and in non-randomized FMT studies.46,98-106,110
As for the antibiotic treatment peri-FMT, if feasible, 24-48 hours prior to FMT, systemic antibiotics should be stopped or replaced by one with less anti-anaerobic activity such as rifaximin for prophylaxis or cefepime for febrile neutropenic treatment.46,98,99
Microbiome sequencing of donor and patient samples could help interpreting clinical outcomes. It could also be valuable in distinguishing between the donor and the recipient as the source of post-FMT infection. However, currently there are no data suggesting that patient stool sequencing prior to FMT could guide its administration or affect the outcome. Therefore, given that the primary outcome should be the clinical response to treatment we recommend treating SR GI aGvHD patients with FMT even if the microbiome analysis is not available. Nonetheless, we do suggest storing stool samples from the donor and the patient (before and after FMT) for later sequencing if it becomes available.
Table 3. Practical aspects of fecal microbiota transplantation.
Further accumulation of data on FMT for SR GI aGvHD will allow wider and more efficient application of this treatment approach.
Open challenges and future directions
Disruption of the intestinal microbiome during allo- HSCT is a multifaceted process with a cause-and-effect relationship between multiple factors such as conditioning, diet and antibiotic treatment. Lately, FMT has emerged as an intervention that can facilitate microbiome recovery and potentially intervene with the above interplay (Figure 1). The intestinal microbial disruption before and during allo-HSCT is clearly associated with transplant-related outcomes, mainly acute GvHD and mortality, and pre-clinical data demonstrate the key role of the intestinal microbiota in protecting the gut from inflammatory damage and in regulating the innate immune system to maintain a more tolerant state.118 While the addition of beneficial bacteria or their metabolites has been shown to ameliorate acute GvHD in animal allo-HSCT models, many challenges remain concerning the role of the intestinal microbiota in allo-HSCT in humans. A substantial amount of basic research is being conducted aiming to better understand the place of microbiome changes in the pathogenesis of acute GvHD. In addition, a large population microbiome analysis is ongoing attempting to delineate the interplay between other factors, such as antibiotics and diet, and the microbiota disruption, and to determine the optimal strategy allowing to preserve the microbiota intact.119 However, while these issues are still under investigation, clinical trials evaluating the efficacy of FMT and other abovementioned interventions in the HSCT setting are underway (Table 2). Joint efforts to further explore biological, correlative and recovery functions of the intestinal microbiota could ultimately lead to decreased transplantrelated mortality, and even pave the way to personalized therapeutic strategies in HSCT.
Figure 1. The multifactorial interplay between environmental factors, intestinal microbiota and tissue damage affects transplant-related outcomes. During allogeneic hematopoietic stem cell transplantation (allo-HSCT), conditioning chemotherapy causes damage to the intestinal mucosa cells such as intestinal epithelial cells, intestinal stem cells, paneth cells and mucus producing goblet cells. Gut microbiota is already disrupted before allo-HSCT and due to prophylactic and systemic antibiotic therapy the microbiota disruption worsens with loss of butyrate producing bacteria and other beneficial commensals, along with increase in pathogenic bacteria such as Enterococcus. Depletion of bacterial metabolites postpones epithelial cell repair and restoration of the mucus barrier. Pathogenic bacteria can disseminate through the damaged mucosa and cause blood stream infections, which will necessitate the administration of systemic antibiotics further disrupting the intestinal microbiota. This vicious cycle is associated with graft-versus-host disease (GvHD), increased mortality and diminished overall survival. The question remains whether fecal microbiota transplantation (FMT) and other interventions such as prebiotics and the use of antibiotics with less anti-anaerobic activity could eventually break the cycle and improve outcomes. IEC:– intestinal epithelial cells; ISC: intestinal stem cells.
Supplementary Material
Disclosures and Contributions
Acknowledgements
The authors wish to thank Sonia Kamenetsky for her assistance in the preparation of this manuscript. | Oral | DrugAdministrationRoute | CC BY-NC | 33241674 | 19,323,303 | 2021-04-01 |
What was the dosage of drug 'BUSULFAN'? | The clinical role of the gut microbiome and fecal microbiota transplantation in allogeneic stem cell transplantation.
Outcomes of allogeneic hematopoietic stem cell transplantation (allo- HSCT) have improved in the recent decade; however, infections and graft-versus-host disease remain two leading complications significantly contributing to early transplant-related mortality. In past years, the human intestinal microbial composition (microbiota) has been found to be associated with various disease states, including cancer, response to cancer immunotherapy and to modulate the gut innate and adaptive immune response. In the setting of allo-HSCT, the intestinal microbiota diversity and composition appear to have an impact on infection risk, mortality and overall survival. Microbial metabolites have been shown to contribute to the health and integrity of intestinal epithelial cells during inflammation, thus mitigating graft-versus-host disease in animal models. While the cause-andeffect relationship between the intestinal microbiota and transplant-associated complications has not yet been fully elucidated, the above findings have already resulted in the implementation of various interventions aiming to restore the intestinal microbiota diversity and composition. Among others, these interventions include the administration of fecal microbiota transplantation. The present review, based on published data, is intended to define the role of the latter approach in the setting of allo-HSCT.
Introduction
The past decades have witnessed important advances in the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT),1 mainly attributed to the reduction in non-relapse mortality.2 Yet, the need for further improvement is compelling. Acute graft-versus-host disease (aGvHD) and infections are two of the main causes of early transplant-related mortality (TRM), jointly accounting for 36% and 43% of deaths by day 100 in matched related and matched unrelated transplants, respectively.1
One of the emerging and extensively explored allo-HSCT-associated issues is the change in the gut microbial flora, as well as its effect on the pathogenesis of transplant- related complications and association with transplant outcomes.
The human body hosts a hundred trillion microbial organisms; the majority of them are bacteria, predominantly colonizing the gut, with the lower intestine being most densely colonized (1011-1012 organisms/g of intestinal content).3 The composition of bacteria in the gut is referred to as the intestinal microbiota and their collective genome is termed the “intestinal microbiome”.3 The two main phyla constituting more than 90% of the gut microbiota are the Firmicutes and Bacteroidetes and among less dominant phyla are Proteobacteria, Actinobacteria, and Verrucomicrobia.4 This composition is relatively flexible and can rapidly change in response to different environmental factors, adjusting the metabolic and immunologic performance accordingly.5 Intestinal microbiota has been recently found to have a significant impact on both health and disease states. It appears to be crucial for the maturation and education of the immune system and has a role in intestinal cell proliferation, intestine vascularization and endocrine functions. Moreover, it produces energy, synthesizes vitamins, metabolizes bile acids and even inactivates drugs.6-13 The microbiome has been reported to be associated with a variety of disorders such as obesity, type 2 diabetes, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis.14-17 This association is also suggested to be true for cancer18 and response to cancer immunotherapy.19 The gut microbiota has a close and reciprocal relationship with the host immune system. Intestinal epithelial cells, goblet and paneth cells produce the luminal protective mucosal layer and antimicrobial peptides, allowing the transcellular transport of immunoglobulin A (IgA) antibodies. These functions regulate luminal microbial colonization.20
Homeostasis of the immune response in the gut mucosa is maintained by the balance between pro-inflammatory cells, which include T-helper 1 (Th1) cells producing interferon γ (IFNγ), Th17 cells producing IL-17A and IL-22, diverse innate lymphoid cells with cytokine effector features resembling those of Th2 and Th17 cells, the antiinflammatory Foxp3+ regulatory T-cells (Tregs) and IgAsecreting B-cells. This homeostasis can be modulated by the gut microbiota.21-23 In pre-clinical studies, intestinal microbiota has been shown to regulate the expression of pro-inflammatory cytokines, human leukocyte antigen (HLA) type I and type II molecules and increase T-cell proliferation. 18 Effects of the microbiota on cytokine expression and immune cell subsets are not limited to the gut, and are extended to regional mesenteric and systemic lymph nodes.24 Furthermore, while some bacterial strains can induce pro-inflammatory intestinal Th17 cells,25 others induce anti-inflammatory Tregs26,27 and can thus ameliorate inflammatory colitis.28 Moreover, human host gut microbiota has been shown to correlate with expression pattern of the cytokines secreted from peripheral blood mononuclear cells isolated from the host.29 Microbial metabolites such as the short chain fatty acid (SCFA) butyrate or indole derivatives produced by tryptophan metabolism act to maintain the intestinal epithelial cell health, mucosal barrier, and to promote anti-inflammatory responses.30,31
Currently available molecular techniques allowing rapid and wide genomic sequencing enable extensive exploration of the microbiome. The most commonly used method is the 16S ribosomal RNA sequencing by PCR. Bioinformatics analysis tools assign the sequences to microbial taxon at different taxonomic levels. Other methods include shotgun next-generation metagenomics sequencing enabling massive and deeper genomic sequencing and allowing better identification of taxonomic species and potential functional pathways of the organisms, metatranscriptomics using high throughput RNA sequencing to profile gene expression, metaproteomics capable to provide large-scale characterization of the entire proteins in the environmental sample and metabolomics, identifying and quantifying all metabolites in the tested samples.32,33 The two main microbiome features that have been widely characterized in health and disease are its diversity and the abundance of specific bacteria or bacterial subgroups.34
The revelation of significant relationship between the microbiome, the immune system and disease has led to interventional studies aiming to normalize the microbiome composition and diversity thus ameliorating disease conditions. One of such interventions is the use of fecal microbiota transplantation (FMT), the term referring to the transfer of the fecal microbial content from a healthy individual into the intestine of a diseased individual. FMT, the standard of care for refractory or recurrent Clostridium difficile infection (CDI), proved to be highly effective in this condition. At the same time, mixed results were demonstrated in the studies evaluating the use of FMT for the management of inflammatory bowel disease, irritable bowel syndrome and hepatic encephalopathy. To date, FMT application for indications other than CDI has been limited to the experimental setting only.35,36
The setting of allo-HSCT imposes a significant disruption on the gut microbiome homeostasis through a variety of mechanisms (all part of the transplantation procedure), such as the use of broad-spectrum antibiotics, dietary changes (restriction), gut epithelial damage by conditioning regimens and introduction of a donor immune system.
Data from clinical studies support the association of alterations in the gut microbiome profile, mainly loss of diversity and change in composition during allo-HSCT, with patient outcomes such as aGvHD, GvHD-related mortality, non-relapse mortality (NRM) and overall survival (OS).37-40 Moreover, the gut microbial composition is reported to have an impact on infection risk, including CDI and blood stream infections (BSI), in this clinical setting. 38,41 Findings of these associations have led to a preponderance of research in this field,42 and although the causeand- effect relationship between the microbiome and transplant complications has not been unequivocally established, many ongoing clinical trials are implementing various interventions aiming to maintain microbiome diversity, thus potentially preventing transplant-related complications and treating aGvHD. These interventions include the use of probiotics,43 prebiotics,44 change in antibiotic prophylaxis45 and administration of FMT.46 This review appraises the currently available evidence on the association of gut microbiota and allo-HSCT and analyzes a potential role of FMT in allo-HSCT, by presenting two illustrative clinical cases, where effects on the gut microbiota composition could be employed either as a prophylactic or therapeutic measure.
Case 1
A 54-year old male, with mutated FLT3-ITD acute myeloid leukemia (AML) in complete remission (CR) after induction and re-induction chemotherapies, during which he acquired gut colonization with carbapenemresistant Klebsiella pneumoniae. He underwent an allo- HSCT from a mismatched 9/10 unrelated female donor with myeloablative conditioning (busulfan, fludarabine) and received levofloxacin for infection prophylaxis. During the transplantation period, he had a BSI event with extended spectrum β lactamase Escherichia coli (E. coli) treated with meropenem for 10 days, followed by a CDI event treated with oral vancomycin. His neutrophils engrafted on day +15 and on day +33 he developed diarrhea and was diagnosed with grade 3 acute lower gastrointestinal (GI) GvHD that was steroid refractory.
This case raises a number of important questions related to the role of gut flora in allo-HSCT.
Is the microbiome already disrupted prior to allogeneic hematopoietic stem cell transplantation conditioning?
There is ample evidence suggesting that the pre-transplant patient microbiome is already disrupted. The insult to the microbiome starts with preceding chemotherapy and antibiotic exposure. Galloway-Pena et al.47 analyzed 487 stool samples from 30 AML patients and found that their pre-induction microbiome diversity was not significantly different from that of healthy volunteers participating in the Human Microbiome Project (HMP). However, following neutrophil recovery, patient microbiome composition changed, with a significant decrease in diversity. Importantly, this reduction in diversity was associated with an increased risk of infections. The use of carbapenem antibiotics for more than 3 days during induction elevated the risk for a subsequent loss of diversity.47Moreover, exposure to anti-anaerobic antibiotics, like piperacillin-tazobactam, ticarcillin, meropenem, clindamycin and metronidazole, within the 3 months preceding allo-HSCT was associated with a significant decrease in pre-transplant microbiome diversity.38 With more courses of intensive chemotherapy, such as re-induction or salvage, the microbiome disruption was shown to enhance, leading to ecosystem instability and outgrowth of pathogenic bacteria like Enterococcus.48 This disruption in patient microbiome continued up to the time of allo-HSCT, as shown in the largest to date inter-center effort, where 8,767 sequential stool samples were collected from 1,362 patients prior to and throughout the transplantation period and analyzed using 16S ribosomal RNA sequencing. The pre-transplant microbiome of patients obtained on days -30 to -6 (n=606), was compared to that of healthy volunteers (n=246), demonstrating a significant reduction in diversity in patient microbiome.37 Additionally, evidence from another recently published study showed that the pre-transplant microbiome and the one derived from healthy controls differed in composition, displaying decreased abundance of beneficial bacteria of genera Bifidobacterium and butyrate producing genera such as Faecalibacterium and Lachnospiraceae in the former case.49 To conclude, pre-transplant microbiome disruption is clearly evident.
What is the microbiome status during the transplantation period and at time of recovery?
Data from several studies demonstrate that during the transplantation course, the microbiome diversity significantly decreases and its composition changes.37,50 The lower-diversity microbiome is reported to be characterized by abundance of pathogenic bacteria such as Enterococcus, Klebsiella, Escherichia, Staphylococcus and Streptococcus. The single taxonomic unit domination (abundance ≥30%) peaks at 1 week post-transplant, which is followed by a subsequent moderate decrease. The most common dominating taxonomic groups belong to the genera Enterococcus and Streptococcus.37 Along the same lines, other studies have found the Enterococcus genus to be more prolific during the first month posttransplant, with significantly higher abundance in patients with active or subsequent aGvHD.51,52 Following allo-HSCT, the microbiome recovery appears to be prolonged and incomplete. In a large cohort of patients (n=753), the post-transplant recovery of the gut microbiota has been reported to start around day +50, but even by day +100 the composition and bacterial abundance observed pre-transplant have not been fully achieved.53 Moreover, in some patients, microbiota has remained disrupted even 1 year after HSCT, this being particularly the case with butyrate-producing bacteria and Bifidobacterium.54 Eventually, the effect of environmental insult on the intestinal microbiota during allo-HSCT can be so severe that its recovery may require a long time.
Is the disrupted microbiome in allogeneic hematopoietic stem cell transplantation recipients clinically significant?
In the above-mentioned study by Peled et al., reduced microbiome diversity both pre-transplant (days -30 to -6) and peri-engraftment (days +7 to 21), was shown to be significantly associated with lower 2-year OS, while a persistent decrease of this parameter in the latter period was also associated with higher 2-year treatment-related mortality (TRM). Moreover, lower peri-engraftment microbiome diversity in T-cell replete allo-HSCT corresponded to increased GvHD-related mortality, which was not observed in T-cell depleted transplantations. This difference suggests a connection between the microbiota and T-cell alloreactivity.37 Liu et al. revealed a similar association of pre-transplant diversity with mortality as well as a correlation between post-transplant microbiome disruption and acute GI GvHD risk.55 Furthermore, in a study of 66 patients whose stool specimens were analyzed weekly during the transplantation period up to day +100, Golob et al. found a trend of association between near-engraftment low microbiome diversity and the risk for grade 3-4 aGvHD.56 Likewise, Mancini et al. evaluating a cohort of 100 patients, observed a significant connection between low microbiome diversity by day +10 and an increased risk for early (within 30 days) aGvHD.38
A number of studies also reported an impact of pre- or post-transplant bacterial abundance on patient outcomes (Table 1). Results of a two-cohort study (a total of 115 adult patients) conducted at the Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated that increased abundance of the genus Blautia, including anaerobic commensal bacteria, observed 12 days post-transplant, was associated with reduced GvHD-related mortality and improved OS. At the same time, the use of antibiotics with anti-anaerobic activity and total parenteral nutrition (TPN) correlated with loss of Blautia.57 In the pediatric setting, Biagi et al. reported an association of pre-transplant high abundance of Blautia and low abundance of Fusobacterium with diminished risk for grade 2-4 acute GI GvHD.58 Additionally, pre-transplant Enterobacteriaceae abundance of >5% was associated with an increased risk of BSI and Lachnospiraceae abundance of ≤10% appeared to correspond to increased mortality.38 In a large study from the MSKCC, very high abundance of a bacterial group, mainly composed of Eubacterium limosum, in pretransplant samples or the presence of this group in periengraftment samples was found to correspond to a decreased relapse risk,59 once again emphasizing the association of the microbiome and T-cell immunity. Furthermore, in the study from the Osaka University,54 Enterococcus relative abundance of ≥1% at 1 month posttransplant appeared to be indicative of poor OS, with a 2- year survival of 83.9% for patients with relative abundance of Enterococcus <1% versus 47.6% for those in whom this parameter was ≥1%. It is noteworthy that none of the surviving patients at 1 year post-transplant displayed Enterococcus abundance higher than 1%, suggesting that this cutoff could serve as a prognosticator of a long-term outcome in this clinical setting.54 The above evidence suggests that the microbiota changes before and during allo-HSCT are significantly associated with transplant complications and outcomes and might even serve as a predictive marker in this setting.
Table 1. Intestine microbial changes in diversity and abundance during pre-transplant and peri-engraftment periods, associated with outcomes of allogeneic hematopoietic stem cell transplantation
Can prophylactic fecal microbiota transplantation reduce the risk of infections during allogeneic hematopoietic stem cell transplantation?
In allo-HSCT recipients, curtailment of infection risk is crucial for reducing TRM, particularly due to increased frequency of BSI with multidrug resistant (MDR) bacteria. MDR colonization is established to range between 16% for gram-negative bacteria and 39% for vancomycin- resistant Enterococcus (VRE). While BSI have been reported in 16-41% of patients colonized with MDR bacteria, findings regarding a possible association of such colonization with TRM or infection-related mortality are inconclusive.60-62 In addition, MDR gram-negative colonization has neither been found to correspond to an increased risk for sepsis.38,63 In the lack of clear evidence, proof-of-concept studies are becoming of increasing importance. Battipaglia et al.64 have evaluated four patients colonized with MDR bacteria who had received FMT on days -46 to -9 before transplant with an aim to limit the risk for infectious complications during HSCT. All the four patients responded with decolonization of the MDR bacteria. One patient developed grade 3 acute gut GvHD on day +30 after transplant (day +51 after FMT) and two others developed bacteremia with sensitive bacteria. Notably, despite receiving broad-spectrum antibiotics during the transplantation period, none of the patients had recolonization of the gut with MDR bacteria. 64 Similar results were reported in a 63-year old HSCT recipient.65
The ongoing ODYSSEE trial (clinicaltrials gov. Identifier: 02928523) is aimed at reducing complications that may arise as a result of a loss of microbiota diversity, including infectious complications, poor nutritional status, prolonged hospitalization, as well as therapy discontinuation due to induction treatment-related toxicity in AML patients. Twenty newly diagnosed patients collected pre-induction autologous stools. This autologous FMT was later administered as enema after neutrophil recovery and prior to consolidation chemotherapy. Preliminary results demonstrated safety of this approach, with evidence of stool diversity restoration 10 days after FMT and reduction in antibiotic resistant gene copy count by 43%. Yet, clinical efficacy of this method still needs to be confirmed. 66
An important pathogen to consider for intervention with FMT is Clostridium difficile. The incidence of CDI during allo-HSCT varies between 13% and 30%, mostly in the first month after transplant.67-69 The disease is usually of mild-to-moderate severity, with good response to treatment; there is no association with TRM, and its possible correlation to subsequent acute GI GvHD is indefinite. 68-70 Given these facts, and the paucity of data on potential efficacy of prophylactic FMT in reducing the risk of CDI among Clostridium difficile carriers, FMT prophylaxis may not be required for this indication.
As for the treatment of recurrent CDI, results of three small studies demonstrate safety of FMT administration to a total of 16 patients with recurrent CDI after allo- HSCT, with only three patients recurring after the procedure. 71-73
Currently available data are insufficient to definitively conclude that prophylactic FMT will reduce the infection rate in the allo-HSCT setting.
Can prophylactic fecal microbiota transplantation reduce the risk of acute graft-versus-host disease or transplant-related mortality?
The incidence of clinically significant aGvHD ranges between 22% in allo-HSCT from a matched related donor to 29% in case of a mismatched unrelated donor, with grade 3-4 disease incidence being 8.6% and 12%, respectively.24 Whether any intervention that restores the microbiome composition could also decrease aGvHD rates is yet to be revealed. Hitherto, only two small studies have reported results of using prophylactic FMT in the post-engraftment period. In the study by Defillip et al.,25 aiming to evaluate safety and feasibility of early restoration of the gut microbiome, frozen capsules of FMT derived from unrelated donors were administered to 13 allo-HSCT recipients 4 weeks after neutrophil engraftment. No FMT-related bacteremia events occurred and two cases of acute GI GvHD were registered. Analysis of stool composition indicated improvement in intestinal microbiome diversity after FMT that was mainly attributed to operational taxonomic units (OTU) originating from the FMT donor.25 In the study by Taur et al.,53 within 3-28 days of engraftment, patients not receiving broadspectrum antibiotics, not critically ill and with low abundance of Bacteroides (<0.1% of the total 16S sequencing) at that time period, were randomized to either receive autologous FMT (n=14) or to a control group (n=11).
Solely the FMT group was found to reconstitute their microbiome diversity and composition to the pre-transplant state. Of note, the use of autologous FMT raises concern for disrupted microbiota due to prior antibiotic exposure.53
These data suggest feasibility and safety of prophylactic FMT; however, its clinical benefit has not been demonstrated yet.
Should additional interventions along with fecal microbiota transplantation aiming to attenuate mircobiome disruption be considered?
Given that a variety of factors could affect the microbiome diversity and composition during the transplantation course, their adequate control might potentially preclude such microbiome changes. The question remains whether FMT alone is sufficient enough or it should be combined with other interventions to provide the required control.
Transplant conditioning
Conditioning chemotherapy itself has a disruptive effect on the microbiome, as found by Montassier et al.26 who evaluated eight lymphoma patients undergoing autologous HSCT with the BEAM (carmustine, etoposide, cytarabine arabine, melphalan) protocol. Since none of the patients received nasogastric tube nutrition, total parenteral nutrition, ciprofloxacin prophylaxis or systemic antibiotic treatment, only the chemotherapy effect on the microbiome was measured. Compared to pretransplant samples, those drawn at 1 week post-conditioning demonstrated significantly reduced diversity, decreased abundance of Firmicutes and Actinobacteria and increased presence in bacteroides and proteobacteria, indicating chemotherapy-induced disruption of the intestinal microbiota.26 Of note, this disruptive effect might be related to etoposide, which has bacterial inhibitory activity. 27,28 Remarkably, the post-transplant decrease in microbiome diversity appeared to be more profound when more intensive conditioning was applied.74 However, reducing the conditioning intensity was not shown to consistently decrease the rate of aGvHD.75 Moreover, it might increase the relapse rate and decrease long-term OS.76,77 Therefore, changing the conditioning regimen in an attempt to attenuate the insult on the microbiome is not currently recommended.
Diet
Dietary interventions such as TPN, prebiotics and probiotics could potentially influence the microbiome composition before or during the transplantation course. TPN administration was reported to be associated with decreased recovery of post-transplant (up to day +120) diversity compared to enteral nutrition. In addition, SCFA levels in the gut content were found to be lower in the TPN group.78 Iyama et al. retrospectively compared a group of patients whose diet was supplemented with prebiotics, i.e., glutamine, fiber and oligosaccharides (GFO) with a group that did not receive such supplementation. GFO was started 7 days before conditioning and continued up to day +28. In the GFO group, duration of diarrhea, mucositis and TPN requirement was shorter and the weight loss was also less prominent.44 An ongoing prospective trial (clinicaltrials gov. Identifier: 02763033) is evaluating the efficacy of resistant potato starch supplementation between day -7 and day +100 in HSCT recipients. This starch is a non-absorbable carbohydrate that is metabolized by the anaerobic commensal bacteria to produce the SCFA butyrate,79 shown to reduce the severity of acute GI GvHD in an experimental model.31 Preliminary results demonstrate the feasibility of this approach in terms of patient compliance, increase in intestinal butyrate levels and abundance of butyrate producing bacteria. 80 As for probiotic supplementation, the available data do not suggest its influence on the microbiome composition or clinical outcomes. It is worth mentioning that the products used in the studies contained only one bacterial strain and not a diversity of bacteria,43,81 and safety of probiotic administration is of concern in immunocompromised patients.82
The loss of diversity during the transplantation course is accompanied with microbiome domination by single taxonomic units such as Enterococcus.37 This enterococcal expansion has been found to be most prominent in patients developing acute GI GvHD.52 Stein-Thoeringer et al. have shown in a gnotobiotic mouse model of allo- HSCT that enterococcal expansion in the gut depends on lactose and its depletion decreases the enterococcal abundance and thus attenuates GvHD severity. Furthermore, in patients with a lactose malabsorption genotype, Enterococcus abundance appears to be higher than in patients without this genotype.83 This finding may give rise to a new approach to dietary intervention during HSCT. Interestingly, in the study by Khandelwal et al., where pediatric allo-HSCT patients under the age of 5 were treated with ready to eat human milk and breast feeding (n=24) or formula (n=14), plasma levels of IL6, IL10, and Reg3α were significantly lower in the group receiving human milk. The microbiome composition also differed between the two groups, with an increase in pathogenic species such as E. coli in the formula-receiving group. Despite the fact that human milk oligosaccharides are metabolized to SCFA by the commensal bacteria, butyrate levels in the stool were similar in both groups. Moreover, no significant difference in the rate of grade 2-4 acute GI GvHD between the groups was revealed. However, the limited size of this study calls for cautious interpretation of these encouraging results.84 Overall, dietary interventions emerge as a promising way to shape the intestinal microbiota during allo-HSCT. However, results are too preliminary and more research is required before implementing any of these methods.
Antibiotic treatment
The antibiotic treatment applied during the transplantation course is the main factor affecting the microbiome. Quinolone prophylaxis during afebrile neutropenia and systemic broad-spectrum antibiotic treatment with piperacillin-tazobactam or meropenem are widely accepted. 85-87 However, data demonstrate that the use of other antibiotics can better preserve gut beneficial commensals and is associated with improved outcomes.
The study from the University of Regensburg in Germany employed the non-absorbable antibiotic rifaximin and compared it to ciprofloxacin and metronidazole used in a historic cohort of patients for infection prophylaxis during allo-HSCT.45 Antibiotics were given from day -8 up to engraftment. The urine 3-indoxyl sulfate (3-IS) level was measured as a marker of microbiome diversity.88 In the rifaximin cohort, the pre-engraftment 3-IS levels were significantly higher without an increase in the sepsis rate or colonization with pathogenic bacteria. This group had significantly lower TRM, prolonged OS and the acute GI GvHD rate tended to be lower in these patients. The observed advantage remained evident even in patients who later received systemic antibiotics for neutropenic fever. 45
Given the major role of microbiome diversity preservation during allo-HSCT and an association of impaired diversity with acute GI GvHD and adverse patient outcome, Weber et al. further compared the effects of various prophylactic and systemic antibiotics in an attempt to identify the ones that could spare commensal bacteria.89 At 10 days post-transplant, the patient groups receiving rifaximin without systemic antibiotics or rifaximin with systemic antibiotics maintained their microbiome diversity and Clostridia abundance and had higher 3-IS levels compared to patients treated with ciprofloxacin/metronidazole ± systemic antibiotics. These results suggest that rifaximin could better preserve microbiome diversity even when systemic broad-spectrum antibiotics are administered during transplantation. Moreover, in the study conducted in two Canadian hospitals and assessing the effect of antibiotic prophylaxis or treatment given before day 0 on frequency of aGvHD and mortality, the authors compared the outcome of a cohort of patients exposed to antibiotics (n=239) to those who did not receive this therapy (n=261).90 The antibiotic-receiving group demonstrated a significantly higher incidence of grade 2-4 aGvHD and significantly shorter OS at 1, 2 and 10 years posttransplant, indicating an association between the deleterious effect of such treatment on intestinal bacteria and inferior patient outcome.
Importantly, early start of systemic antibiotics (before engraftment) was found to be associated with a lower 3- IS urine level and decreased Clostridia abundance in the stool. Furthermore, the TRM rate in such cases was higher than in patients who did not require systemic antibiotics during HSCT or started them after engraftment.91
Similarly, systemic treatment with piperacillin-tazobactam and meropenem was reported to correlate with decreased microbiome diversity during the transplantation37 and significant loss of commensal anaerobic bacteria. 92 In pediatric patients, Simms-Waldrip et al.93 found that higher load of anti-anaerobic antibiotics was associated with a significant decrease in anti-inflammatory Clostridia (AIC) abundance, and in patients with aGvHD the abundance decrease was severe (10-log fold) compared to patients without GvHD. In a mouse allo-HSCT model, clindamycin administration was associated with AIC decrease and more severe GvHD, while re-administration of AIC increased its levels in the gut and improved survival.93 Additionally, Lee et al.94 compared patients who did not require any systemic antibiotic treatment during the transplantation course with those who received cefepime and those who were treated with carbapenem antibiotics. The carbapenem group displayed a significant loss of microbial diversity at engraftment and an increased rate of acute GI GvHD (32.1%) compared to the noantibiotics group (11.6%). Interestingly, the cefepime group retained a diverse microbiome, demonstrating only a trend to a higher GI GvHD rate (26.4%).
Furthermore, a large multicenter study retrospectively evaluating 857 patients revealed that the use of piperacillin-tazobactam and imipenem-cilastatin was associated with increased 5-year GvHD-related mortality, 95 while this was not observed in patients receiving cefepime and aztreonam. The former antibiotics caused a significant decrease in abundance of Bacteroidetes and Lactobacillus compared to the latter ones. These results suggest that some antibiotics may be more beneficial than others in the setting of allo-HSCT, and that this beneficial effect is related to the antibiotic ability to be less detrimental to intestinal commensal bacteria.95 Findings in the pediatric setting were consistent with these data, and exposure to anti-anaerobic antibiotics was reported to result in a significant decrease in butyrate-producing bacteria and the butyrate level in luminal content by day +14. Pediatric patients who later developed aGvHD had a significantly lower butyrate level at that time point than patients without GvHD.96
It was also demonstrated that specific antibiotic use during allo-HSCT could change the abundance of specific taxa which was associated with BSI risk. In a cohort of 94 patients, Taur Y et al.50 found that domination of the gut microbiome (abundance ≥30%) by single bacterial taxa Enterococcus and Streptococcus occurred at the peri-engraftment period (days +10 to +20) in two thirds of the patients. However, treatment with metronidazole increased the risk for enterococcal domination by 3-fold, and this domination elevated the risk for VRE bacteremia by 9-fold. Altogether, these data establish an essential role of antibiotics in disrupting or preserving the intestinal microbiota during allo-HSCT.
Case 1: conclusions
Several issues should be considered in decision-making regarding the appropriate management of this case. This patient has pre-transplant intestinal microbiota disruption and assumed colonization by MDR bacteria and probably by Clostridium difficile. His risk for aGvHD is high, since he has undergone allo-HSCT from a mismatched unrelated donor. Quinolone prophylaxis and meropenem treatment for BSI have further disrupted his intestinal microbiota. The existence of pre-transplant microbiota disruption, mainly attributed to the use of broad-spectrum antibiotics during intensive chemotherapy, is associated with increased TRM, shorter OS and GvHD-related mortality. Pre-transplant FMT can potentially enrich the microbiome diversity and eradicate MDR bacteria or Clostridium difficile; however, without controlling such factors as antibiotic prophylaxis and the type of systemic antibiotic therapy employed, the intervention by FMT may not completely achieve its goals.
Table 2. Clinical trials of fecal microbiota transplant in allogeneic hematopoietic stem cell transplantation.
So far, no data are available regarding a clinical benefit of prophylactic pre-transplant FMT.
While an association between peri-engraftment microbiome low diversity and patient outcome is established, implying potential feasibility of FMT use at that stage, data regarding FMT application before engraftment are not available, and for safety reasons this approach will probably not be attempted. Results of several small-scale studies suggest safety and feasibility of post-engraftment FMT in restoring microbiome diversity (Table 2); however, it remains unknown if this strategy could decrease the risk for aGvHD-related mortality and TRM.
As for dietary interventions at this period, their efficacy is still under investigation. Choosing a different antibiotic prophylaxis, such as rifaximin and systemic antibiotics such as cefepime, looks promising. Nevertheless, new strategies need to be tested to prove their non-inferiority in OS85 and to establish less disruption for the microbiome (clinicaltrials gov. Identifier: 03078010), especially since fourth-generation cephalosporins have been found in one study to be associated with an increased risk for aGvHD.97
Case 1: recommendations
In this case, based on the currently available data, we do not recommend prophylactic administration of pretransplant or post-engraftment FMT.
Case 2
A 25-year old female with intermediate-risk AML in CR underwent an allo-HSCT with BuCy myeloablative conditioning from her matched sibling. Her neutrophils engrafted by day +14. On day +34 she developed grade 3 aGvHD of the lower GI tract which was steroid refractory (SR). She did not respond to the addition of budesonide, extracorporeal photopheresis (ECP), mofetil mycophenolate or infliximab.
Can fecal microbiota transplantation mitigate prevailing acute gastrointestinal graft-versushost disease?
The current data regarding the use of FMT for the treatment of acute GI GvHD are limited to case reports and small case series (Table 2). A total of 58 described patients were treated with FMT for SR GI grade 2-4 aGvHD. The FMT source was an unrelated donor in 36 cases, a related donor – in six cases and in eight cases a commercial pooled highly diverse FMT was used. FMT was processed and either given fresh within a few hours of collection or it was frozen and later thawed before administration. FMT was administered orally as packed capsules, through a nasogastric/ nasoduodenal tube or an enema. Of 58 patients, 28 received FMT after two or more therapy lines, while 19 received it as second-line therapy right after steroid failure. Response was observed in 74% (43 of 58) of patients, with complete response in 57% (33 of 58) and partial response in 17% (10 of 58). Complete response was observed in 73% of patients receiving FMT as second-line therapy. Ten of the responding patients relapsed and 29 patients were alive at the last follow-up (54%; 29 of 54 patients with available data).
Response to treatment was seen within a median of 14 days (range: 3-28), with a median of two FMT (range: 1-7), and a median of 7 days between treatments (range: 2-60).46,98-106
Infectious complications occurred in 11 patients. Two had sepsis with bacteria not originating from FMT,102 and one patient developed diarrhea due to Norovirus that was traced to FMT.106 Other infections were attributed to the severe immunocompromised state of patients. However, a possible association with FMT could not be ruled out. In responding patients in whom the stool microbiome was sequenced post-FMT, it was found to be significantly more diverse and enriched with Bacteroides, Lactobacillus, Bifidobacterium and Faecalibacterium compared to pre-FMT microbiome.46,98-101 Notably, the diversity increased only upon discontinuation of anti-anaerobic systemic antibiotic treatment, such as piperacillin-tazobactam. However, continuous use or re-initiating treatment with cefepime did not reduce FMT efficiency.46,98,99
These results are highly encouraging and support FMT therapy to be relatively safe and effective in SR GI aGvHD.
Case 2: conclusions
Available data suggest a potentially beneficial effect of FMT in acute lower GI GvHD. It should probably be used earlier rather than later, so that patients' response will not be overcome by infectious complications related to extensive immunosuppressive therapy. Discontinuation of antibiotic treatment prior to FMT administration appears to be an important factor contributing to successful response. If antibiotic treatment is required, using cefepime may allow attenuating microbiome insult while maintaining clinical response.
Current information is based on case reports and small series with a wide variability in patient selection, FMT preparation and mode of administration. However, the reported feasibility, safety and clinical benefit appear to be similar across the studies, implying that intestinal microbiota can be recovered with FMT, irrespective of its administration method. Safety remains a concern,107 especially in advanced GI aGvHD, and if an infectious complication occurs post-FMT, the pathogen should be sequenced and traced to find out if it originates from the FMT.
Case 2: recommendations
Currently, ruxolitinib is the only FDA-approved drug for the treatment of SR aGvHD, while other modalities are also commonly used in this scenario (e.g., extracorporeal photopheresis). Thus, FMT could be recommended for patients with grade 2-4 steroid refractory or dependent aGVHD of the lower GI tract, albeit in the context of a clinical study only.108-110 Other treatment approaches could also be considered, such as adding it to steroids as part of the first-line therapy (clinicaltrials gov. Identifier: 04269850).
Although clinical trials are still ongoing, given the grave prognosis of SR aGvHD with more than 50% mortality,111 and the high rate of response to FMT, we recommend considering FMT as a therapeutic option in this setting.
Practical considerations for fecal microbiota transplantation treatment
As FMT has become the standard of care in recurrent and refractory CDI,112,113 more and more centers are gaining access to FMT programs through either establishing their own stool banks or acquiring FMT from universal stool banks.114,115
One of the limiting factors to wider application of stool banks and FMT programs is the lack or variance of regulatory standards. In different countries, FMT is regulated as a drug, tissue or a combined product composed of both human cells and non-human components (microbial DNA and metabolites). Stool banks are recommended to operate under the designated authority in each country. In the absence of local directives, the scientific committee should be responsible for establishing regulatory protocols.114
FMT donor screening should follow national regulations and international recommendations.114 Screening should include medical history related to the risk for transmitting infections, as well as medical conditions and treatments associated with perturbed microbiome (Table 3). Special considerations are to be applied when planning FMT use in allo-HSCT patients, such as testing the donor for Cytomegalovirus and Epstein-Barr virus IgG and IgM, and administering FMT from seronegative donors to seronegative patients. However, when weighing suitability of an FMT donor, one should be cognizant of the fact that no data are available to support the advantage of a particular donor (a family member, an unrelated donor, or pooled stool from several unrelated donors).
As for autologous FMT, it has not been tested in the setting of aGvHD treatment. Since the microbiota composition of a patient is already disrupted prior to HSCT, using such stool in FMT preparation to be applied for diversity restoration may not be effective. In order to circumvent this problem, in AML patients, we recommend freezing self-stool before the beginning of induction chemotherapy.
In CDI, both fresh and frozen FMT have been shown to be efficient116 as have been the two delivery routes − colonoscopy and oral capsules.117 While there are no data pointing to the superiority of either method of preparation or administration for aGvHD treatment, frozen samples from a stool bank allow FMT to be readily available for immediate use without the need to wait for donor screening and FMT collection.
The basic principles of FMT preparation include weighing the sample, suspension in sterile solution (saline), adding glycerol in case the FMT is planned for freezing and storing, homogenization, filtering and aliquoting the suspension for fresh use or freezing (Table 3). The FMT product should be registered and labeled.114
Based on the available data (Table 2) we suggest evaluating clinical response at 7-14 days after FMT administration. If no response or only partial response is achieved, we recommend administering a second dose of FMT. Whether in such cases the use of FMT from another donor could provide a superior outcome is yet to be determined. In general, in order to consider FMT as an efficacious therapeutic approach for SR GI aGvHD management, an overall response rate of around 60-70%, with a complete response rate of 30-50% should be a desired target, as these rates are achieved with the use of the approved ruxolitinib treatment and in non-randomized FMT studies.46,98-106,110
As for the antibiotic treatment peri-FMT, if feasible, 24-48 hours prior to FMT, systemic antibiotics should be stopped or replaced by one with less anti-anaerobic activity such as rifaximin for prophylaxis or cefepime for febrile neutropenic treatment.46,98,99
Microbiome sequencing of donor and patient samples could help interpreting clinical outcomes. It could also be valuable in distinguishing between the donor and the recipient as the source of post-FMT infection. However, currently there are no data suggesting that patient stool sequencing prior to FMT could guide its administration or affect the outcome. Therefore, given that the primary outcome should be the clinical response to treatment we recommend treating SR GI aGvHD patients with FMT even if the microbiome analysis is not available. Nonetheless, we do suggest storing stool samples from the donor and the patient (before and after FMT) for later sequencing if it becomes available.
Table 3. Practical aspects of fecal microbiota transplantation.
Further accumulation of data on FMT for SR GI aGvHD will allow wider and more efficient application of this treatment approach.
Open challenges and future directions
Disruption of the intestinal microbiome during allo- HSCT is a multifaceted process with a cause-and-effect relationship between multiple factors such as conditioning, diet and antibiotic treatment. Lately, FMT has emerged as an intervention that can facilitate microbiome recovery and potentially intervene with the above interplay (Figure 1). The intestinal microbial disruption before and during allo-HSCT is clearly associated with transplant-related outcomes, mainly acute GvHD and mortality, and pre-clinical data demonstrate the key role of the intestinal microbiota in protecting the gut from inflammatory damage and in regulating the innate immune system to maintain a more tolerant state.118 While the addition of beneficial bacteria or their metabolites has been shown to ameliorate acute GvHD in animal allo-HSCT models, many challenges remain concerning the role of the intestinal microbiota in allo-HSCT in humans. A substantial amount of basic research is being conducted aiming to better understand the place of microbiome changes in the pathogenesis of acute GvHD. In addition, a large population microbiome analysis is ongoing attempting to delineate the interplay between other factors, such as antibiotics and diet, and the microbiota disruption, and to determine the optimal strategy allowing to preserve the microbiota intact.119 However, while these issues are still under investigation, clinical trials evaluating the efficacy of FMT and other abovementioned interventions in the HSCT setting are underway (Table 2). Joint efforts to further explore biological, correlative and recovery functions of the intestinal microbiota could ultimately lead to decreased transplantrelated mortality, and even pave the way to personalized therapeutic strategies in HSCT.
Figure 1. The multifactorial interplay between environmental factors, intestinal microbiota and tissue damage affects transplant-related outcomes. During allogeneic hematopoietic stem cell transplantation (allo-HSCT), conditioning chemotherapy causes damage to the intestinal mucosa cells such as intestinal epithelial cells, intestinal stem cells, paneth cells and mucus producing goblet cells. Gut microbiota is already disrupted before allo-HSCT and due to prophylactic and systemic antibiotic therapy the microbiota disruption worsens with loss of butyrate producing bacteria and other beneficial commensals, along with increase in pathogenic bacteria such as Enterococcus. Depletion of bacterial metabolites postpones epithelial cell repair and restoration of the mucus barrier. Pathogenic bacteria can disseminate through the damaged mucosa and cause blood stream infections, which will necessitate the administration of systemic antibiotics further disrupting the intestinal microbiota. This vicious cycle is associated with graft-versus-host disease (GvHD), increased mortality and diminished overall survival. The question remains whether fecal microbiota transplantation (FMT) and other interventions such as prebiotics and the use of antibiotics with less anti-anaerobic activity could eventually break the cycle and improve outcomes. IEC:– intestinal epithelial cells; ISC: intestinal stem cells.
Supplementary Material
Disclosures and Contributions
Acknowledgements
The authors wish to thank Sonia Kamenetsky for her assistance in the preparation of this manuscript. | MYELOABLATIVE CONDITIONING | DrugDosageText | CC BY-NC | 33241674 | 19,317,760 | 2021-04-01 |
What was the dosage of drug 'FLUDARABINE PHOSPHATE'? | The clinical role of the gut microbiome and fecal microbiota transplantation in allogeneic stem cell transplantation.
Outcomes of allogeneic hematopoietic stem cell transplantation (allo- HSCT) have improved in the recent decade; however, infections and graft-versus-host disease remain two leading complications significantly contributing to early transplant-related mortality. In past years, the human intestinal microbial composition (microbiota) has been found to be associated with various disease states, including cancer, response to cancer immunotherapy and to modulate the gut innate and adaptive immune response. In the setting of allo-HSCT, the intestinal microbiota diversity and composition appear to have an impact on infection risk, mortality and overall survival. Microbial metabolites have been shown to contribute to the health and integrity of intestinal epithelial cells during inflammation, thus mitigating graft-versus-host disease in animal models. While the cause-andeffect relationship between the intestinal microbiota and transplant-associated complications has not yet been fully elucidated, the above findings have already resulted in the implementation of various interventions aiming to restore the intestinal microbiota diversity and composition. Among others, these interventions include the administration of fecal microbiota transplantation. The present review, based on published data, is intended to define the role of the latter approach in the setting of allo-HSCT.
Introduction
The past decades have witnessed important advances in the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT),1 mainly attributed to the reduction in non-relapse mortality.2 Yet, the need for further improvement is compelling. Acute graft-versus-host disease (aGvHD) and infections are two of the main causes of early transplant-related mortality (TRM), jointly accounting for 36% and 43% of deaths by day 100 in matched related and matched unrelated transplants, respectively.1
One of the emerging and extensively explored allo-HSCT-associated issues is the change in the gut microbial flora, as well as its effect on the pathogenesis of transplant- related complications and association with transplant outcomes.
The human body hosts a hundred trillion microbial organisms; the majority of them are bacteria, predominantly colonizing the gut, with the lower intestine being most densely colonized (1011-1012 organisms/g of intestinal content).3 The composition of bacteria in the gut is referred to as the intestinal microbiota and their collective genome is termed the “intestinal microbiome”.3 The two main phyla constituting more than 90% of the gut microbiota are the Firmicutes and Bacteroidetes and among less dominant phyla are Proteobacteria, Actinobacteria, and Verrucomicrobia.4 This composition is relatively flexible and can rapidly change in response to different environmental factors, adjusting the metabolic and immunologic performance accordingly.5 Intestinal microbiota has been recently found to have a significant impact on both health and disease states. It appears to be crucial for the maturation and education of the immune system and has a role in intestinal cell proliferation, intestine vascularization and endocrine functions. Moreover, it produces energy, synthesizes vitamins, metabolizes bile acids and even inactivates drugs.6-13 The microbiome has been reported to be associated with a variety of disorders such as obesity, type 2 diabetes, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis.14-17 This association is also suggested to be true for cancer18 and response to cancer immunotherapy.19 The gut microbiota has a close and reciprocal relationship with the host immune system. Intestinal epithelial cells, goblet and paneth cells produce the luminal protective mucosal layer and antimicrobial peptides, allowing the transcellular transport of immunoglobulin A (IgA) antibodies. These functions regulate luminal microbial colonization.20
Homeostasis of the immune response in the gut mucosa is maintained by the balance between pro-inflammatory cells, which include T-helper 1 (Th1) cells producing interferon γ (IFNγ), Th17 cells producing IL-17A and IL-22, diverse innate lymphoid cells with cytokine effector features resembling those of Th2 and Th17 cells, the antiinflammatory Foxp3+ regulatory T-cells (Tregs) and IgAsecreting B-cells. This homeostasis can be modulated by the gut microbiota.21-23 In pre-clinical studies, intestinal microbiota has been shown to regulate the expression of pro-inflammatory cytokines, human leukocyte antigen (HLA) type I and type II molecules and increase T-cell proliferation. 18 Effects of the microbiota on cytokine expression and immune cell subsets are not limited to the gut, and are extended to regional mesenteric and systemic lymph nodes.24 Furthermore, while some bacterial strains can induce pro-inflammatory intestinal Th17 cells,25 others induce anti-inflammatory Tregs26,27 and can thus ameliorate inflammatory colitis.28 Moreover, human host gut microbiota has been shown to correlate with expression pattern of the cytokines secreted from peripheral blood mononuclear cells isolated from the host.29 Microbial metabolites such as the short chain fatty acid (SCFA) butyrate or indole derivatives produced by tryptophan metabolism act to maintain the intestinal epithelial cell health, mucosal barrier, and to promote anti-inflammatory responses.30,31
Currently available molecular techniques allowing rapid and wide genomic sequencing enable extensive exploration of the microbiome. The most commonly used method is the 16S ribosomal RNA sequencing by PCR. Bioinformatics analysis tools assign the sequences to microbial taxon at different taxonomic levels. Other methods include shotgun next-generation metagenomics sequencing enabling massive and deeper genomic sequencing and allowing better identification of taxonomic species and potential functional pathways of the organisms, metatranscriptomics using high throughput RNA sequencing to profile gene expression, metaproteomics capable to provide large-scale characterization of the entire proteins in the environmental sample and metabolomics, identifying and quantifying all metabolites in the tested samples.32,33 The two main microbiome features that have been widely characterized in health and disease are its diversity and the abundance of specific bacteria or bacterial subgroups.34
The revelation of significant relationship between the microbiome, the immune system and disease has led to interventional studies aiming to normalize the microbiome composition and diversity thus ameliorating disease conditions. One of such interventions is the use of fecal microbiota transplantation (FMT), the term referring to the transfer of the fecal microbial content from a healthy individual into the intestine of a diseased individual. FMT, the standard of care for refractory or recurrent Clostridium difficile infection (CDI), proved to be highly effective in this condition. At the same time, mixed results were demonstrated in the studies evaluating the use of FMT for the management of inflammatory bowel disease, irritable bowel syndrome and hepatic encephalopathy. To date, FMT application for indications other than CDI has been limited to the experimental setting only.35,36
The setting of allo-HSCT imposes a significant disruption on the gut microbiome homeostasis through a variety of mechanisms (all part of the transplantation procedure), such as the use of broad-spectrum antibiotics, dietary changes (restriction), gut epithelial damage by conditioning regimens and introduction of a donor immune system.
Data from clinical studies support the association of alterations in the gut microbiome profile, mainly loss of diversity and change in composition during allo-HSCT, with patient outcomes such as aGvHD, GvHD-related mortality, non-relapse mortality (NRM) and overall survival (OS).37-40 Moreover, the gut microbial composition is reported to have an impact on infection risk, including CDI and blood stream infections (BSI), in this clinical setting. 38,41 Findings of these associations have led to a preponderance of research in this field,42 and although the causeand- effect relationship between the microbiome and transplant complications has not been unequivocally established, many ongoing clinical trials are implementing various interventions aiming to maintain microbiome diversity, thus potentially preventing transplant-related complications and treating aGvHD. These interventions include the use of probiotics,43 prebiotics,44 change in antibiotic prophylaxis45 and administration of FMT.46 This review appraises the currently available evidence on the association of gut microbiota and allo-HSCT and analyzes a potential role of FMT in allo-HSCT, by presenting two illustrative clinical cases, where effects on the gut microbiota composition could be employed either as a prophylactic or therapeutic measure.
Case 1
A 54-year old male, with mutated FLT3-ITD acute myeloid leukemia (AML) in complete remission (CR) after induction and re-induction chemotherapies, during which he acquired gut colonization with carbapenemresistant Klebsiella pneumoniae. He underwent an allo- HSCT from a mismatched 9/10 unrelated female donor with myeloablative conditioning (busulfan, fludarabine) and received levofloxacin for infection prophylaxis. During the transplantation period, he had a BSI event with extended spectrum β lactamase Escherichia coli (E. coli) treated with meropenem for 10 days, followed by a CDI event treated with oral vancomycin. His neutrophils engrafted on day +15 and on day +33 he developed diarrhea and was diagnosed with grade 3 acute lower gastrointestinal (GI) GvHD that was steroid refractory.
This case raises a number of important questions related to the role of gut flora in allo-HSCT.
Is the microbiome already disrupted prior to allogeneic hematopoietic stem cell transplantation conditioning?
There is ample evidence suggesting that the pre-transplant patient microbiome is already disrupted. The insult to the microbiome starts with preceding chemotherapy and antibiotic exposure. Galloway-Pena et al.47 analyzed 487 stool samples from 30 AML patients and found that their pre-induction microbiome diversity was not significantly different from that of healthy volunteers participating in the Human Microbiome Project (HMP). However, following neutrophil recovery, patient microbiome composition changed, with a significant decrease in diversity. Importantly, this reduction in diversity was associated with an increased risk of infections. The use of carbapenem antibiotics for more than 3 days during induction elevated the risk for a subsequent loss of diversity.47Moreover, exposure to anti-anaerobic antibiotics, like piperacillin-tazobactam, ticarcillin, meropenem, clindamycin and metronidazole, within the 3 months preceding allo-HSCT was associated with a significant decrease in pre-transplant microbiome diversity.38 With more courses of intensive chemotherapy, such as re-induction or salvage, the microbiome disruption was shown to enhance, leading to ecosystem instability and outgrowth of pathogenic bacteria like Enterococcus.48 This disruption in patient microbiome continued up to the time of allo-HSCT, as shown in the largest to date inter-center effort, where 8,767 sequential stool samples were collected from 1,362 patients prior to and throughout the transplantation period and analyzed using 16S ribosomal RNA sequencing. The pre-transplant microbiome of patients obtained on days -30 to -6 (n=606), was compared to that of healthy volunteers (n=246), demonstrating a significant reduction in diversity in patient microbiome.37 Additionally, evidence from another recently published study showed that the pre-transplant microbiome and the one derived from healthy controls differed in composition, displaying decreased abundance of beneficial bacteria of genera Bifidobacterium and butyrate producing genera such as Faecalibacterium and Lachnospiraceae in the former case.49 To conclude, pre-transplant microbiome disruption is clearly evident.
What is the microbiome status during the transplantation period and at time of recovery?
Data from several studies demonstrate that during the transplantation course, the microbiome diversity significantly decreases and its composition changes.37,50 The lower-diversity microbiome is reported to be characterized by abundance of pathogenic bacteria such as Enterococcus, Klebsiella, Escherichia, Staphylococcus and Streptococcus. The single taxonomic unit domination (abundance ≥30%) peaks at 1 week post-transplant, which is followed by a subsequent moderate decrease. The most common dominating taxonomic groups belong to the genera Enterococcus and Streptococcus.37 Along the same lines, other studies have found the Enterococcus genus to be more prolific during the first month posttransplant, with significantly higher abundance in patients with active or subsequent aGvHD.51,52 Following allo-HSCT, the microbiome recovery appears to be prolonged and incomplete. In a large cohort of patients (n=753), the post-transplant recovery of the gut microbiota has been reported to start around day +50, but even by day +100 the composition and bacterial abundance observed pre-transplant have not been fully achieved.53 Moreover, in some patients, microbiota has remained disrupted even 1 year after HSCT, this being particularly the case with butyrate-producing bacteria and Bifidobacterium.54 Eventually, the effect of environmental insult on the intestinal microbiota during allo-HSCT can be so severe that its recovery may require a long time.
Is the disrupted microbiome in allogeneic hematopoietic stem cell transplantation recipients clinically significant?
In the above-mentioned study by Peled et al., reduced microbiome diversity both pre-transplant (days -30 to -6) and peri-engraftment (days +7 to 21), was shown to be significantly associated with lower 2-year OS, while a persistent decrease of this parameter in the latter period was also associated with higher 2-year treatment-related mortality (TRM). Moreover, lower peri-engraftment microbiome diversity in T-cell replete allo-HSCT corresponded to increased GvHD-related mortality, which was not observed in T-cell depleted transplantations. This difference suggests a connection between the microbiota and T-cell alloreactivity.37 Liu et al. revealed a similar association of pre-transplant diversity with mortality as well as a correlation between post-transplant microbiome disruption and acute GI GvHD risk.55 Furthermore, in a study of 66 patients whose stool specimens were analyzed weekly during the transplantation period up to day +100, Golob et al. found a trend of association between near-engraftment low microbiome diversity and the risk for grade 3-4 aGvHD.56 Likewise, Mancini et al. evaluating a cohort of 100 patients, observed a significant connection between low microbiome diversity by day +10 and an increased risk for early (within 30 days) aGvHD.38
A number of studies also reported an impact of pre- or post-transplant bacterial abundance on patient outcomes (Table 1). Results of a two-cohort study (a total of 115 adult patients) conducted at the Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated that increased abundance of the genus Blautia, including anaerobic commensal bacteria, observed 12 days post-transplant, was associated with reduced GvHD-related mortality and improved OS. At the same time, the use of antibiotics with anti-anaerobic activity and total parenteral nutrition (TPN) correlated with loss of Blautia.57 In the pediatric setting, Biagi et al. reported an association of pre-transplant high abundance of Blautia and low abundance of Fusobacterium with diminished risk for grade 2-4 acute GI GvHD.58 Additionally, pre-transplant Enterobacteriaceae abundance of >5% was associated with an increased risk of BSI and Lachnospiraceae abundance of ≤10% appeared to correspond to increased mortality.38 In a large study from the MSKCC, very high abundance of a bacterial group, mainly composed of Eubacterium limosum, in pretransplant samples or the presence of this group in periengraftment samples was found to correspond to a decreased relapse risk,59 once again emphasizing the association of the microbiome and T-cell immunity. Furthermore, in the study from the Osaka University,54 Enterococcus relative abundance of ≥1% at 1 month posttransplant appeared to be indicative of poor OS, with a 2- year survival of 83.9% for patients with relative abundance of Enterococcus <1% versus 47.6% for those in whom this parameter was ≥1%. It is noteworthy that none of the surviving patients at 1 year post-transplant displayed Enterococcus abundance higher than 1%, suggesting that this cutoff could serve as a prognosticator of a long-term outcome in this clinical setting.54 The above evidence suggests that the microbiota changes before and during allo-HSCT are significantly associated with transplant complications and outcomes and might even serve as a predictive marker in this setting.
Table 1. Intestine microbial changes in diversity and abundance during pre-transplant and peri-engraftment periods, associated with outcomes of allogeneic hematopoietic stem cell transplantation
Can prophylactic fecal microbiota transplantation reduce the risk of infections during allogeneic hematopoietic stem cell transplantation?
In allo-HSCT recipients, curtailment of infection risk is crucial for reducing TRM, particularly due to increased frequency of BSI with multidrug resistant (MDR) bacteria. MDR colonization is established to range between 16% for gram-negative bacteria and 39% for vancomycin- resistant Enterococcus (VRE). While BSI have been reported in 16-41% of patients colonized with MDR bacteria, findings regarding a possible association of such colonization with TRM or infection-related mortality are inconclusive.60-62 In addition, MDR gram-negative colonization has neither been found to correspond to an increased risk for sepsis.38,63 In the lack of clear evidence, proof-of-concept studies are becoming of increasing importance. Battipaglia et al.64 have evaluated four patients colonized with MDR bacteria who had received FMT on days -46 to -9 before transplant with an aim to limit the risk for infectious complications during HSCT. All the four patients responded with decolonization of the MDR bacteria. One patient developed grade 3 acute gut GvHD on day +30 after transplant (day +51 after FMT) and two others developed bacteremia with sensitive bacteria. Notably, despite receiving broad-spectrum antibiotics during the transplantation period, none of the patients had recolonization of the gut with MDR bacteria. 64 Similar results were reported in a 63-year old HSCT recipient.65
The ongoing ODYSSEE trial (clinicaltrials gov. Identifier: 02928523) is aimed at reducing complications that may arise as a result of a loss of microbiota diversity, including infectious complications, poor nutritional status, prolonged hospitalization, as well as therapy discontinuation due to induction treatment-related toxicity in AML patients. Twenty newly diagnosed patients collected pre-induction autologous stools. This autologous FMT was later administered as enema after neutrophil recovery and prior to consolidation chemotherapy. Preliminary results demonstrated safety of this approach, with evidence of stool diversity restoration 10 days after FMT and reduction in antibiotic resistant gene copy count by 43%. Yet, clinical efficacy of this method still needs to be confirmed. 66
An important pathogen to consider for intervention with FMT is Clostridium difficile. The incidence of CDI during allo-HSCT varies between 13% and 30%, mostly in the first month after transplant.67-69 The disease is usually of mild-to-moderate severity, with good response to treatment; there is no association with TRM, and its possible correlation to subsequent acute GI GvHD is indefinite. 68-70 Given these facts, and the paucity of data on potential efficacy of prophylactic FMT in reducing the risk of CDI among Clostridium difficile carriers, FMT prophylaxis may not be required for this indication.
As for the treatment of recurrent CDI, results of three small studies demonstrate safety of FMT administration to a total of 16 patients with recurrent CDI after allo- HSCT, with only three patients recurring after the procedure. 71-73
Currently available data are insufficient to definitively conclude that prophylactic FMT will reduce the infection rate in the allo-HSCT setting.
Can prophylactic fecal microbiota transplantation reduce the risk of acute graft-versus-host disease or transplant-related mortality?
The incidence of clinically significant aGvHD ranges between 22% in allo-HSCT from a matched related donor to 29% in case of a mismatched unrelated donor, with grade 3-4 disease incidence being 8.6% and 12%, respectively.24 Whether any intervention that restores the microbiome composition could also decrease aGvHD rates is yet to be revealed. Hitherto, only two small studies have reported results of using prophylactic FMT in the post-engraftment period. In the study by Defillip et al.,25 aiming to evaluate safety and feasibility of early restoration of the gut microbiome, frozen capsules of FMT derived from unrelated donors were administered to 13 allo-HSCT recipients 4 weeks after neutrophil engraftment. No FMT-related bacteremia events occurred and two cases of acute GI GvHD were registered. Analysis of stool composition indicated improvement in intestinal microbiome diversity after FMT that was mainly attributed to operational taxonomic units (OTU) originating from the FMT donor.25 In the study by Taur et al.,53 within 3-28 days of engraftment, patients not receiving broadspectrum antibiotics, not critically ill and with low abundance of Bacteroides (<0.1% of the total 16S sequencing) at that time period, were randomized to either receive autologous FMT (n=14) or to a control group (n=11).
Solely the FMT group was found to reconstitute their microbiome diversity and composition to the pre-transplant state. Of note, the use of autologous FMT raises concern for disrupted microbiota due to prior antibiotic exposure.53
These data suggest feasibility and safety of prophylactic FMT; however, its clinical benefit has not been demonstrated yet.
Should additional interventions along with fecal microbiota transplantation aiming to attenuate mircobiome disruption be considered?
Given that a variety of factors could affect the microbiome diversity and composition during the transplantation course, their adequate control might potentially preclude such microbiome changes. The question remains whether FMT alone is sufficient enough or it should be combined with other interventions to provide the required control.
Transplant conditioning
Conditioning chemotherapy itself has a disruptive effect on the microbiome, as found by Montassier et al.26 who evaluated eight lymphoma patients undergoing autologous HSCT with the BEAM (carmustine, etoposide, cytarabine arabine, melphalan) protocol. Since none of the patients received nasogastric tube nutrition, total parenteral nutrition, ciprofloxacin prophylaxis or systemic antibiotic treatment, only the chemotherapy effect on the microbiome was measured. Compared to pretransplant samples, those drawn at 1 week post-conditioning demonstrated significantly reduced diversity, decreased abundance of Firmicutes and Actinobacteria and increased presence in bacteroides and proteobacteria, indicating chemotherapy-induced disruption of the intestinal microbiota.26 Of note, this disruptive effect might be related to etoposide, which has bacterial inhibitory activity. 27,28 Remarkably, the post-transplant decrease in microbiome diversity appeared to be more profound when more intensive conditioning was applied.74 However, reducing the conditioning intensity was not shown to consistently decrease the rate of aGvHD.75 Moreover, it might increase the relapse rate and decrease long-term OS.76,77 Therefore, changing the conditioning regimen in an attempt to attenuate the insult on the microbiome is not currently recommended.
Diet
Dietary interventions such as TPN, prebiotics and probiotics could potentially influence the microbiome composition before or during the transplantation course. TPN administration was reported to be associated with decreased recovery of post-transplant (up to day +120) diversity compared to enteral nutrition. In addition, SCFA levels in the gut content were found to be lower in the TPN group.78 Iyama et al. retrospectively compared a group of patients whose diet was supplemented with prebiotics, i.e., glutamine, fiber and oligosaccharides (GFO) with a group that did not receive such supplementation. GFO was started 7 days before conditioning and continued up to day +28. In the GFO group, duration of diarrhea, mucositis and TPN requirement was shorter and the weight loss was also less prominent.44 An ongoing prospective trial (clinicaltrials gov. Identifier: 02763033) is evaluating the efficacy of resistant potato starch supplementation between day -7 and day +100 in HSCT recipients. This starch is a non-absorbable carbohydrate that is metabolized by the anaerobic commensal bacteria to produce the SCFA butyrate,79 shown to reduce the severity of acute GI GvHD in an experimental model.31 Preliminary results demonstrate the feasibility of this approach in terms of patient compliance, increase in intestinal butyrate levels and abundance of butyrate producing bacteria. 80 As for probiotic supplementation, the available data do not suggest its influence on the microbiome composition or clinical outcomes. It is worth mentioning that the products used in the studies contained only one bacterial strain and not a diversity of bacteria,43,81 and safety of probiotic administration is of concern in immunocompromised patients.82
The loss of diversity during the transplantation course is accompanied with microbiome domination by single taxonomic units such as Enterococcus.37 This enterococcal expansion has been found to be most prominent in patients developing acute GI GvHD.52 Stein-Thoeringer et al. have shown in a gnotobiotic mouse model of allo- HSCT that enterococcal expansion in the gut depends on lactose and its depletion decreases the enterococcal abundance and thus attenuates GvHD severity. Furthermore, in patients with a lactose malabsorption genotype, Enterococcus abundance appears to be higher than in patients without this genotype.83 This finding may give rise to a new approach to dietary intervention during HSCT. Interestingly, in the study by Khandelwal et al., where pediatric allo-HSCT patients under the age of 5 were treated with ready to eat human milk and breast feeding (n=24) or formula (n=14), plasma levels of IL6, IL10, and Reg3α were significantly lower in the group receiving human milk. The microbiome composition also differed between the two groups, with an increase in pathogenic species such as E. coli in the formula-receiving group. Despite the fact that human milk oligosaccharides are metabolized to SCFA by the commensal bacteria, butyrate levels in the stool were similar in both groups. Moreover, no significant difference in the rate of grade 2-4 acute GI GvHD between the groups was revealed. However, the limited size of this study calls for cautious interpretation of these encouraging results.84 Overall, dietary interventions emerge as a promising way to shape the intestinal microbiota during allo-HSCT. However, results are too preliminary and more research is required before implementing any of these methods.
Antibiotic treatment
The antibiotic treatment applied during the transplantation course is the main factor affecting the microbiome. Quinolone prophylaxis during afebrile neutropenia and systemic broad-spectrum antibiotic treatment with piperacillin-tazobactam or meropenem are widely accepted. 85-87 However, data demonstrate that the use of other antibiotics can better preserve gut beneficial commensals and is associated with improved outcomes.
The study from the University of Regensburg in Germany employed the non-absorbable antibiotic rifaximin and compared it to ciprofloxacin and metronidazole used in a historic cohort of patients for infection prophylaxis during allo-HSCT.45 Antibiotics were given from day -8 up to engraftment. The urine 3-indoxyl sulfate (3-IS) level was measured as a marker of microbiome diversity.88 In the rifaximin cohort, the pre-engraftment 3-IS levels were significantly higher without an increase in the sepsis rate or colonization with pathogenic bacteria. This group had significantly lower TRM, prolonged OS and the acute GI GvHD rate tended to be lower in these patients. The observed advantage remained evident even in patients who later received systemic antibiotics for neutropenic fever. 45
Given the major role of microbiome diversity preservation during allo-HSCT and an association of impaired diversity with acute GI GvHD and adverse patient outcome, Weber et al. further compared the effects of various prophylactic and systemic antibiotics in an attempt to identify the ones that could spare commensal bacteria.89 At 10 days post-transplant, the patient groups receiving rifaximin without systemic antibiotics or rifaximin with systemic antibiotics maintained their microbiome diversity and Clostridia abundance and had higher 3-IS levels compared to patients treated with ciprofloxacin/metronidazole ± systemic antibiotics. These results suggest that rifaximin could better preserve microbiome diversity even when systemic broad-spectrum antibiotics are administered during transplantation. Moreover, in the study conducted in two Canadian hospitals and assessing the effect of antibiotic prophylaxis or treatment given before day 0 on frequency of aGvHD and mortality, the authors compared the outcome of a cohort of patients exposed to antibiotics (n=239) to those who did not receive this therapy (n=261).90 The antibiotic-receiving group demonstrated a significantly higher incidence of grade 2-4 aGvHD and significantly shorter OS at 1, 2 and 10 years posttransplant, indicating an association between the deleterious effect of such treatment on intestinal bacteria and inferior patient outcome.
Importantly, early start of systemic antibiotics (before engraftment) was found to be associated with a lower 3- IS urine level and decreased Clostridia abundance in the stool. Furthermore, the TRM rate in such cases was higher than in patients who did not require systemic antibiotics during HSCT or started them after engraftment.91
Similarly, systemic treatment with piperacillin-tazobactam and meropenem was reported to correlate with decreased microbiome diversity during the transplantation37 and significant loss of commensal anaerobic bacteria. 92 In pediatric patients, Simms-Waldrip et al.93 found that higher load of anti-anaerobic antibiotics was associated with a significant decrease in anti-inflammatory Clostridia (AIC) abundance, and in patients with aGvHD the abundance decrease was severe (10-log fold) compared to patients without GvHD. In a mouse allo-HSCT model, clindamycin administration was associated with AIC decrease and more severe GvHD, while re-administration of AIC increased its levels in the gut and improved survival.93 Additionally, Lee et al.94 compared patients who did not require any systemic antibiotic treatment during the transplantation course with those who received cefepime and those who were treated with carbapenem antibiotics. The carbapenem group displayed a significant loss of microbial diversity at engraftment and an increased rate of acute GI GvHD (32.1%) compared to the noantibiotics group (11.6%). Interestingly, the cefepime group retained a diverse microbiome, demonstrating only a trend to a higher GI GvHD rate (26.4%).
Furthermore, a large multicenter study retrospectively evaluating 857 patients revealed that the use of piperacillin-tazobactam and imipenem-cilastatin was associated with increased 5-year GvHD-related mortality, 95 while this was not observed in patients receiving cefepime and aztreonam. The former antibiotics caused a significant decrease in abundance of Bacteroidetes and Lactobacillus compared to the latter ones. These results suggest that some antibiotics may be more beneficial than others in the setting of allo-HSCT, and that this beneficial effect is related to the antibiotic ability to be less detrimental to intestinal commensal bacteria.95 Findings in the pediatric setting were consistent with these data, and exposure to anti-anaerobic antibiotics was reported to result in a significant decrease in butyrate-producing bacteria and the butyrate level in luminal content by day +14. Pediatric patients who later developed aGvHD had a significantly lower butyrate level at that time point than patients without GvHD.96
It was also demonstrated that specific antibiotic use during allo-HSCT could change the abundance of specific taxa which was associated with BSI risk. In a cohort of 94 patients, Taur Y et al.50 found that domination of the gut microbiome (abundance ≥30%) by single bacterial taxa Enterococcus and Streptococcus occurred at the peri-engraftment period (days +10 to +20) in two thirds of the patients. However, treatment with metronidazole increased the risk for enterococcal domination by 3-fold, and this domination elevated the risk for VRE bacteremia by 9-fold. Altogether, these data establish an essential role of antibiotics in disrupting or preserving the intestinal microbiota during allo-HSCT.
Case 1: conclusions
Several issues should be considered in decision-making regarding the appropriate management of this case. This patient has pre-transplant intestinal microbiota disruption and assumed colonization by MDR bacteria and probably by Clostridium difficile. His risk for aGvHD is high, since he has undergone allo-HSCT from a mismatched unrelated donor. Quinolone prophylaxis and meropenem treatment for BSI have further disrupted his intestinal microbiota. The existence of pre-transplant microbiota disruption, mainly attributed to the use of broad-spectrum antibiotics during intensive chemotherapy, is associated with increased TRM, shorter OS and GvHD-related mortality. Pre-transplant FMT can potentially enrich the microbiome diversity and eradicate MDR bacteria or Clostridium difficile; however, without controlling such factors as antibiotic prophylaxis and the type of systemic antibiotic therapy employed, the intervention by FMT may not completely achieve its goals.
Table 2. Clinical trials of fecal microbiota transplant in allogeneic hematopoietic stem cell transplantation.
So far, no data are available regarding a clinical benefit of prophylactic pre-transplant FMT.
While an association between peri-engraftment microbiome low diversity and patient outcome is established, implying potential feasibility of FMT use at that stage, data regarding FMT application before engraftment are not available, and for safety reasons this approach will probably not be attempted. Results of several small-scale studies suggest safety and feasibility of post-engraftment FMT in restoring microbiome diversity (Table 2); however, it remains unknown if this strategy could decrease the risk for aGvHD-related mortality and TRM.
As for dietary interventions at this period, their efficacy is still under investigation. Choosing a different antibiotic prophylaxis, such as rifaximin and systemic antibiotics such as cefepime, looks promising. Nevertheless, new strategies need to be tested to prove their non-inferiority in OS85 and to establish less disruption for the microbiome (clinicaltrials gov. Identifier: 03078010), especially since fourth-generation cephalosporins have been found in one study to be associated with an increased risk for aGvHD.97
Case 1: recommendations
In this case, based on the currently available data, we do not recommend prophylactic administration of pretransplant or post-engraftment FMT.
Case 2
A 25-year old female with intermediate-risk AML in CR underwent an allo-HSCT with BuCy myeloablative conditioning from her matched sibling. Her neutrophils engrafted by day +14. On day +34 she developed grade 3 aGvHD of the lower GI tract which was steroid refractory (SR). She did not respond to the addition of budesonide, extracorporeal photopheresis (ECP), mofetil mycophenolate or infliximab.
Can fecal microbiota transplantation mitigate prevailing acute gastrointestinal graft-versushost disease?
The current data regarding the use of FMT for the treatment of acute GI GvHD are limited to case reports and small case series (Table 2). A total of 58 described patients were treated with FMT for SR GI grade 2-4 aGvHD. The FMT source was an unrelated donor in 36 cases, a related donor – in six cases and in eight cases a commercial pooled highly diverse FMT was used. FMT was processed and either given fresh within a few hours of collection or it was frozen and later thawed before administration. FMT was administered orally as packed capsules, through a nasogastric/ nasoduodenal tube or an enema. Of 58 patients, 28 received FMT after two or more therapy lines, while 19 received it as second-line therapy right after steroid failure. Response was observed in 74% (43 of 58) of patients, with complete response in 57% (33 of 58) and partial response in 17% (10 of 58). Complete response was observed in 73% of patients receiving FMT as second-line therapy. Ten of the responding patients relapsed and 29 patients were alive at the last follow-up (54%; 29 of 54 patients with available data).
Response to treatment was seen within a median of 14 days (range: 3-28), with a median of two FMT (range: 1-7), and a median of 7 days between treatments (range: 2-60).46,98-106
Infectious complications occurred in 11 patients. Two had sepsis with bacteria not originating from FMT,102 and one patient developed diarrhea due to Norovirus that was traced to FMT.106 Other infections were attributed to the severe immunocompromised state of patients. However, a possible association with FMT could not be ruled out. In responding patients in whom the stool microbiome was sequenced post-FMT, it was found to be significantly more diverse and enriched with Bacteroides, Lactobacillus, Bifidobacterium and Faecalibacterium compared to pre-FMT microbiome.46,98-101 Notably, the diversity increased only upon discontinuation of anti-anaerobic systemic antibiotic treatment, such as piperacillin-tazobactam. However, continuous use or re-initiating treatment with cefepime did not reduce FMT efficiency.46,98,99
These results are highly encouraging and support FMT therapy to be relatively safe and effective in SR GI aGvHD.
Case 2: conclusions
Available data suggest a potentially beneficial effect of FMT in acute lower GI GvHD. It should probably be used earlier rather than later, so that patients' response will not be overcome by infectious complications related to extensive immunosuppressive therapy. Discontinuation of antibiotic treatment prior to FMT administration appears to be an important factor contributing to successful response. If antibiotic treatment is required, using cefepime may allow attenuating microbiome insult while maintaining clinical response.
Current information is based on case reports and small series with a wide variability in patient selection, FMT preparation and mode of administration. However, the reported feasibility, safety and clinical benefit appear to be similar across the studies, implying that intestinal microbiota can be recovered with FMT, irrespective of its administration method. Safety remains a concern,107 especially in advanced GI aGvHD, and if an infectious complication occurs post-FMT, the pathogen should be sequenced and traced to find out if it originates from the FMT.
Case 2: recommendations
Currently, ruxolitinib is the only FDA-approved drug for the treatment of SR aGvHD, while other modalities are also commonly used in this scenario (e.g., extracorporeal photopheresis). Thus, FMT could be recommended for patients with grade 2-4 steroid refractory or dependent aGVHD of the lower GI tract, albeit in the context of a clinical study only.108-110 Other treatment approaches could also be considered, such as adding it to steroids as part of the first-line therapy (clinicaltrials gov. Identifier: 04269850).
Although clinical trials are still ongoing, given the grave prognosis of SR aGvHD with more than 50% mortality,111 and the high rate of response to FMT, we recommend considering FMT as a therapeutic option in this setting.
Practical considerations for fecal microbiota transplantation treatment
As FMT has become the standard of care in recurrent and refractory CDI,112,113 more and more centers are gaining access to FMT programs through either establishing their own stool banks or acquiring FMT from universal stool banks.114,115
One of the limiting factors to wider application of stool banks and FMT programs is the lack or variance of regulatory standards. In different countries, FMT is regulated as a drug, tissue or a combined product composed of both human cells and non-human components (microbial DNA and metabolites). Stool banks are recommended to operate under the designated authority in each country. In the absence of local directives, the scientific committee should be responsible for establishing regulatory protocols.114
FMT donor screening should follow national regulations and international recommendations.114 Screening should include medical history related to the risk for transmitting infections, as well as medical conditions and treatments associated with perturbed microbiome (Table 3). Special considerations are to be applied when planning FMT use in allo-HSCT patients, such as testing the donor for Cytomegalovirus and Epstein-Barr virus IgG and IgM, and administering FMT from seronegative donors to seronegative patients. However, when weighing suitability of an FMT donor, one should be cognizant of the fact that no data are available to support the advantage of a particular donor (a family member, an unrelated donor, or pooled stool from several unrelated donors).
As for autologous FMT, it has not been tested in the setting of aGvHD treatment. Since the microbiota composition of a patient is already disrupted prior to HSCT, using such stool in FMT preparation to be applied for diversity restoration may not be effective. In order to circumvent this problem, in AML patients, we recommend freezing self-stool before the beginning of induction chemotherapy.
In CDI, both fresh and frozen FMT have been shown to be efficient116 as have been the two delivery routes − colonoscopy and oral capsules.117 While there are no data pointing to the superiority of either method of preparation or administration for aGvHD treatment, frozen samples from a stool bank allow FMT to be readily available for immediate use without the need to wait for donor screening and FMT collection.
The basic principles of FMT preparation include weighing the sample, suspension in sterile solution (saline), adding glycerol in case the FMT is planned for freezing and storing, homogenization, filtering and aliquoting the suspension for fresh use or freezing (Table 3). The FMT product should be registered and labeled.114
Based on the available data (Table 2) we suggest evaluating clinical response at 7-14 days after FMT administration. If no response or only partial response is achieved, we recommend administering a second dose of FMT. Whether in such cases the use of FMT from another donor could provide a superior outcome is yet to be determined. In general, in order to consider FMT as an efficacious therapeutic approach for SR GI aGvHD management, an overall response rate of around 60-70%, with a complete response rate of 30-50% should be a desired target, as these rates are achieved with the use of the approved ruxolitinib treatment and in non-randomized FMT studies.46,98-106,110
As for the antibiotic treatment peri-FMT, if feasible, 24-48 hours prior to FMT, systemic antibiotics should be stopped or replaced by one with less anti-anaerobic activity such as rifaximin for prophylaxis or cefepime for febrile neutropenic treatment.46,98,99
Microbiome sequencing of donor and patient samples could help interpreting clinical outcomes. It could also be valuable in distinguishing between the donor and the recipient as the source of post-FMT infection. However, currently there are no data suggesting that patient stool sequencing prior to FMT could guide its administration or affect the outcome. Therefore, given that the primary outcome should be the clinical response to treatment we recommend treating SR GI aGvHD patients with FMT even if the microbiome analysis is not available. Nonetheless, we do suggest storing stool samples from the donor and the patient (before and after FMT) for later sequencing if it becomes available.
Table 3. Practical aspects of fecal microbiota transplantation.
Further accumulation of data on FMT for SR GI aGvHD will allow wider and more efficient application of this treatment approach.
Open challenges and future directions
Disruption of the intestinal microbiome during allo- HSCT is a multifaceted process with a cause-and-effect relationship between multiple factors such as conditioning, diet and antibiotic treatment. Lately, FMT has emerged as an intervention that can facilitate microbiome recovery and potentially intervene with the above interplay (Figure 1). The intestinal microbial disruption before and during allo-HSCT is clearly associated with transplant-related outcomes, mainly acute GvHD and mortality, and pre-clinical data demonstrate the key role of the intestinal microbiota in protecting the gut from inflammatory damage and in regulating the innate immune system to maintain a more tolerant state.118 While the addition of beneficial bacteria or their metabolites has been shown to ameliorate acute GvHD in animal allo-HSCT models, many challenges remain concerning the role of the intestinal microbiota in allo-HSCT in humans. A substantial amount of basic research is being conducted aiming to better understand the place of microbiome changes in the pathogenesis of acute GvHD. In addition, a large population microbiome analysis is ongoing attempting to delineate the interplay between other factors, such as antibiotics and diet, and the microbiota disruption, and to determine the optimal strategy allowing to preserve the microbiota intact.119 However, while these issues are still under investigation, clinical trials evaluating the efficacy of FMT and other abovementioned interventions in the HSCT setting are underway (Table 2). Joint efforts to further explore biological, correlative and recovery functions of the intestinal microbiota could ultimately lead to decreased transplantrelated mortality, and even pave the way to personalized therapeutic strategies in HSCT.
Figure 1. The multifactorial interplay between environmental factors, intestinal microbiota and tissue damage affects transplant-related outcomes. During allogeneic hematopoietic stem cell transplantation (allo-HSCT), conditioning chemotherapy causes damage to the intestinal mucosa cells such as intestinal epithelial cells, intestinal stem cells, paneth cells and mucus producing goblet cells. Gut microbiota is already disrupted before allo-HSCT and due to prophylactic and systemic antibiotic therapy the microbiota disruption worsens with loss of butyrate producing bacteria and other beneficial commensals, along with increase in pathogenic bacteria such as Enterococcus. Depletion of bacterial metabolites postpones epithelial cell repair and restoration of the mucus barrier. Pathogenic bacteria can disseminate through the damaged mucosa and cause blood stream infections, which will necessitate the administration of systemic antibiotics further disrupting the intestinal microbiota. This vicious cycle is associated with graft-versus-host disease (GvHD), increased mortality and diminished overall survival. The question remains whether fecal microbiota transplantation (FMT) and other interventions such as prebiotics and the use of antibiotics with less anti-anaerobic activity could eventually break the cycle and improve outcomes. IEC:– intestinal epithelial cells; ISC: intestinal stem cells.
Supplementary Material
Disclosures and Contributions
Acknowledgements
The authors wish to thank Sonia Kamenetsky for her assistance in the preparation of this manuscript. | MYELOABLATIVE CONDITIONING | DrugDosageText | CC BY-NC | 33241674 | 19,317,760 | 2021-04-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple-drug resistance'. | Triacetyluridine treats epileptic encephalopathy from CAD mutations: a case report and review.
Refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism. We report a case of an 8-year-old girl with history of developmental delay, autism and intractable epilepsy that was found to have a pathogenic variant in CAD. We briefly review the biochemical pathway of CAD and the preclinical and clinical studies that suggest uridine supplementation can rescue the CAD deficiency phenotypes. Our case demonstrates a relatively late-onset case of refractory epilepsy with a rapid response to treatment using the uridine pro-drug triacetyluridine (TAU), the FDA-approved treatment for hereditary orotic aciduria.
Case Presentation
An 8‐year‐old girl with developmental delay, autism, and intractable epilepsy presented with increased seizures in the setting of parainfluenza respiratory infection. She had a history of multiple seizure semiologies including tonic, generalized tonic–clonic, staring with behavioral arrest, and focal motor seizures. Seizures varied in frequency and duration, and she had several prior episodes of status epilepticus requiring hospitalization. Six months prior to presentation, she had prolonged status epilepticus, followed by regression in functional skills, gait ataxia, hand tremors, incoordination, and increased seizures.
She was born by normal vaginal birth. It was not clear when developmental delays were first noticed, but she was diagnosed with autism at age 4. Seizures started with febrile illness at 17 months old. Over time, seizures became increasingly difficult to control requiring escalating doses and number of anti‐convulsant medications. The family history showed childhood epilepsy and behavioral concerns on the paternal side. The parents were consanguineous being distant cousins.
At the time of admission, the patient was taking phenytoin 5 mg/kg per day, levetiracetam 68 mg/kg per day, and clobazam 1.5 mg/kg per day.
Video EEG was completed to characterize limb and eye movements concerning for seizures. Focal seizures were captured although the majority of episodes of concern were not seizures. The EEG was notable for diffuse delta slowing and multifocal epileptiform discharges, consistent with epileptic encephalopathy.
Complete blood count showed macrocytic anemia (Hgb 10.6 g/dL; MCV 91.4 fL) and mild thrombocytopenia (135 TH/µL). Basic chemistries showed mild transaminitis.
Computed tomography imaging of the brain showed no acute abnormalities. Brain magnetic resonance imaging at age 4 years was normal. Her karyotype was normal. A chromosomal microarray showed areas of homozygosity without any clinically significant copy number variants. A commercial epilepsy gene panel testing 181 genes in 2019 was unremarkable. Her plasma amino acids, lactate, ammonia, pyruvate, lead, and urine organic acids were normal.
During the hospitalization, the patient developed worsening coordination, nystagmus, tremor, and encephalopathy initially thought to be secondary to medications. It became difficult to find an acceptable balance between seizures and medication side effects. An epilepsy gene panel testing 193 genes revealed a homozygous variant (c.98T > G. p.Met33Arg) in the Carbamoyl‐Phosphate Synthetase 2, Aspartate Transcarbamylase, and Dihydroorotase (CAD) gene, which was reported as likely pathogenic. This variant is found in the general population at very low frequencies in the heterozygous state, and CAD missense variants are depleted in the population databases, suggesting that mutations in this gene are pathogenic (https://gnomad.broadinstitute.org). The mutation lies within one of the areas of homozygosity that was noted on the patient’s microarray; however the variant was not confirmed in the parents as they declined genetic testing.
Pathologic variants in the CAD gene result in a rare neurometabolic disorder characterized by autosomal recessive early epileptic encephalopathy, developmental delay, and intractable epilepsy, as well as a macrocytic anemia.
1
In its untreated form, this disorder is progressive and fatal, however, there are reports in the literature of patients who have been successfully treated with uridine supplementation.
1
,
2
CAD Gene and Uridine Supplementation
The CAD gene, located on chromosome 2 (2p23.3), encodes a highly conserved trifunctional enzyme complex involving carbamoyl‐phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase.
3
This enzyme complex is important in the pathway for de novo synthesis of pyrimidine nucleotides. The final product, uridine monophosphate (UMP), is the substrate for all cellular pyrimidines and therefore essential for RNA and DNA synthesis. UMP derivatives (tri‐ and diphosphate, UTP/UDP) are also important in protein glycosylation, polysaccharide biosynthesis, and lipid metabolism. The importance of uridine is highlighted in the inborn error of metabolism disorder hereditary orotic aciduria (UMPS deficiency), in which there is a primary deficiency in uridine synthesis, leading to failure to thrive, megaloblastic anemia, congenital malformations, immunodeficiency, and developmental delay.
4
Given that cells are able to take up and phosphorylate exogenous uridine, supplementation with uridine can provide a mechanism to overcome deficiencies in the synthetic pathway. Accordingly, uridine triacetate (or triacetyluridine, TAU) is the FDA‐approved treatment for hereditary orotic aciduria.
5
Uridine therapy has also been used in uridine‐nucleotide depletion disease,
6
for overdose of fluorouracil and capecitabine,
5
and is currently under investigation for treatment of mitochondrial diseases. Supplementation with TAU is typically favored over uridine given the bioavailability of TAU is 4–6 times greater than uridine, thereby requiring lower dosages for treatment. TAU is absorbed in the gastrointestinal tract and readily converted to free uridine and acetate by esterases in the gut epithelium. Rare side effects include mild nausea, vomiting, or diarrhea.
5
There is a growing body of evidence demonstrating that uridine supplementation can also be helpful in deficiencies occurring in earlier steps of pyrimidine synthesis, including CAD mutations. In the preclinical setting, Ng et al. (2015) demonstrated that fibroblast cells from a 4‐year‐old patient with compound heterozygous mutations in CAD expressed reduced de novo pyrimidine nucleotides and reduction in all UDP‐activated sugars tested.
7
Supplementation of exogenous uridine rescued these abnormalities. In addition, a study using a CAD‐knockout cell line showed 16 of 25 biallelic variants, including our patient’s specific variant, failed to rescue or only partially rescued the growth phenotype of these cells in the absence of uridine.
8
This suggests that these mutations diminish CAD activity and that uridine supplementation may be helpful to restore the normal phenotype.
In the clinical setting, Koch et al. described four patients with CAD mutations in 2017, two of which were siblings from a consanguineous family who harbored the same mutation as our patient.
1
All four patients had developmental delay, followed by refractory epilepsy, epileptic encephalopathy, developmental regression at 2–4 years old, and anemia. Two of the four patients were treated with oral uridine 100 mg/kg per day divided in four dose administrations. These patients showed significant improvement in their clinical course. The treated child who had our patient’s mutation showed cessation of seizures for at least 6 months, with stable or improved gross motor, fine motor, cognitive and speech function. The anemia also normalized. Cultured fibroblasts from this patient initially showed reduced levels of UDP, UDP‐glucose, UDP‐N‐acetylglucosamine, CTP, and UTP, which all normalized with uridine supplementation. The other treated patient went from a minimally conscious state to being awake, alert, and able to take steps with assistance. The two patients that were not treated died at 4 and 5 years old after progressive neurodegeneration, loss of acquired skills, and refractory seizures. In 2020, a 5‐year‐old boy with a different compound heterozygous CAD mutation who shared a similar phenotype to those described previously also had significant improvement in his seizures, development, and anemia after uridine supplementation.
2
Case Conclusion
Prior to TAU therapy, our patient had up to 6–12 seizures daily, refractory to various combinations of phenytoin, levetiracetam, clobazam, cannabidiol, and carbamazepine, with encephalopathy and regression of functional skills. Supplementation with TAU was initiated at a dose of 100 mg/kg per day divided four times daily. After supplementation, seizures ceased within 4 days and her mental status improved. When assessed after 2 months, the patient was alert, playful, speaking in multi‐word sentences, had coordinated movements, and was ambulating independently. She was continued on clobazam 1 mg/kg per day, levetiracetam 40 mg/kg per day, and TAU. When last assessed, the patient had not had a seizure in 1 year since starting TAU supplementation and continued to make developmental progress.
Discussion
Here, we present a child with an epileptic encephalopathy resulting from a homozygous variant in the CAD gene (c.98T > G.p.Met33Arg) whose seizures resolved and encephalopathy improved with TAU treatment. There is a growing body of work demonstrating that refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism.
9
,
10
Furthermore, the effectiveness of therapies that are targeted to specific metabolic pathways has been well‐documented.
11
,
12
,
13
For example, Hunt et al. (1954) documented a case of neonatal epilepsy resolved by daily pyridoxine treatment, with genetic studies in the past 2 decades highlighting the involvement of ALDH7A1 and PROSC in pyridoxine‐dependent epilepsy.
14
,
15
Since then, various metabolic pathways involving biotin recycling, glucose transport, creatine synthesis, purine metabolism, and Coenzyme Q10 deficiency have been implicated in pediatric epilepsy syndromes, with substantial response to replacement therapies.
9
The success of uridine supplementation in the treatment of several cases of epileptic encephalopathy resulting from CAD mutations further demonstrates the impact of genetic‐based epilepsy therapies. Exome sequencing as well as targeted gene panels have been shown to play an increasingly important role in elucidating these rare and often de novo genetic variants underlying epileptic encephalopathies.
16
,
17
Our patient is the first child reported with intractable epilepsy and developmental regression secondary to CAD mutation who responded clinically to treatment with the uridine prodrug TAU. Exogenous uridine is thought to bypass the loss of CAD function, thereby rescuing pyrimidine synthesis and downstream pathways. Our case uniquely demonstrates a relatively late‐onset case of refractory epilepsy in the setting of a homozygous variant in the CAD gene, with a striking, rapid response to replacement therapy. As the number of reported cases of refractory epilepsy from inborn errors of metabolism continues to grow, it is critical for us to develop comprehensive, commercially‐available epilepsy gene panels for screening of this population to potentially prevent the long‐term detrimental effects of these metabolic pathway errors.
Conflict of Interest
Aliya Frederick – reports no disclosures. Kimberly Sherer ‐ reports no disclosures. Linda Nguyen– reports no disclosures. Shawn Ali– reports no disclosures. Anupam Garg – reports no disclosures. Richard Haas– reports no disclosures. Michelle Sahagian ‐ reports no disclosures. Jonathan Bui‐ reports no disclosures. | CANNABIDIOL, CARBAMAZEPINE, CLOBAZAM, LEVETIRACETAM, PHENYTOIN | DrugsGivenReaction | CC BY | 33249780 | 18,954,694 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Parainfluenzae virus infection'. | Triacetyluridine treats epileptic encephalopathy from CAD mutations: a case report and review.
Refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism. We report a case of an 8-year-old girl with history of developmental delay, autism and intractable epilepsy that was found to have a pathogenic variant in CAD. We briefly review the biochemical pathway of CAD and the preclinical and clinical studies that suggest uridine supplementation can rescue the CAD deficiency phenotypes. Our case demonstrates a relatively late-onset case of refractory epilepsy with a rapid response to treatment using the uridine pro-drug triacetyluridine (TAU), the FDA-approved treatment for hereditary orotic aciduria.
Case Presentation
An 8‐year‐old girl with developmental delay, autism, and intractable epilepsy presented with increased seizures in the setting of parainfluenza respiratory infection. She had a history of multiple seizure semiologies including tonic, generalized tonic–clonic, staring with behavioral arrest, and focal motor seizures. Seizures varied in frequency and duration, and she had several prior episodes of status epilepticus requiring hospitalization. Six months prior to presentation, she had prolonged status epilepticus, followed by regression in functional skills, gait ataxia, hand tremors, incoordination, and increased seizures.
She was born by normal vaginal birth. It was not clear when developmental delays were first noticed, but she was diagnosed with autism at age 4. Seizures started with febrile illness at 17 months old. Over time, seizures became increasingly difficult to control requiring escalating doses and number of anti‐convulsant medications. The family history showed childhood epilepsy and behavioral concerns on the paternal side. The parents were consanguineous being distant cousins.
At the time of admission, the patient was taking phenytoin 5 mg/kg per day, levetiracetam 68 mg/kg per day, and clobazam 1.5 mg/kg per day.
Video EEG was completed to characterize limb and eye movements concerning for seizures. Focal seizures were captured although the majority of episodes of concern were not seizures. The EEG was notable for diffuse delta slowing and multifocal epileptiform discharges, consistent with epileptic encephalopathy.
Complete blood count showed macrocytic anemia (Hgb 10.6 g/dL; MCV 91.4 fL) and mild thrombocytopenia (135 TH/µL). Basic chemistries showed mild transaminitis.
Computed tomography imaging of the brain showed no acute abnormalities. Brain magnetic resonance imaging at age 4 years was normal. Her karyotype was normal. A chromosomal microarray showed areas of homozygosity without any clinically significant copy number variants. A commercial epilepsy gene panel testing 181 genes in 2019 was unremarkable. Her plasma amino acids, lactate, ammonia, pyruvate, lead, and urine organic acids were normal.
During the hospitalization, the patient developed worsening coordination, nystagmus, tremor, and encephalopathy initially thought to be secondary to medications. It became difficult to find an acceptable balance between seizures and medication side effects. An epilepsy gene panel testing 193 genes revealed a homozygous variant (c.98T > G. p.Met33Arg) in the Carbamoyl‐Phosphate Synthetase 2, Aspartate Transcarbamylase, and Dihydroorotase (CAD) gene, which was reported as likely pathogenic. This variant is found in the general population at very low frequencies in the heterozygous state, and CAD missense variants are depleted in the population databases, suggesting that mutations in this gene are pathogenic (https://gnomad.broadinstitute.org). The mutation lies within one of the areas of homozygosity that was noted on the patient’s microarray; however the variant was not confirmed in the parents as they declined genetic testing.
Pathologic variants in the CAD gene result in a rare neurometabolic disorder characterized by autosomal recessive early epileptic encephalopathy, developmental delay, and intractable epilepsy, as well as a macrocytic anemia.
1
In its untreated form, this disorder is progressive and fatal, however, there are reports in the literature of patients who have been successfully treated with uridine supplementation.
1
,
2
CAD Gene and Uridine Supplementation
The CAD gene, located on chromosome 2 (2p23.3), encodes a highly conserved trifunctional enzyme complex involving carbamoyl‐phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase.
3
This enzyme complex is important in the pathway for de novo synthesis of pyrimidine nucleotides. The final product, uridine monophosphate (UMP), is the substrate for all cellular pyrimidines and therefore essential for RNA and DNA synthesis. UMP derivatives (tri‐ and diphosphate, UTP/UDP) are also important in protein glycosylation, polysaccharide biosynthesis, and lipid metabolism. The importance of uridine is highlighted in the inborn error of metabolism disorder hereditary orotic aciduria (UMPS deficiency), in which there is a primary deficiency in uridine synthesis, leading to failure to thrive, megaloblastic anemia, congenital malformations, immunodeficiency, and developmental delay.
4
Given that cells are able to take up and phosphorylate exogenous uridine, supplementation with uridine can provide a mechanism to overcome deficiencies in the synthetic pathway. Accordingly, uridine triacetate (or triacetyluridine, TAU) is the FDA‐approved treatment for hereditary orotic aciduria.
5
Uridine therapy has also been used in uridine‐nucleotide depletion disease,
6
for overdose of fluorouracil and capecitabine,
5
and is currently under investigation for treatment of mitochondrial diseases. Supplementation with TAU is typically favored over uridine given the bioavailability of TAU is 4–6 times greater than uridine, thereby requiring lower dosages for treatment. TAU is absorbed in the gastrointestinal tract and readily converted to free uridine and acetate by esterases in the gut epithelium. Rare side effects include mild nausea, vomiting, or diarrhea.
5
There is a growing body of evidence demonstrating that uridine supplementation can also be helpful in deficiencies occurring in earlier steps of pyrimidine synthesis, including CAD mutations. In the preclinical setting, Ng et al. (2015) demonstrated that fibroblast cells from a 4‐year‐old patient with compound heterozygous mutations in CAD expressed reduced de novo pyrimidine nucleotides and reduction in all UDP‐activated sugars tested.
7
Supplementation of exogenous uridine rescued these abnormalities. In addition, a study using a CAD‐knockout cell line showed 16 of 25 biallelic variants, including our patient’s specific variant, failed to rescue or only partially rescued the growth phenotype of these cells in the absence of uridine.
8
This suggests that these mutations diminish CAD activity and that uridine supplementation may be helpful to restore the normal phenotype.
In the clinical setting, Koch et al. described four patients with CAD mutations in 2017, two of which were siblings from a consanguineous family who harbored the same mutation as our patient.
1
All four patients had developmental delay, followed by refractory epilepsy, epileptic encephalopathy, developmental regression at 2–4 years old, and anemia. Two of the four patients were treated with oral uridine 100 mg/kg per day divided in four dose administrations. These patients showed significant improvement in their clinical course. The treated child who had our patient’s mutation showed cessation of seizures for at least 6 months, with stable or improved gross motor, fine motor, cognitive and speech function. The anemia also normalized. Cultured fibroblasts from this patient initially showed reduced levels of UDP, UDP‐glucose, UDP‐N‐acetylglucosamine, CTP, and UTP, which all normalized with uridine supplementation. The other treated patient went from a minimally conscious state to being awake, alert, and able to take steps with assistance. The two patients that were not treated died at 4 and 5 years old after progressive neurodegeneration, loss of acquired skills, and refractory seizures. In 2020, a 5‐year‐old boy with a different compound heterozygous CAD mutation who shared a similar phenotype to those described previously also had significant improvement in his seizures, development, and anemia after uridine supplementation.
2
Case Conclusion
Prior to TAU therapy, our patient had up to 6–12 seizures daily, refractory to various combinations of phenytoin, levetiracetam, clobazam, cannabidiol, and carbamazepine, with encephalopathy and regression of functional skills. Supplementation with TAU was initiated at a dose of 100 mg/kg per day divided four times daily. After supplementation, seizures ceased within 4 days and her mental status improved. When assessed after 2 months, the patient was alert, playful, speaking in multi‐word sentences, had coordinated movements, and was ambulating independently. She was continued on clobazam 1 mg/kg per day, levetiracetam 40 mg/kg per day, and TAU. When last assessed, the patient had not had a seizure in 1 year since starting TAU supplementation and continued to make developmental progress.
Discussion
Here, we present a child with an epileptic encephalopathy resulting from a homozygous variant in the CAD gene (c.98T > G.p.Met33Arg) whose seizures resolved and encephalopathy improved with TAU treatment. There is a growing body of work demonstrating that refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism.
9
,
10
Furthermore, the effectiveness of therapies that are targeted to specific metabolic pathways has been well‐documented.
11
,
12
,
13
For example, Hunt et al. (1954) documented a case of neonatal epilepsy resolved by daily pyridoxine treatment, with genetic studies in the past 2 decades highlighting the involvement of ALDH7A1 and PROSC in pyridoxine‐dependent epilepsy.
14
,
15
Since then, various metabolic pathways involving biotin recycling, glucose transport, creatine synthesis, purine metabolism, and Coenzyme Q10 deficiency have been implicated in pediatric epilepsy syndromes, with substantial response to replacement therapies.
9
The success of uridine supplementation in the treatment of several cases of epileptic encephalopathy resulting from CAD mutations further demonstrates the impact of genetic‐based epilepsy therapies. Exome sequencing as well as targeted gene panels have been shown to play an increasingly important role in elucidating these rare and often de novo genetic variants underlying epileptic encephalopathies.
16
,
17
Our patient is the first child reported with intractable epilepsy and developmental regression secondary to CAD mutation who responded clinically to treatment with the uridine prodrug TAU. Exogenous uridine is thought to bypass the loss of CAD function, thereby rescuing pyrimidine synthesis and downstream pathways. Our case uniquely demonstrates a relatively late‐onset case of refractory epilepsy in the setting of a homozygous variant in the CAD gene, with a striking, rapid response to replacement therapy. As the number of reported cases of refractory epilepsy from inborn errors of metabolism continues to grow, it is critical for us to develop comprehensive, commercially‐available epilepsy gene panels for screening of this population to potentially prevent the long‐term detrimental effects of these metabolic pathway errors.
Conflict of Interest
Aliya Frederick – reports no disclosures. Kimberly Sherer ‐ reports no disclosures. Linda Nguyen– reports no disclosures. Shawn Ali– reports no disclosures. Anupam Garg – reports no disclosures. Richard Haas– reports no disclosures. Michelle Sahagian ‐ reports no disclosures. Jonathan Bui‐ reports no disclosures. | CANNABIDIOL, CARBAMAZEPINE, CLOBAZAM, LEVETIRACETAM, PHENYTOIN | DrugsGivenReaction | CC BY | 33249780 | 18,954,694 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombocytopenia'. | Triacetyluridine treats epileptic encephalopathy from CAD mutations: a case report and review.
Refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism. We report a case of an 8-year-old girl with history of developmental delay, autism and intractable epilepsy that was found to have a pathogenic variant in CAD. We briefly review the biochemical pathway of CAD and the preclinical and clinical studies that suggest uridine supplementation can rescue the CAD deficiency phenotypes. Our case demonstrates a relatively late-onset case of refractory epilepsy with a rapid response to treatment using the uridine pro-drug triacetyluridine (TAU), the FDA-approved treatment for hereditary orotic aciduria.
Case Presentation
An 8‐year‐old girl with developmental delay, autism, and intractable epilepsy presented with increased seizures in the setting of parainfluenza respiratory infection. She had a history of multiple seizure semiologies including tonic, generalized tonic–clonic, staring with behavioral arrest, and focal motor seizures. Seizures varied in frequency and duration, and she had several prior episodes of status epilepticus requiring hospitalization. Six months prior to presentation, she had prolonged status epilepticus, followed by regression in functional skills, gait ataxia, hand tremors, incoordination, and increased seizures.
She was born by normal vaginal birth. It was not clear when developmental delays were first noticed, but she was diagnosed with autism at age 4. Seizures started with febrile illness at 17 months old. Over time, seizures became increasingly difficult to control requiring escalating doses and number of anti‐convulsant medications. The family history showed childhood epilepsy and behavioral concerns on the paternal side. The parents were consanguineous being distant cousins.
At the time of admission, the patient was taking phenytoin 5 mg/kg per day, levetiracetam 68 mg/kg per day, and clobazam 1.5 mg/kg per day.
Video EEG was completed to characterize limb and eye movements concerning for seizures. Focal seizures were captured although the majority of episodes of concern were not seizures. The EEG was notable for diffuse delta slowing and multifocal epileptiform discharges, consistent with epileptic encephalopathy.
Complete blood count showed macrocytic anemia (Hgb 10.6 g/dL; MCV 91.4 fL) and mild thrombocytopenia (135 TH/µL). Basic chemistries showed mild transaminitis.
Computed tomography imaging of the brain showed no acute abnormalities. Brain magnetic resonance imaging at age 4 years was normal. Her karyotype was normal. A chromosomal microarray showed areas of homozygosity without any clinically significant copy number variants. A commercial epilepsy gene panel testing 181 genes in 2019 was unremarkable. Her plasma amino acids, lactate, ammonia, pyruvate, lead, and urine organic acids were normal.
During the hospitalization, the patient developed worsening coordination, nystagmus, tremor, and encephalopathy initially thought to be secondary to medications. It became difficult to find an acceptable balance between seizures and medication side effects. An epilepsy gene panel testing 193 genes revealed a homozygous variant (c.98T > G. p.Met33Arg) in the Carbamoyl‐Phosphate Synthetase 2, Aspartate Transcarbamylase, and Dihydroorotase (CAD) gene, which was reported as likely pathogenic. This variant is found in the general population at very low frequencies in the heterozygous state, and CAD missense variants are depleted in the population databases, suggesting that mutations in this gene are pathogenic (https://gnomad.broadinstitute.org). The mutation lies within one of the areas of homozygosity that was noted on the patient’s microarray; however the variant was not confirmed in the parents as they declined genetic testing.
Pathologic variants in the CAD gene result in a rare neurometabolic disorder characterized by autosomal recessive early epileptic encephalopathy, developmental delay, and intractable epilepsy, as well as a macrocytic anemia.
1
In its untreated form, this disorder is progressive and fatal, however, there are reports in the literature of patients who have been successfully treated with uridine supplementation.
1
,
2
CAD Gene and Uridine Supplementation
The CAD gene, located on chromosome 2 (2p23.3), encodes a highly conserved trifunctional enzyme complex involving carbamoyl‐phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase.
3
This enzyme complex is important in the pathway for de novo synthesis of pyrimidine nucleotides. The final product, uridine monophosphate (UMP), is the substrate for all cellular pyrimidines and therefore essential for RNA and DNA synthesis. UMP derivatives (tri‐ and diphosphate, UTP/UDP) are also important in protein glycosylation, polysaccharide biosynthesis, and lipid metabolism. The importance of uridine is highlighted in the inborn error of metabolism disorder hereditary orotic aciduria (UMPS deficiency), in which there is a primary deficiency in uridine synthesis, leading to failure to thrive, megaloblastic anemia, congenital malformations, immunodeficiency, and developmental delay.
4
Given that cells are able to take up and phosphorylate exogenous uridine, supplementation with uridine can provide a mechanism to overcome deficiencies in the synthetic pathway. Accordingly, uridine triacetate (or triacetyluridine, TAU) is the FDA‐approved treatment for hereditary orotic aciduria.
5
Uridine therapy has also been used in uridine‐nucleotide depletion disease,
6
for overdose of fluorouracil and capecitabine,
5
and is currently under investigation for treatment of mitochondrial diseases. Supplementation with TAU is typically favored over uridine given the bioavailability of TAU is 4–6 times greater than uridine, thereby requiring lower dosages for treatment. TAU is absorbed in the gastrointestinal tract and readily converted to free uridine and acetate by esterases in the gut epithelium. Rare side effects include mild nausea, vomiting, or diarrhea.
5
There is a growing body of evidence demonstrating that uridine supplementation can also be helpful in deficiencies occurring in earlier steps of pyrimidine synthesis, including CAD mutations. In the preclinical setting, Ng et al. (2015) demonstrated that fibroblast cells from a 4‐year‐old patient with compound heterozygous mutations in CAD expressed reduced de novo pyrimidine nucleotides and reduction in all UDP‐activated sugars tested.
7
Supplementation of exogenous uridine rescued these abnormalities. In addition, a study using a CAD‐knockout cell line showed 16 of 25 biallelic variants, including our patient’s specific variant, failed to rescue or only partially rescued the growth phenotype of these cells in the absence of uridine.
8
This suggests that these mutations diminish CAD activity and that uridine supplementation may be helpful to restore the normal phenotype.
In the clinical setting, Koch et al. described four patients with CAD mutations in 2017, two of which were siblings from a consanguineous family who harbored the same mutation as our patient.
1
All four patients had developmental delay, followed by refractory epilepsy, epileptic encephalopathy, developmental regression at 2–4 years old, and anemia. Two of the four patients were treated with oral uridine 100 mg/kg per day divided in four dose administrations. These patients showed significant improvement in their clinical course. The treated child who had our patient’s mutation showed cessation of seizures for at least 6 months, with stable or improved gross motor, fine motor, cognitive and speech function. The anemia also normalized. Cultured fibroblasts from this patient initially showed reduced levels of UDP, UDP‐glucose, UDP‐N‐acetylglucosamine, CTP, and UTP, which all normalized with uridine supplementation. The other treated patient went from a minimally conscious state to being awake, alert, and able to take steps with assistance. The two patients that were not treated died at 4 and 5 years old after progressive neurodegeneration, loss of acquired skills, and refractory seizures. In 2020, a 5‐year‐old boy with a different compound heterozygous CAD mutation who shared a similar phenotype to those described previously also had significant improvement in his seizures, development, and anemia after uridine supplementation.
2
Case Conclusion
Prior to TAU therapy, our patient had up to 6–12 seizures daily, refractory to various combinations of phenytoin, levetiracetam, clobazam, cannabidiol, and carbamazepine, with encephalopathy and regression of functional skills. Supplementation with TAU was initiated at a dose of 100 mg/kg per day divided four times daily. After supplementation, seizures ceased within 4 days and her mental status improved. When assessed after 2 months, the patient was alert, playful, speaking in multi‐word sentences, had coordinated movements, and was ambulating independently. She was continued on clobazam 1 mg/kg per day, levetiracetam 40 mg/kg per day, and TAU. When last assessed, the patient had not had a seizure in 1 year since starting TAU supplementation and continued to make developmental progress.
Discussion
Here, we present a child with an epileptic encephalopathy resulting from a homozygous variant in the CAD gene (c.98T > G.p.Met33Arg) whose seizures resolved and encephalopathy improved with TAU treatment. There is a growing body of work demonstrating that refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism.
9
,
10
Furthermore, the effectiveness of therapies that are targeted to specific metabolic pathways has been well‐documented.
11
,
12
,
13
For example, Hunt et al. (1954) documented a case of neonatal epilepsy resolved by daily pyridoxine treatment, with genetic studies in the past 2 decades highlighting the involvement of ALDH7A1 and PROSC in pyridoxine‐dependent epilepsy.
14
,
15
Since then, various metabolic pathways involving biotin recycling, glucose transport, creatine synthesis, purine metabolism, and Coenzyme Q10 deficiency have been implicated in pediatric epilepsy syndromes, with substantial response to replacement therapies.
9
The success of uridine supplementation in the treatment of several cases of epileptic encephalopathy resulting from CAD mutations further demonstrates the impact of genetic‐based epilepsy therapies. Exome sequencing as well as targeted gene panels have been shown to play an increasingly important role in elucidating these rare and often de novo genetic variants underlying epileptic encephalopathies.
16
,
17
Our patient is the first child reported with intractable epilepsy and developmental regression secondary to CAD mutation who responded clinically to treatment with the uridine prodrug TAU. Exogenous uridine is thought to bypass the loss of CAD function, thereby rescuing pyrimidine synthesis and downstream pathways. Our case uniquely demonstrates a relatively late‐onset case of refractory epilepsy in the setting of a homozygous variant in the CAD gene, with a striking, rapid response to replacement therapy. As the number of reported cases of refractory epilepsy from inborn errors of metabolism continues to grow, it is critical for us to develop comprehensive, commercially‐available epilepsy gene panels for screening of this population to potentially prevent the long‐term detrimental effects of these metabolic pathway errors.
Conflict of Interest
Aliya Frederick – reports no disclosures. Kimberly Sherer ‐ reports no disclosures. Linda Nguyen– reports no disclosures. Shawn Ali– reports no disclosures. Anupam Garg – reports no disclosures. Richard Haas– reports no disclosures. Michelle Sahagian ‐ reports no disclosures. Jonathan Bui‐ reports no disclosures. | CANNABIDIOL, CARBAMAZEPINE, CLOBAZAM, LEVETIRACETAM, PHENYTOIN | DrugsGivenReaction | CC BY | 33249780 | 18,954,694 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Transaminases increased'. | Triacetyluridine treats epileptic encephalopathy from CAD mutations: a case report and review.
Refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism. We report a case of an 8-year-old girl with history of developmental delay, autism and intractable epilepsy that was found to have a pathogenic variant in CAD. We briefly review the biochemical pathway of CAD and the preclinical and clinical studies that suggest uridine supplementation can rescue the CAD deficiency phenotypes. Our case demonstrates a relatively late-onset case of refractory epilepsy with a rapid response to treatment using the uridine pro-drug triacetyluridine (TAU), the FDA-approved treatment for hereditary orotic aciduria.
Case Presentation
An 8‐year‐old girl with developmental delay, autism, and intractable epilepsy presented with increased seizures in the setting of parainfluenza respiratory infection. She had a history of multiple seizure semiologies including tonic, generalized tonic–clonic, staring with behavioral arrest, and focal motor seizures. Seizures varied in frequency and duration, and she had several prior episodes of status epilepticus requiring hospitalization. Six months prior to presentation, she had prolonged status epilepticus, followed by regression in functional skills, gait ataxia, hand tremors, incoordination, and increased seizures.
She was born by normal vaginal birth. It was not clear when developmental delays were first noticed, but she was diagnosed with autism at age 4. Seizures started with febrile illness at 17 months old. Over time, seizures became increasingly difficult to control requiring escalating doses and number of anti‐convulsant medications. The family history showed childhood epilepsy and behavioral concerns on the paternal side. The parents were consanguineous being distant cousins.
At the time of admission, the patient was taking phenytoin 5 mg/kg per day, levetiracetam 68 mg/kg per day, and clobazam 1.5 mg/kg per day.
Video EEG was completed to characterize limb and eye movements concerning for seizures. Focal seizures were captured although the majority of episodes of concern were not seizures. The EEG was notable for diffuse delta slowing and multifocal epileptiform discharges, consistent with epileptic encephalopathy.
Complete blood count showed macrocytic anemia (Hgb 10.6 g/dL; MCV 91.4 fL) and mild thrombocytopenia (135 TH/µL). Basic chemistries showed mild transaminitis.
Computed tomography imaging of the brain showed no acute abnormalities. Brain magnetic resonance imaging at age 4 years was normal. Her karyotype was normal. A chromosomal microarray showed areas of homozygosity without any clinically significant copy number variants. A commercial epilepsy gene panel testing 181 genes in 2019 was unremarkable. Her plasma amino acids, lactate, ammonia, pyruvate, lead, and urine organic acids were normal.
During the hospitalization, the patient developed worsening coordination, nystagmus, tremor, and encephalopathy initially thought to be secondary to medications. It became difficult to find an acceptable balance between seizures and medication side effects. An epilepsy gene panel testing 193 genes revealed a homozygous variant (c.98T > G. p.Met33Arg) in the Carbamoyl‐Phosphate Synthetase 2, Aspartate Transcarbamylase, and Dihydroorotase (CAD) gene, which was reported as likely pathogenic. This variant is found in the general population at very low frequencies in the heterozygous state, and CAD missense variants are depleted in the population databases, suggesting that mutations in this gene are pathogenic (https://gnomad.broadinstitute.org). The mutation lies within one of the areas of homozygosity that was noted on the patient’s microarray; however the variant was not confirmed in the parents as they declined genetic testing.
Pathologic variants in the CAD gene result in a rare neurometabolic disorder characterized by autosomal recessive early epileptic encephalopathy, developmental delay, and intractable epilepsy, as well as a macrocytic anemia.
1
In its untreated form, this disorder is progressive and fatal, however, there are reports in the literature of patients who have been successfully treated with uridine supplementation.
1
,
2
CAD Gene and Uridine Supplementation
The CAD gene, located on chromosome 2 (2p23.3), encodes a highly conserved trifunctional enzyme complex involving carbamoyl‐phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase.
3
This enzyme complex is important in the pathway for de novo synthesis of pyrimidine nucleotides. The final product, uridine monophosphate (UMP), is the substrate for all cellular pyrimidines and therefore essential for RNA and DNA synthesis. UMP derivatives (tri‐ and diphosphate, UTP/UDP) are also important in protein glycosylation, polysaccharide biosynthesis, and lipid metabolism. The importance of uridine is highlighted in the inborn error of metabolism disorder hereditary orotic aciduria (UMPS deficiency), in which there is a primary deficiency in uridine synthesis, leading to failure to thrive, megaloblastic anemia, congenital malformations, immunodeficiency, and developmental delay.
4
Given that cells are able to take up and phosphorylate exogenous uridine, supplementation with uridine can provide a mechanism to overcome deficiencies in the synthetic pathway. Accordingly, uridine triacetate (or triacetyluridine, TAU) is the FDA‐approved treatment for hereditary orotic aciduria.
5
Uridine therapy has also been used in uridine‐nucleotide depletion disease,
6
for overdose of fluorouracil and capecitabine,
5
and is currently under investigation for treatment of mitochondrial diseases. Supplementation with TAU is typically favored over uridine given the bioavailability of TAU is 4–6 times greater than uridine, thereby requiring lower dosages for treatment. TAU is absorbed in the gastrointestinal tract and readily converted to free uridine and acetate by esterases in the gut epithelium. Rare side effects include mild nausea, vomiting, or diarrhea.
5
There is a growing body of evidence demonstrating that uridine supplementation can also be helpful in deficiencies occurring in earlier steps of pyrimidine synthesis, including CAD mutations. In the preclinical setting, Ng et al. (2015) demonstrated that fibroblast cells from a 4‐year‐old patient with compound heterozygous mutations in CAD expressed reduced de novo pyrimidine nucleotides and reduction in all UDP‐activated sugars tested.
7
Supplementation of exogenous uridine rescued these abnormalities. In addition, a study using a CAD‐knockout cell line showed 16 of 25 biallelic variants, including our patient’s specific variant, failed to rescue or only partially rescued the growth phenotype of these cells in the absence of uridine.
8
This suggests that these mutations diminish CAD activity and that uridine supplementation may be helpful to restore the normal phenotype.
In the clinical setting, Koch et al. described four patients with CAD mutations in 2017, two of which were siblings from a consanguineous family who harbored the same mutation as our patient.
1
All four patients had developmental delay, followed by refractory epilepsy, epileptic encephalopathy, developmental regression at 2–4 years old, and anemia. Two of the four patients were treated with oral uridine 100 mg/kg per day divided in four dose administrations. These patients showed significant improvement in their clinical course. The treated child who had our patient’s mutation showed cessation of seizures for at least 6 months, with stable or improved gross motor, fine motor, cognitive and speech function. The anemia also normalized. Cultured fibroblasts from this patient initially showed reduced levels of UDP, UDP‐glucose, UDP‐N‐acetylglucosamine, CTP, and UTP, which all normalized with uridine supplementation. The other treated patient went from a minimally conscious state to being awake, alert, and able to take steps with assistance. The two patients that were not treated died at 4 and 5 years old after progressive neurodegeneration, loss of acquired skills, and refractory seizures. In 2020, a 5‐year‐old boy with a different compound heterozygous CAD mutation who shared a similar phenotype to those described previously also had significant improvement in his seizures, development, and anemia after uridine supplementation.
2
Case Conclusion
Prior to TAU therapy, our patient had up to 6–12 seizures daily, refractory to various combinations of phenytoin, levetiracetam, clobazam, cannabidiol, and carbamazepine, with encephalopathy and regression of functional skills. Supplementation with TAU was initiated at a dose of 100 mg/kg per day divided four times daily. After supplementation, seizures ceased within 4 days and her mental status improved. When assessed after 2 months, the patient was alert, playful, speaking in multi‐word sentences, had coordinated movements, and was ambulating independently. She was continued on clobazam 1 mg/kg per day, levetiracetam 40 mg/kg per day, and TAU. When last assessed, the patient had not had a seizure in 1 year since starting TAU supplementation and continued to make developmental progress.
Discussion
Here, we present a child with an epileptic encephalopathy resulting from a homozygous variant in the CAD gene (c.98T > G.p.Met33Arg) whose seizures resolved and encephalopathy improved with TAU treatment. There is a growing body of work demonstrating that refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism.
9
,
10
Furthermore, the effectiveness of therapies that are targeted to specific metabolic pathways has been well‐documented.
11
,
12
,
13
For example, Hunt et al. (1954) documented a case of neonatal epilepsy resolved by daily pyridoxine treatment, with genetic studies in the past 2 decades highlighting the involvement of ALDH7A1 and PROSC in pyridoxine‐dependent epilepsy.
14
,
15
Since then, various metabolic pathways involving biotin recycling, glucose transport, creatine synthesis, purine metabolism, and Coenzyme Q10 deficiency have been implicated in pediatric epilepsy syndromes, with substantial response to replacement therapies.
9
The success of uridine supplementation in the treatment of several cases of epileptic encephalopathy resulting from CAD mutations further demonstrates the impact of genetic‐based epilepsy therapies. Exome sequencing as well as targeted gene panels have been shown to play an increasingly important role in elucidating these rare and often de novo genetic variants underlying epileptic encephalopathies.
16
,
17
Our patient is the first child reported with intractable epilepsy and developmental regression secondary to CAD mutation who responded clinically to treatment with the uridine prodrug TAU. Exogenous uridine is thought to bypass the loss of CAD function, thereby rescuing pyrimidine synthesis and downstream pathways. Our case uniquely demonstrates a relatively late‐onset case of refractory epilepsy in the setting of a homozygous variant in the CAD gene, with a striking, rapid response to replacement therapy. As the number of reported cases of refractory epilepsy from inborn errors of metabolism continues to grow, it is critical for us to develop comprehensive, commercially‐available epilepsy gene panels for screening of this population to potentially prevent the long‐term detrimental effects of these metabolic pathway errors.
Conflict of Interest
Aliya Frederick – reports no disclosures. Kimberly Sherer ‐ reports no disclosures. Linda Nguyen– reports no disclosures. Shawn Ali– reports no disclosures. Anupam Garg – reports no disclosures. Richard Haas– reports no disclosures. Michelle Sahagian ‐ reports no disclosures. Jonathan Bui‐ reports no disclosures. | CANNABIDIOL, CARBAMAZEPINE, CLOBAZAM, LEVETIRACETAM, PHENYTOIN | DrugsGivenReaction | CC BY | 33249780 | 18,954,694 | 2021-01 |
What was the dosage of drug 'PHENYTOIN'? | Triacetyluridine treats epileptic encephalopathy from CAD mutations: a case report and review.
Refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism. We report a case of an 8-year-old girl with history of developmental delay, autism and intractable epilepsy that was found to have a pathogenic variant in CAD. We briefly review the biochemical pathway of CAD and the preclinical and clinical studies that suggest uridine supplementation can rescue the CAD deficiency phenotypes. Our case demonstrates a relatively late-onset case of refractory epilepsy with a rapid response to treatment using the uridine pro-drug triacetyluridine (TAU), the FDA-approved treatment for hereditary orotic aciduria.
Case Presentation
An 8‐year‐old girl with developmental delay, autism, and intractable epilepsy presented with increased seizures in the setting of parainfluenza respiratory infection. She had a history of multiple seizure semiologies including tonic, generalized tonic–clonic, staring with behavioral arrest, and focal motor seizures. Seizures varied in frequency and duration, and she had several prior episodes of status epilepticus requiring hospitalization. Six months prior to presentation, she had prolonged status epilepticus, followed by regression in functional skills, gait ataxia, hand tremors, incoordination, and increased seizures.
She was born by normal vaginal birth. It was not clear when developmental delays were first noticed, but she was diagnosed with autism at age 4. Seizures started with febrile illness at 17 months old. Over time, seizures became increasingly difficult to control requiring escalating doses and number of anti‐convulsant medications. The family history showed childhood epilepsy and behavioral concerns on the paternal side. The parents were consanguineous being distant cousins.
At the time of admission, the patient was taking phenytoin 5 mg/kg per day, levetiracetam 68 mg/kg per day, and clobazam 1.5 mg/kg per day.
Video EEG was completed to characterize limb and eye movements concerning for seizures. Focal seizures were captured although the majority of episodes of concern were not seizures. The EEG was notable for diffuse delta slowing and multifocal epileptiform discharges, consistent with epileptic encephalopathy.
Complete blood count showed macrocytic anemia (Hgb 10.6 g/dL; MCV 91.4 fL) and mild thrombocytopenia (135 TH/µL). Basic chemistries showed mild transaminitis.
Computed tomography imaging of the brain showed no acute abnormalities. Brain magnetic resonance imaging at age 4 years was normal. Her karyotype was normal. A chromosomal microarray showed areas of homozygosity without any clinically significant copy number variants. A commercial epilepsy gene panel testing 181 genes in 2019 was unremarkable. Her plasma amino acids, lactate, ammonia, pyruvate, lead, and urine organic acids were normal.
During the hospitalization, the patient developed worsening coordination, nystagmus, tremor, and encephalopathy initially thought to be secondary to medications. It became difficult to find an acceptable balance between seizures and medication side effects. An epilepsy gene panel testing 193 genes revealed a homozygous variant (c.98T > G. p.Met33Arg) in the Carbamoyl‐Phosphate Synthetase 2, Aspartate Transcarbamylase, and Dihydroorotase (CAD) gene, which was reported as likely pathogenic. This variant is found in the general population at very low frequencies in the heterozygous state, and CAD missense variants are depleted in the population databases, suggesting that mutations in this gene are pathogenic (https://gnomad.broadinstitute.org). The mutation lies within one of the areas of homozygosity that was noted on the patient’s microarray; however the variant was not confirmed in the parents as they declined genetic testing.
Pathologic variants in the CAD gene result in a rare neurometabolic disorder characterized by autosomal recessive early epileptic encephalopathy, developmental delay, and intractable epilepsy, as well as a macrocytic anemia.
1
In its untreated form, this disorder is progressive and fatal, however, there are reports in the literature of patients who have been successfully treated with uridine supplementation.
1
,
2
CAD Gene and Uridine Supplementation
The CAD gene, located on chromosome 2 (2p23.3), encodes a highly conserved trifunctional enzyme complex involving carbamoyl‐phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase.
3
This enzyme complex is important in the pathway for de novo synthesis of pyrimidine nucleotides. The final product, uridine monophosphate (UMP), is the substrate for all cellular pyrimidines and therefore essential for RNA and DNA synthesis. UMP derivatives (tri‐ and diphosphate, UTP/UDP) are also important in protein glycosylation, polysaccharide biosynthesis, and lipid metabolism. The importance of uridine is highlighted in the inborn error of metabolism disorder hereditary orotic aciduria (UMPS deficiency), in which there is a primary deficiency in uridine synthesis, leading to failure to thrive, megaloblastic anemia, congenital malformations, immunodeficiency, and developmental delay.
4
Given that cells are able to take up and phosphorylate exogenous uridine, supplementation with uridine can provide a mechanism to overcome deficiencies in the synthetic pathway. Accordingly, uridine triacetate (or triacetyluridine, TAU) is the FDA‐approved treatment for hereditary orotic aciduria.
5
Uridine therapy has also been used in uridine‐nucleotide depletion disease,
6
for overdose of fluorouracil and capecitabine,
5
and is currently under investigation for treatment of mitochondrial diseases. Supplementation with TAU is typically favored over uridine given the bioavailability of TAU is 4–6 times greater than uridine, thereby requiring lower dosages for treatment. TAU is absorbed in the gastrointestinal tract and readily converted to free uridine and acetate by esterases in the gut epithelium. Rare side effects include mild nausea, vomiting, or diarrhea.
5
There is a growing body of evidence demonstrating that uridine supplementation can also be helpful in deficiencies occurring in earlier steps of pyrimidine synthesis, including CAD mutations. In the preclinical setting, Ng et al. (2015) demonstrated that fibroblast cells from a 4‐year‐old patient with compound heterozygous mutations in CAD expressed reduced de novo pyrimidine nucleotides and reduction in all UDP‐activated sugars tested.
7
Supplementation of exogenous uridine rescued these abnormalities. In addition, a study using a CAD‐knockout cell line showed 16 of 25 biallelic variants, including our patient’s specific variant, failed to rescue or only partially rescued the growth phenotype of these cells in the absence of uridine.
8
This suggests that these mutations diminish CAD activity and that uridine supplementation may be helpful to restore the normal phenotype.
In the clinical setting, Koch et al. described four patients with CAD mutations in 2017, two of which were siblings from a consanguineous family who harbored the same mutation as our patient.
1
All four patients had developmental delay, followed by refractory epilepsy, epileptic encephalopathy, developmental regression at 2–4 years old, and anemia. Two of the four patients were treated with oral uridine 100 mg/kg per day divided in four dose administrations. These patients showed significant improvement in their clinical course. The treated child who had our patient’s mutation showed cessation of seizures for at least 6 months, with stable or improved gross motor, fine motor, cognitive and speech function. The anemia also normalized. Cultured fibroblasts from this patient initially showed reduced levels of UDP, UDP‐glucose, UDP‐N‐acetylglucosamine, CTP, and UTP, which all normalized with uridine supplementation. The other treated patient went from a minimally conscious state to being awake, alert, and able to take steps with assistance. The two patients that were not treated died at 4 and 5 years old after progressive neurodegeneration, loss of acquired skills, and refractory seizures. In 2020, a 5‐year‐old boy with a different compound heterozygous CAD mutation who shared a similar phenotype to those described previously also had significant improvement in his seizures, development, and anemia after uridine supplementation.
2
Case Conclusion
Prior to TAU therapy, our patient had up to 6–12 seizures daily, refractory to various combinations of phenytoin, levetiracetam, clobazam, cannabidiol, and carbamazepine, with encephalopathy and regression of functional skills. Supplementation with TAU was initiated at a dose of 100 mg/kg per day divided four times daily. After supplementation, seizures ceased within 4 days and her mental status improved. When assessed after 2 months, the patient was alert, playful, speaking in multi‐word sentences, had coordinated movements, and was ambulating independently. She was continued on clobazam 1 mg/kg per day, levetiracetam 40 mg/kg per day, and TAU. When last assessed, the patient had not had a seizure in 1 year since starting TAU supplementation and continued to make developmental progress.
Discussion
Here, we present a child with an epileptic encephalopathy resulting from a homozygous variant in the CAD gene (c.98T > G.p.Met33Arg) whose seizures resolved and encephalopathy improved with TAU treatment. There is a growing body of work demonstrating that refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism.
9
,
10
Furthermore, the effectiveness of therapies that are targeted to specific metabolic pathways has been well‐documented.
11
,
12
,
13
For example, Hunt et al. (1954) documented a case of neonatal epilepsy resolved by daily pyridoxine treatment, with genetic studies in the past 2 decades highlighting the involvement of ALDH7A1 and PROSC in pyridoxine‐dependent epilepsy.
14
,
15
Since then, various metabolic pathways involving biotin recycling, glucose transport, creatine synthesis, purine metabolism, and Coenzyme Q10 deficiency have been implicated in pediatric epilepsy syndromes, with substantial response to replacement therapies.
9
The success of uridine supplementation in the treatment of several cases of epileptic encephalopathy resulting from CAD mutations further demonstrates the impact of genetic‐based epilepsy therapies. Exome sequencing as well as targeted gene panels have been shown to play an increasingly important role in elucidating these rare and often de novo genetic variants underlying epileptic encephalopathies.
16
,
17
Our patient is the first child reported with intractable epilepsy and developmental regression secondary to CAD mutation who responded clinically to treatment with the uridine prodrug TAU. Exogenous uridine is thought to bypass the loss of CAD function, thereby rescuing pyrimidine synthesis and downstream pathways. Our case uniquely demonstrates a relatively late‐onset case of refractory epilepsy in the setting of a homozygous variant in the CAD gene, with a striking, rapid response to replacement therapy. As the number of reported cases of refractory epilepsy from inborn errors of metabolism continues to grow, it is critical for us to develop comprehensive, commercially‐available epilepsy gene panels for screening of this population to potentially prevent the long‐term detrimental effects of these metabolic pathway errors.
Conflict of Interest
Aliya Frederick – reports no disclosures. Kimberly Sherer ‐ reports no disclosures. Linda Nguyen– reports no disclosures. Shawn Ali– reports no disclosures. Anupam Garg – reports no disclosures. Richard Haas– reports no disclosures. Michelle Sahagian ‐ reports no disclosures. Jonathan Bui‐ reports no disclosures. | 5 MILLIGRAMS PER KILOGRAMS PER DAY | DrugDosageText | CC BY | 33249780 | 18,954,694 | 2021-01 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.