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Ibrutinib: treatment toxicities and outcomes
Introduction
Ibrutinib is an orally bioavailable, irreversible inhibitor of Bruton tyrosine kinase (BTK). It is a standard of care in the treatment of chronic lymphocytic leukemia (CLL) in the relapsed/refractory1-3 as well as front-line4 settings.
The toxicities of ibrutinib and reasons for its discontin- uation were initially defined through several landmark studies comparing ibrutinib to chlorambucil (front-line, RESONATE 2),4 ofatumumab (RESONATE)2 and ben- damustine and rituximab +/- ibrutinib versus placebo (HELIOS).5 Higher proportions of patients discontinuing therapy (ranging from 25% to 51%) have been found with long-term follow-up (median follow-ups ranging between 20 months and approximately 5 years) of these and other ibrutinib clinical trials. Although the percentage of discon- tinuations due to progression of disease (21% to 45%) remained similar, there were high proportions of discon- tinuations due to adverse events, ranging from 12% to 32%.6-10
Woyach et al. suggested that discontinuation due to CLL progression (distinguished from disease transformation) occurred later in the disease course (cumulative incidence of 7.3% at 2 years, 19.1% at 4 years) while other reasons for discontinuation, such as Richter transformation, peaked early and reached a plateau by 3 years (18.7% at 2 years, 23.9% at 3 years).8 In clinical practice, adverse events were found to be the most common cause of ibru- tinib discontinuation among 143 patients, approaching 50%.11 Atrial fibrillation, infectious complications, and cytopenias were the most commonly described adverse events.11 High percentages of patients discontinuing thera- py, ranging from 19-41%, were encountered in additional studies conducted in the USA and outside of the USA; however, these studies were limited by relatively small sample sizes and short follow-up periods.12-15
We, therefore, aimed to characterize patterns of care among ibrutinib-treated CLL patients in clinical practice in the USA focusing on rates and reasons for discontinuation, and how these affect outcomes. To our knowledge, this series is the largest report on ibrutinib-treated CLL patients.
Methods
We conducted a multicenter, retrospective cohort study of CLL patients at nine USA cancer centers and from the Connect® CLL Registry (199 USA centers, 80% community sites) who were treated with ibrutinib either as part of a clinical trial or with com- mercially available drug.16 The institutional review board of each participating institution approved this study. Investigators at each institution were asked to utilize chart review, institutional elec- tronic medical records and clinical/pathological databases to obtain required information for all CLL patients treated with ibru- tinib. Data collected included: patients’ demographics, genetic characteristics, number of prior therapies, dosing and dose adjust- ments, discontinuation rates and reasons, toxicities and outcomes. The period of enrollment was January 2014 to August 2016.
The primary study endpoint was progression-free survival, which was defined as time from ibrutinib treatment to progres- sion or death from any cause as per the Kaplan Meier method.17 Patients were otherwise censored, regardless of progression status, at the time of last follow-up and at the time of next therapy. When interpreting medical records, investigators were advised to use the
International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria to define response and progression of disease.18,19 Patients were stratified by line of therapy (front-line versus relapsed/refractory), reason for discontinuation (intolerance versus progressive disease), clinical trial participation versus commercial use, and depth of response (complete response versus partial response and partial response with lymphocytosis). Secondary endpoints included overall survival and reasons for ibrutinib dis- continuation. Overall survival was defined as the time in months from initiation of ibrutinib to death.
Reasons for ibrutinib discontinuation were categorized as fol- lows: toxicity, progressive disease, Richter transformation to either diffuse large B-cell lymphoma or Hodgkin lymphoma, planned cellular therapy (allogeneic hematopoietic stem cell trans- plantation or chimeric antigen receptor genetically modified T-cell therapy), secondary malignancies, physician’s or patient’s prefer- ence, financial concerns, and other/unrelated death. Toxicities leading to discontinuation were categorized as: hematologic toxi- city, infection, atrial fibrillation, congestive heart failure, drug- induced pneumonitis, drug-induced colitis, transaminitis, bleed- ing, arthralgia/myalgia, dermatological, neurotoxicity, other, or unknown.
Survival data were compared using the log-rank test.20 Univariate Cox regression analyses were used to estimate hazard ratios.21 All other comparison analyses were descriptive. All tests were two-sided at the 5% level. Statistical analyses were per- formed using STATA 10.1 (Stata Statistical Software: Release 10. 2007; StataCorp LP, College Station, TX, USA).
Results
Patients
We identified 616 patients who received ibrutinib, including 536 relapsed-refractory and 80 previously untreated patients. Data from the nine contributing aca- demic centers were collected retrospectively and included information for 399 patients treated with ibrutinib; data from the Connect CLL registry were collected prospec- tively and included information on 217 patients largely collected from community sites (80% community). The patients’ baseline characteristics stratified by line of thera- py are available in Table 1. A total of 546 (88%) patients were treated with commercially available drug/off study. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01), had a similar time from diagnosis to treat- ment with ibrutinib (mean 85 versus 87 months, P=0.8) and were more consistently initiated at a dose of 420 mg daily (100% versus 89%).
Reasons for discontinuation, toxicities and timing of events
At a median follow-up of 17 months (range, 1-60 months), 41% of patients discontinued ibrutinib. The median time to ibrutinib discontinuation was 7 months (range, 0.1–41), with a median time of 6 months for patients who discontinued due to intolerance and 10 months for those who discontinued due to progression of disease (Online Supplementary Figure S1). Among patients on ibrutinib monotherapy, 41% discontinued therapy while the percentage of discontinuation among patients receiving ibrutinib-based combination therapy was 43.9%. Ibrutinib starting dose (420 mg daily versus <420 mg daily) did not correlate with the proportion of patients who discontinued ibrutinib due to toxicity (51% versus
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