Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis.

Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies.

Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies.

Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n = 195) and PCYC-1115/1116 (RESONATE-2, n = 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n = 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n = 173, 52% any-grade; n = 15, 5% grade 3) and fatigue (n = 119, 36% any-grade; n = 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n = 60, 18%) and pneumonia (n = 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade ≥3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069.

Safety Analysis of Four Randomized Controlled Studies of Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or Mantle Cell Lymphoma.

BACKGROUND: Multiple studies have demonstrated the efficacy and safety of ibrutinib for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). This first-in-class inhibitor of Bruton's tyrosine kinase has become a standard treatment for patients with CLL and MCL. PATIENTS AND METHODS: We conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with ibrutinib versus comparators. Data were pooled from 4 completed randomized controlled studies that had included 756 ibrutinib-treated and 749 comparator-treated patients with CLL/SLL or relapsed/refractory MCL. Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates. RESULTS: The median treatment duration was 13.3 months (maximum, 28.2 months) for ibrutinib and 5.8 months (maximum, 27.3 months) for comparators. When adjusted for exposure, diarrhea, atrial fibrillation, and hypertension were the only common grade ≥ 3 AEs more often reported with ibrutinib than with the comparators. Dose reductions (7% vs. 14%) and discontinuation (12% vs. 16%) because of AEs occurred less often with ibrutinib, and deaths due to AEs occurred at similar rates (6% vs. 7%). When adjusted for exposure, the corresponding data were all lower with ibrutinib than with the comparators (0.06 vs. 0.22, 0.11 vs. 0.22, and 0.06 vs. 0.09 patient-exposure-years, respectively). The prevalence of common grade 3/4 AEs with ibrutinib generally decreased over time, with the exception of hypertension. CONCLUSION: These results from an integrated analysis support a favorable benefit/risk profile of ibrutinib in patients with CLL/SLL and MCL.