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

Abstract

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.

Serum profiling identifies ibrutinib as a treatment option for young adults with B‐cell acute lymphoblastic leukaemia

“…In addition, BMX is a target of ibrutinib, a small molecule therapy that targets the BTK pathway. Ibrutinib is being used in several clinical trials for patients with mature B‐cell malignancies including relapsed/refractory chronic lymphocytic leukaemia (Coutre et al , ; Nuttall et al , ; Shanafelt et al , ), small lymphocytic lymphoma (Coutre et al , ), and mantle cell lymphoma (Wang et al , ) and BMX expression in 4/6 adult B‐ALL patients in this study, the antigenicity of BMX as shown by proto‐array analysis and recent study showing the ability of ibrutinib to target pre‐BCR signalling in B‐ALL (Kim et al , ) all suggest the value of using ibrutinib to treat adults with B‐ALL.…”

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

“…Of note, PFS benefit with ibrutinib remained in the final analysis after 6‐year of follow‐up . Patients with ≥2 prior therapies and those with TP53 or SF3B1 mutations had shorter PFS …”

“…The most common AEs contributing to drug discontinuation were pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). 18 Of note, PFS benefit with ibrutinib remained in the final analysis after 6-year of follow-up. 20 Patients with ≥2 prior therapies and those with TP53 or SF3B1 mutations had shorter PFS.…”

“…Prevalence of AEs (diarrhea, fatigue, grade 3 infection, bleeding, and neutropenia) tended to decrease over time while the rate of hypertension eventually increased despite an early initial decrease seen after the first year. The most common AEs contributing to drug discontinuation were pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3) . Of note, PFS benefit with ibrutinib remained in the final analysis after 6‐year of follow‐up .…”

“…20 Patients with ≥2 prior therapies and those with TP53 or SF3B1 mutations had shorter PFS. [18][19][20] Several reports have described the efficacy and toxicity of ibrutinib in patients in a real-world setting. [21][22][23] In this respect Mato et al 23 found that the median PFS was 35 months which is shorter than that reported in the final 6-year follow-up analysis of the RESO-NATE study (median PFS 44.1 months).…”