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

Blood Adv. 2019 Jun 25;3(12):1799-1807. doi: 10.1182/bloodadvances.2018028761.

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.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anemia / chemically induced
  • Anemia / epidemiology
  • Atrial Fibrillation / chemically induced
  • Atrial Fibrillation / epidemiology
  • Diarrhea / chemically induced
  • Diarrhea / epidemiology
  • Drug Tolerance / physiology
  • Fatigue / chemically induced
  • Fatigue / epidemiology
  • Female
  • Follow-Up Studies
  • Hemorrhage / chemically induced
  • Hemorrhage / epidemiology
  • Humans
  • Hypertension / chemically induced
  • Hypertension / epidemiology
  • Infections / chemically induced
  • Infections / epidemiology
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Male
  • Middle Aged
  • Neutropenia / chemically induced
  • Neutropenia / epidemiology
  • Pneumonia / chemically induced
  • Pneumonia / epidemiology
  • Prevalence
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects*
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazoles / administration & dosage
  • Pyrazoles / adverse effects*
  • Pyrazoles / therapeutic use*
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects*
  • Pyrimidines / therapeutic use*
  • Safety

Substances

  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • ibrutinib

Associated data

  • ClinicalTrials.gov/NCT01578707
  • ClinicalTrials.gov/NCT01105247
  • ClinicalTrials.gov/NCT01722487
  • ClinicalTrials.gov/NCT01724346
  • ClinicalTrials.gov/NCT01109069