Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib

Blood Adv. 2019 May 14;3(9):1553-1562. doi: 10.1182/bloodadvances.2018030007.

Abstract

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib improves patient outcomes in chronic lymphocytic leukemia (CLL); however, some patients experience adverse events (AEs) leading to discontinuation. Acalabrutinib is a potent, covalent BTK inhibitor with greater selectivity than ibrutinib. We evaluated the safety and efficacy of 100 mg of acalabrutinib twice daily or 200 mg once daily in patients with CLL who discontinued ibrutinib because of intolerance as determined by the investigators. Among 33 treated patients (61% men; median age, 64 years; range, 50-82 years), median duration of prior ibrutinib treatment was 11.6 months (range, 1-62 months); median time from ibrutinib discontinuation to acalabrutinib start was 47 days (range, 3-331 days). After a median of 19.0 months (range, 0.2-30.6 months), 23 patients remained on acalabrutinib; 10 had discontinued (progressive disease, n = 4; AEs, n = 3). No acalabrutinib dose reductions occurred. During acalabrutinib treatment, the most frequent AEs included diarrhea (58%), headache (39%), and cough (33%). Grade 3/4 AEs occurred in 58%, most commonly neutropenia (12%) and thrombocytopenia (9%). Of 61 ibrutinib-related AEs associated with intolerance, 72% did not recur and 13% recurred at a lower grade with acalabrutinib. Overall response rate was 76%, including 1 complete and 19 partial responses and 5 partial responses with lymphocytosis. Among 25 responders, median duration of response was not reached. Median progression-free survival (PFS) was not reached; 1-year PFS was 83.4% (95% confidence interval, 64.5%-92.7%). Acalabrutinib was well tolerated with a high response rate in patients who were previously intolerant to ibrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / metabolism
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use*
  • Benzamides / adverse effects
  • Benzamides / metabolism
  • Benzamides / therapeutic use*
  • Diarrhea / etiology
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Male
  • Middle Aged
  • Phosphorylation
  • Progression-Free Survival
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazines / adverse effects
  • Pyrazines / metabolism
  • Pyrazines / therapeutic use*
  • Pyrazoles / therapeutic use
  • Pyrimidines / therapeutic use
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Benzamides
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyrazoles
  • Pyrimidines
  • ibrutinib
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • acalabrutinib

Associated data

  • ClinicalTrials.gov/NCT02029443