Ibrutinib and Bruton's Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: Focus on Atrial Fibrillation and Ventricular Tachyarrhythmias/Sudden Cardiac Death

Chemotherapy. 2023;68(2):61-72. doi: 10.1159/000528019. Epub 2022 Nov 10.


Background: The natural history of chronic lymphocytic leukemia (CLL) was dramatically improved by the introduction of ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. In this review, we aimed to summarize and critically evaluate the association between first- and second-generation BTK inhibitors and the risk of atrial fibrillation (AF) and ventricular arrhythmias (VA).

Summary: Since the first clinical experience, the development of AF was observed as the result of off-target effects that likely combined with patient's predisposing risk factors and concomitant cardiac morbidities. More recently, both ibrutinib dose reduction and arrhythmia management allowed long-term treatment, with positive effects on progression-free survival and reduced all-cause mortality as well. Second-generation BTK inhibitors, acalabrutinib, and zanubrutinib have been tested and validated in CLL. A lower occurrence of AF as compared with ibrutinib has been found, although AF has always been a secondary endpoint of all studies that probed these agents.

Key messages: For this reason, caution should be exercised before concluding that second-generation BTK inhibitors are safer than ibrutinib. Recent data on the effectiveness of ibrutinib over a follow-up of 8 years show a remarkable benefit on all-cause mortality, which is of great value also for interpreting the clinical impact of the few cases of VA and sudden cardiac death (SCD) reported for ibrutinib, independently of QT lengthening. Since a risk of VA and SCD has been recently reported also during treatment with second-generation BTK inhibitors, it appears that this risk, usually reaching its maximum size effect at long-term follow-up, likely denotes a class effect of BTK inhibitors.

Keywords: Acalabrutinib; Arrhythmias; Atrial fibrillation; Bruton kinase inhibitors; Cardiac toxicity; Ibrutinib; Sudden cardiac death; Ventricular tachyarrhythmias; Zanubrutinib.

Publication types

  • Review

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Atrial Fibrillation* / chemically induced
  • Atrial Fibrillation* / etiology
  • Death, Sudden, Cardiac
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell* / complications
  • Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy
  • Protein Kinase Inhibitors / adverse effects
  • Tachycardia, Ventricular* / chemically induced
  • Tachycardia, Ventricular* / drug therapy
  • Tyrosine Kinase Inhibitors


  • Agammaglobulinaemia Tyrosine Kinase
  • ibrutinib
  • Tyrosine Kinase Inhibitors
  • Protein Kinase Inhibitors