Adjudication of Adverse Cardiovascular Events in Patients with Chronic Lymphocytic Leukaemia Treated with Ibrutinib: Deaths in GLOW or Blowing in the Wind?

Anti-cancer tyrosine kinase inhibitors are less selective than usually believed and may cause cardiovascular off-target effects. Ibrutinib, a first-in-class covalent inhibitor of Bruton tyrosine kinase, is a pillar of treatment of chronic lymphocytic leukaemia (CLL) and other B-cell malignancies yet is associated with risks of hypertension, AF and, less frequently, heart failure or ventricular tachyarrhythmias, which may lead to sudden death. The GLOW trial of ibrutinib plus the Bcl-2 inhibitor venetoclax as the first-line, fixed-duration treatment of CLL in elderly patients reported a number of cardiac and sudden deaths; these have been cited by many to downplay the otherwise unprecedented efficacy of this treatment. This article demonstrates that deaths in GLOW were mistakenly attributed to ibrutinib and should have been interpreted in the light of a complex composite of patient characteristics and the dynamics of cardiovascular events. Critical analysis of deaths in GLOW should serve as a lesson to improve clinicians' appraisal of the risk:benefit ratio of using one cancer drug or another.