Bruton tyrosine kinase inhibitors and cardiovascular adverse events

Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukaemia and other B-cell malignancies, yet their therapeutic benefit is tempered by clinically relevant cardiovascular toxicities (predominantly atrial fibrillation, hypertension, bleeding and ventricular arrhythmias). Pharmacological differences in cardiotoxicity arise from binding mode and kinase selectivity profiles. First- and second-generation covalent BTKi (ibrutinib, acalabrutinib, zanubrutinib) irreversibly target Cys481, leading to off-target engagement of other kinases that regulate cardiac electrophysiology and also express homologous cysteine residues. In contrast, non-covalent BTKi, such as pirtobrutinib, achieve selective and persistent BTK occupancy through Cys481-independent interactions, substantially attenuating off-target kinase inhibition and associated cardiotoxicity. Mechanistic insights support proactive baseline cardiovascular risk assessment and structured longitudinal surveillance to enable early detection, risk-adapted management and sustained BTKi therapy. This mini-review describes how such concepts apply to the issue of BTKi-associated cardiovascular adverse events.