In silico analysis of atrial fibrillation and hypertension mechanism of action secondary to ibrutinib/acalabrutinib in chronic lymphocytic leukemia.

Ibrutinib and acalabrutinib are first- and next-generation Bruton Tyrosine Kinase inhibitors (BTKi), respectively, approved for chronic lymphocytic leukemia (CLL). Ibrutinib has been associated with cardiovascular events, including atrial fibrillation (AF) and hypertension. Acalabrutinib has demonstrated non-inferior progression-free survival than ibrutinib in relapsed/refractory CLL patients, with a lower cardiovascular event incidence. These adverse events seem to be derived from off-targets rather than BTK inhibition. Machine learning algorithms were applied to identify targets likely to trigger AF and hypertension in simulated CLL patients receiving acalabrutinib or ibrutinib. Common ibrutinib and acalabrutinib off-targets showed association with AF through structural remodeling and electrophysiology/ectopic activity mechanisms (TEC and ERBB4). There was association with hypertension through inflammation (ERBB4) and oxidative stress and endothelial dysfunction (ERBB4 and RIPK2). Ibrutinib-specific off-targets showed association with AF through structural remodeling (HCK, FGR, LYN, FYN, YES1, and FLT3) and electrophysiology activity (LYN and SRC), and with hypertension through inflammation (LCK, JAK3, and FLT3) and oxidative stress and endothelial dysfunction (ERBB2, BLK, SRC, and CSK). No acalabrutinib-specific off-targets were identified for AF or hypertension. This study supports that BTKi off-target selectivity may justify the different AF and hypertension incidences, suggesting their association with several ibrutinib-specific off-targets and identifying no acalabrutinib-specific ones.