Abstract 17859: Real World Cardiovascular Events With Next Generation Bruton's Tyrosine Kinase Inhibitors - An Updated Analysis

Abstract

Introduction: Acalabrutinib and zanubrutinib are next generation Bruton’s tyrosine kinase inhibitors (BTKIs) associated with dramatic efficacy against B cell malignancies. In early trials, these BTKIs show less cardiac activity than ibrutinib. Yet, whether this is seen in longer term follow up is unknown. Methods: Leveraging the US Food and Drug Administration’s Adverse Events Reporting System (FAERS), we identified the relative incidence and predictive factors for atrial fibrillation (AF) after BTKI initiation from 2015-2022. Secondary outcomes were the reporting odds ratios (ROR) of major adverse cardiovascular adverse events (AEs), defined as AF, non-AF atrial arrhythmias, heart failure, conduction blocks, and ventricular arrythymias. In addition, using a registry cohort of 838 hematologic malignancy patients treated with ibrutinib or acalabrutinib from 2012-2020, we assessed the comparative incidence of new AF. Observed incident AF rates were compared with Framingham heart predicted rates, and absolute excess risks of AF were estimated. Multivariable logistic-regression models were used to identify factors associated with AF, other cardiac AEs, and mortality. Results: Among 21,435 events reported to FAERS during BTKI use, 3,453 were cardiovascular AEs. AF was the most reported AE (ROR 8.8, 95% CI, 8.3-9.4; Figure A ). The likelihood (ROR) of cardiac AE reporting in next generation BTKI treated patients was >3.0 ( P <0.05; Figure A ) for AF events. Furthermore, in acalabrutinib treated registry patients, 9.7% developed incident AF over a median follow up of 42 months. In those without prior ibrutinib use, the weighted average incidence was 281 per 10,000 person years compared to the Framingham predicted rate of 103 per 10,000 person years (RR 2.73, P <0.001; AER 178; Figure B ). Conclusions: These data suggest residual AF risk with next generation BTKIs.