Abstract 12000: Ventricular Arrhythmias and Sudden Death Events Following Acalabrutinib Therapy Initiation for Hematology Malignancies

Introduction: Acalabrutinib, a next generation Bruton’s tyrosine kinase inhibitor (BTKi) associates with dramatic efficacy against hematology malignancies. Unexplained ventricular arrhythmias (VAs) with next generation BTKi therapy have been reported. Yet, whether acalabrutinib associates with VAs in long-term follow up is unknown. Methods: Leveraging a cohort of 290 consecutive hematologic malignancy patients treated with acalabrutinib (2014-2020), we assessed VA incidence. The primary endpoint was incident VA development (ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular contractions). Probability Scores determined likelihood of acalabrutinib association. Incident rates as function of time on therapy were calculated. Weighted average incidence rates were compared to observed rates in a large contemporary similar aged general population using relative risk. Absolute excess risk (AER) for acalabrutinib associated VAs was estimated. Results: Over 1,063 person years of follow up, there were 8 incident VA cases, including 6 in those without coronary disease (CAD) or heart failure (HF), and 1 sudden death; median time to event was 14.9 months. Among those without prior ibrutinib use, CAD, or HF, weighted average incidence was 394 per 100,000 person years. This compares to 596 for ibrutinib related VAs (RR 0.66, P<0.01; figure) and 48.1 among similar aged non-BTKi treated subjects (RR 8.2, P<0.001; AER 346). Outside of age, no cardiac or electrocardiographic variables associated with VA development . Conclusions: Acalabrutinib associates with increased risk of incident VAs. Collectively, these data suggest VAs may be a class effect of BTKi therapies. Figure: Ventricular arrhythmia (VA) crude (A) and cumulative (B) incidence rates in acalabrutinib users versus ibrutinib and non BTKi treated populations. *Those without prior ibrutinib use or structural heart disease. **Assumes linear a event rate over time.