Ventricular arrhythmias and sudden death events following acalabrutinib initiation

• Published in: Blood Vol. 140; no. 20; pp. 2142 - 2145
• Main Authors: Bhat, Seema A., Gambril, John, Azali, Leylah, Chen, Sunnia T., Rosen, Lindsay, Palettas, Marilly, Wiczer, Tracy E., Kalathoor, Sujay, Zhao, Qiuhong, Rogers, Kerry A., Kittai, Adam, Grever, Michael, Awan, Farrukh, Ruz, Patrick, Byrd, John C., Woyach, Jennifer, Addison, Daniel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.11.2022
• Subjects: Aged; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - epidemiology; Benzamides; Death, Sudden; Heart Failure; Humans; Pyrazines
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2022016953

•Patients treated with next generation BTKi therapy acalabrutinib still see a >8 fold risk of ventricular arrhythmia and sudden death events.•Ventricular arrhythmias may be a class effect of BTKi therapy, and vigilance is needed. [Display omitted] Acalabrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), associates with dramatic efficacy against B-cell malignancies. Recently, 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. Leveraging a large-cohort of 290 consecutive B-cell malignancy patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence of VAs. The primary-endpoint was incident VA development (ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular contractions). Probability-scores were assessed to determine likelihood of acalabrutinib-association. Incident rates as function of time-on-therapy were calculated. Weighted average observed incidence rates were compared with expected population rates using relative-risks. Absolute excess risk (AER) for acalabrutinib-associated VAs was estimated. Over 1063 person-years of follow-up, there were 8 cases of incident-VAs, including 6 in those without coronary disease (CAD) or heart failure (HF) and 1 sudden-death; median time-to-event 14.9 months. Among those without prior ibrutinib-use, CAD, or HF, the weighted average incidence was 394 per 100 000 person years compared with a reported incidence of 48.1 among similar-aged non–BTKi-treated subjects (relative risk, 8.2; P < .001; AER, 346). Outside of age, no cardiac or electrocardiographic variables associated with VA development. Collectively, these data suggest VAs may be a class-effect of BTKi therapies. Bhat and colleagues evaluate the incidence of symptomatic ventricular arrhythmias in a large-case series of acalabrutinib-treated patients. Although lower than the rate reported with ibrutinib, the occurrence in nearly 3% of acalabrutinib-treated patients is an estimated 8-fold higher than similar untreated control subjects. Their data suggest that ventricular arrhythmias may be a class-effect of Bruton tyrosine kinase inhibitors and increase impetus for time-limited treatment regimens.