Sudden death and asymptomatic arrhythmia in chronic lymphocytic leukemia patients treated with ibrutinib

Background Ibrutinib (IBR) is a first-in-class Bruton's tyrosine kinase inhibitor (BTKi) approved in multiple hematologic conditions for indefinite use until disease progression or toxicity. Hypertension and atrial fibrillation are well-recognized cardiac complications of BTKi; more recently, heart failure, additional arrhythmias, and sudden cardiac death (SCD) have been attributed to IBR. Next-generation covalent BTKi are also associated with cardiovascular complications, including SCD, albeit to a lesser degree. Objective The incidence and clinical features of patients experiencing SCD and asymptomatic arrhythmias on IBR remain ill defined. We aimed to characterize the incidence of SCD and asymptomatic arrhythmias on IBR. Methods We report (1) a retrospective cohort analysis of 131 patients with a median of 66.5 months on IBR using available cardiac testing, genetic sequencing, and autopsy review and (2) a cross-sectional cardiac analysis of 21 asymptomatic patients on IBR including ambulatory electrocardiogram, stress tests, and transthoracic echocardiograms. Results The incidence of SCD in patients on IBR (n = 5) was 801 per 100,000 patient-years, approximately 2-4× higher than the general population. All patients with SCD on IBR had at least 1 cardiac risk factor. Autopsies conducted in 3 of 5 patients with SCD did not reveal acute pathologic processes, but did demonstrate evolving cardiac pathology. Cardiovascular testing in asymptomatic patients on IBR revealed previously unknown clinically significant arrhythmias in 4 patients (19%), leading to precautionary IBR discontinuation in 2 patients. Conclusion IBR increases the risk of SCD among patients with cardiac risk factors. Stress and ambulatory electrocardiogram on IBR identified asymptomatic arrhythmias altering clinical management in 19% of patients. These data highlight the need for risk-mitigation strategies for patients starting or receiving IBR, possibly extending to other BTKis.