Ibrutinib-Associated Sudden Death in Patients with CLL

INTRODUCTION: Ibrutinib therapy is associated with an increased risk of cardiac arrhythmias. There is currently no standard for cardiac screening or monitoring in patients on ibrutinib and it remains unknown which factors predispose patients to serious or fatal arrhythmias.

METHODS: We report a retrospective cohort study of patients with chronic lymphocytic leukemia (CLL) on ibrutinib-based therapies at the NIH Clinical Center from 2012-2022. Electronic medical records were reviewed for cardiac symptoms, cardiac testing, and autopsy reports. Patients with sudden death were analyzed for 41 genes associated with inherited and syndromic conditions involving cardiac arrhythmias (Invitae). Serum concentrations of ibrutinib from stored samples were measured.

RESULTS: A total of 131 patients with CLL received ibrutinib-based therapy (128 single-agent ibrutinib and 3 ibrutinib-duvelisib). Five patients (3.82%) had sudden death over an observation period of 624 patient-years. At time of death, 4 patients were receiving ibrutinib monotherapy and 1 was receiving ibrutinib in combination with duvelisib. The median age of sudden death was 62 (range 48-70) and the median duration of ibrutinib treatment at time of death was 21 months (range 0.1-56.2). All patients with sudden death had elevated body mass indices, 4 had pre-existing concurrent hypertension and hyperlipidemia, 2 had cardiac symptoms prior to starting ibrutinib (palpitations, chest pain, dizziness, dyspnea on exertion), and only 1 developed cardiac symptoms while on ibrutinib (palpitations at 33 months). Three patients had documented arrhythmias while on ibrutinib, including 2 with occasional ectopy and bradycardia on resting EKG and 1 with ventricular couplets on exercise stress test. In serum samples collected 0.1-8.1 months prior to death, only 1 patient had an elevated ibrutinib concentration of 278.18 ng/mL, above the expected average Cmax of 190 ng/mL after a 420mg dose of ibrutinib (Advani et al. J Clin Oncol, 2013). Genetic analysis revealed no pathologic variants associated with cardiac arrhythmia genes, but did show 2 different variants of uncertain significance in 2 patients. Autopsies were performed in 3 patients and identified structural cardiac abnormalities in 2 patients: 1 with hypertensive cardiomyopathy and another with cardiovascular dysplasia and fibrotic bundle branches. None of the autopsies showed obstructive coronary artery disease, heart failure, ischemia, embolism, or other apparent cause of sudden death.

DISCUSSION: Continuous ibrutinib therapy until disease progression or treatment toxicity is a treatment strategy widely used in CLL. However, limited data are available regarding the relationship between ibrutinib, ventricular arrhythmias, and sudden death. The incidence of sudden death in our study was 801 per 100,000 patient-years, which is similar to a previous estimate of 788 per 100,000 patient-years among ibrutinib-treated patients (Lampson et al. Blood, 2017) and higher than 102 per 100,000 patient-years (95% CI 24-180) in an age-matched cohort (Maruyama et al. BMJ Open, 2012). One patient showed cardiovascular dysplasia and fibrosis at autopsy; interestingly, pre-clinical data in mice showed ibrutinib-induced myocardial fibrosis as a contributing factor to the development of atrial fibrillation (Xiao et al. Circulation, 2020). However, autopsies could not identify a common cause of death between the 3 patients.

CONCLUSION: Early identification of cardiac arrhythmias on treatment may prevent serious arrhythmias and sudden death. Recently introduced guidance in the ibrutinib prescribing information describes dose reductions or discontinuation at the first occurrence of grade 2 or higher cardiac failure or arrhythmia in patients with CLL. Further research is warranted to identify risk mitigation strategies.

Itsara:Adaptive Biotechnologies: Other: Spouse: current employee and holder of stock options. Wiestner:Abbvie: Research Funding; Acerta Pharma: Research Funding; GenMab: Research Funding; Merck: Research Funding; Nurix: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding. Sun:Genmab: Research Funding.