Cardiac Monitoring of Patients on Btki for Chronic Lymphocytic Leukemia

Background:

The first-in-class Bruton tyrosine kinase inhibitor (BTKi) ibrutinib is associated with an increased risk of atrial fibrillation (AF), ventricular arrhythmia, and sudden death. While next-generation BTKis, acalabrutinib and zanubrutinib, are more selective, growing evidence has indicated a persistent, albeit attenuated, risk of arrhythmia. Most data relating to BTKi-associated arrhythmia pertain specifically to AF, which are typically not fatal on their own, but may progress to ventricular arrhythmia. Ventricular arrhythmias increase the risk of sudden cardiac death even in the absence of structural heart disease, ischemia, or QT prolongation (Lampson, et al. Blood 2017). There are currently no standard cardiac assessments prior to or during treatment with a BTKi. We hypothesized that comprehensive cardiac screening and on-treatment monitoring would result in earlier identification (and intervention) of arrhythmias and decreased cardiovascular morbidity and mortality.

Methods:

This is a single-center prospective study to evaluate the arrhythmogenic effects of BTKi. Results from Cohort B are presented herein. Cardiac tests included resting electrocardiogram (EKG), transthoracic echocardiogram, 14-day ambulatory EKG, and stress EKG. Patients were provided with a portable 6-lead EKG device to be used as needed for symptoms suggestive of arrhythmia (e.g., palpitations, syncope, chest pain). All tests were reviewed by a general cardiologist and electrophysiologist to identify clinically significant and other arrhythmias that were prespecified by study protocol. Patients underwent repeat evaluation if they developed an arrhythmia or if they discontinued BTKi therapy for any reason. Annual follow-up was performed to assess for interval history of arrhythmia and survival.

Results:

Cohort B enrolled 45 patients on treatment with a BTKi (22 with acalabrutinib, 14 with ibrutinib, and 9 with zanubrutinib). The median age was 70 years (range 23 - 86 years), 28 (62%) were male, 17 (38%) were female, 43 (96%) had chronic lymphocytic leukemia, 2 (4%) had Waldenstrom macroglobulinemia, and the median time on BTKi was 66 months (range 3 - 143 months). Five patients (11%) were found to have a clinically significant arrhythmia upon cardiac testing: AF duration >24 hours (n=3), ventricular ectopy with >2,000 premature ventricular complexes (PVCs)/day (n=1), and polymorphic ventricular tachycardia (VT) (n=1). As a result, BTKi was discontinued in 4 of 5 patients. Repeat cardiac testing showed resolution or decreased burden of AF (n=1 each), decreased burden of ventricular ectopy (n=1), and resolution of polymorphic VT (n=1) following BTKi discontinuation. One patient diagnosed with AF continued ibrutinib and started metoprolol succinate for rate control. Clinically significant arrhythmias were detected in 4 patients on ibrutinib, and 1 patient on acalabrutinib. On univariate analysis, male gender and advanced age were associated with a greater risk of developing a clinically significant arrhythmia (p=0.0087 and p=0.078, respectively). Compared to ibrutinib, when correcting for age and gender, the odds ratio (OR) of developing a clinically significant arrhythmia was lower for acalabrutinib (OR 0.024, p=0.034). No patients on zanubrutinib were found to have a clinically significant arrhythmia. Time on BTKi, irrespective of which drug, was associated with increased risk of developing a clinically significant arrhythmia (OR 1.04, p = 0.043). An additional 5 patients (11%) were found to have other arrhythmias: monomorphic ventricular tachycardia duration <30 seconds (n=3) and ventricular ectopy with 500-2000 PVCs/24 hours (n=2). Overall, patients on acalabrutinib or zanubrutinib had a lower risk of developing any arrhythmia compared to ibrutinib (OR 0.056, p=0.015 and OR 0.043, p=0.033, respectively) when corrected for age and gender. No sudden death has occurred.

In conclusion, cardiac testing uncovered clinically significant arrhythmias in 11% of patients on a BTKi, providing rationale for cardiac monitoring during BTKi therapy, especially in patients receiving ibrutinib.

Tomasulo:AstraZeneca: Consultancy; Sanofi: Consultancy; Abbvie: Consultancy. Wiestner:Genmab: Research Funding; Nurix: Research Funding; Merck: Research Funding; Pharmacyclics, an Abbvie company: Research Funding; Acerta, Astra-Zeneca group: Research Funding. Sun:Gemab: Research Funding.