Comparative Cardiovascular Safety and Exploratory Bleeding Outcomes of Ibrutinib, Acalabrutinib, and Zanubrutinib in Mantle Cell Lymphoma: A Propensity Score‐Matched Real‐World Analysis

BACKGROUND: Bruton tyrosine kinase inhibitors are central to the treatment of relapsed or refractory mantle cell lymphoma, but cardiovascular and bleeding toxicities influence treatment selection. Ibrutinib has been associated with atrial fibrillation/flutter and other cardiovascular adverse events, whereas second-generation covalent BTK inhibitors were developed to improve kinase selectivity and tolerability. Mantle cell lymphoma-specific real-world comparative safety data across ibrutinib, acalabrutinib, and zanubrutinib remain limited. OBJECTIVE: To compare cardiovascular and bleeding outcomes among patients with mantle cell lymphoma treated with ibrutinib, acalabrutinib, or zanubrutinib. METHODS: We conducted a retrospective propensity score-matched TriNetX cohort study of patients with mantle cell lymphoma treated with ibrutinib, acalabrutinib, or zanubrutinib. Alternate BTK inhibitor exposure and prior recorded outcomes were excluded. Outcomes included newly recorded atrial fibrillation/flutter, heart failure, and gastrointestinal bleeding. Matching included demographics, comorbidities, cardiovascular risk factors, anthracycline exposure, and antithrombotic use. RESULTS: After matching, the 365-day cohorts included 738 patients per group for acalabrutinib versus ibrutinib, 522 per group for zanubrutinib versus ibrutinib, and 532 per group for acalabrutinib versus zanubrutinib. Newly recorded atrial fibrillation/flutter was lower with acalabrutinib than ibrutinib, 4.5% versus 12.0%, RR 0.371, HR 0.387, and with zanubrutinib than ibrutinib, 5.0% versus 12.3%, RR 0.408, HR 0.421. Atrial fibrillation/flutter rates were similar between acalabrutinib and zanubrutinib, 4.0% versus 5.7%, RR 0.704, HR 0.714. Heart failure did not differ statistically, and 180-day sensitivity analyses were consistent. Exploratory gastrointestinal bleeding was higher with ibrutinib than acalabrutinib, 4.3% versus 2.2%, and numerically higher with ibrutinib than zanubrutinib, 4.7% versus 3.3%; acalabrutinib-versus-zanubrutinib gastrointestinal bleeding output was unavailable. CONCLUSIONS: Ibrutinib was associated with a higher risk of atrial fibrillation/flutter than acalabrutinib or zanubrutinib. These findings may support individualized BTK inhibitor selection, particularly among patients with baseline cardiovascular risk.