Background: Zanubrutinib is a highly selective, next-generation covalent Bruton's tyrosine kinase (BTK) inhibitor designed to maximize target engagement while minimizing off-target activity. In pivotal studies across various hematologic malignancies, zanubrutinib has demonstrated durable responses with fewer adverse effects compared to first-generation BTK inhibitors such as ibrutinib. Although ibrutinib's cardiotoxic risks are well documented, zanubrutinib's cardiovascular safety has not been comprehensively characterized. This meta-analysis of phase III randomized controlled trials (RCTs) evaluates the incidence and relative risk of cardiac adverse events in patients treated with zanubrutinib compared to controls, including both ibrutinib and non-BTK-based therapies.

Methods: A comprehensive literature search was performed using MEDLINE and EMBASE from inception through July 22, 2025. Eligible studies included phase III randomized controlled trials investigating zanubrutinib in patients with hematologic malignancies that reported cardiac adverse events. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method. Between-study heterogeneity was assessed using Cochran's Q-statistic, and a random-effects model was applied to account for variability across trials.

Results: Across four phase III trials (ALPINE n=648; ASPEN n=142; SEQUOIA n=578; ROSEWOOD n=214), 1,639 patients were evaluated for cardiac safety. High-grade cardiac events occurred in 6.1% of those treated with zanubrutinib compared to 12.9% in the control group (RR 0.58; 95% CI, 0.35-0.95; p=0.03). Though any-grade cardiac events were slightly less frequent with zanubrutinib (17.8% vs. 25.1%; RR 0.85; 95% CI, 0.54-1.33; p=0.47), this difference did not reach statistical significance.

Detailed analyses of specific arrhythmias likewise showed no significant differences: ventricular tachyarrhythmias (0.32% vs. 0.27%; RR 1.22; 95% CI, 0.24-6.33, p=0.81), ventricular or supraventricular extrasystoles (0.76% vs. 0.97%; RR 0.98; 95% CI, 0.35-2.73, p=0.97), ventricular tachycardia (0.43% vs. 0.14%; RR 2.19; 95% CI, 0.42-11.34, p=0.35), high-grade atrial fibrillation or flutter (2.39% vs. 2.08%; RR 1.09; 95% CI, 0.31-3.80, p=0.89), and any-grade atrial fibrillation or flutter (3.48% vs. 4.02%; RR 0.82; 95% CI, 0.19-3.47, p=0.78) all comparisons yielded p-values >0.05, indicating no statistically significant differences.

Regarding myocardial infarction, zanubrutinib-treated patients did not experience MI that led to treatment discontinuation or death, whereas the control arm recorded one discontinuation and two fatal MIs.

Conclusions:

In this pooled analysis of four phase III randomized controlled trials, zanubrutinib was associated with a statistically significant reduction in the incidence of high-grade cardiac adverse events, without evidence of unanticipated cardiotoxicity. These findings support the emerging cardiovascular safety advantage of zanubrutinib in the treatment of hematologic malignancies. Continued long-term follow-up and prospective studies are warranted to further delineate its benefit–risk profile and confirm the durability of cardiac tolerability.

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2025
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