Comparative Cardiotoxicity of BTK Inhibitors in CLL: A Real-World Analysis
Introduction/Background/Significance: The advent of Bruton tyrosine kinase inhibitors has significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL). However, as utilization of these treatment options expands, ongoing assessment of associated adverse events remains necessary. We sought to complete a real-world analysis of adverse cardiac events with BTK inhibitors (BTKi) approved for use in the United States in CLL.
Materials and Methods/Case Presentation/Objective: We conducted a retrospective cohort study using real-world data from the TriNetX United States Research Database, a federated network of de-identified electronic health records (EHRs) from over 70 healthcare organizations. The study period included all relevant data from July 12nd, 2005, to July 12nd, 2025, or a standard 20-year lookback period. Propensity score matching was utilized to adjust for confounders, time-to-event analysis was applied via Cox proportional hazards models, and statistical significance was determined by p < 0.001. The risk ratio (RR) of the development of atrial fibrillation (Afib) was set as a primary outcome, and several additional cardiotoxicities were explored as secondary outcomes. (Due to space constraints, only select secondary endpoints are reported below.)
Results/Description/Main Outcome Measures: 14.959 patients were identified with CLL and prior treatment with any BTKi, of which 9,722 were treated with ibrutinib, 4,714 with acalabrutinib, 2,298 with zanubrutinib, and 349 with pirtobrutinib. Cardiotoxic outcomes were first compared between ibrutinib and all other types of BTKis, with those in the ibrutinib cohort experiencing an Afib RR of 1.625 (CI 1.471-1.795) and additional risks of atrial flutter (RR 2.515, CI 1.683-3.758), acute myocardial infarction (RR 1.853, CI 1.578-2.175), all-cause heart failure (RR 1.499, CI 1.380-1.629), all-cause cerebral infarction (RR 1.819, CI 1.521-2.177), hypertensive crises (RR 2.574, CI 1.842-3.598), and acute hypotension (RR 1.571, CI 1.431-1.723).
In individualized head-to-head comparisons, ibrutinib demonstrated higher Afib risk versus acalabrutinib (RR 1.323, CI 1.202-1.457) and zanubrutinib (RR 1.718, CI 1.478-1.997); pirtobrutinib demonstrated increased risk but with p = 0.0213 (RR 1.512, CI 1.059-2.157). Additionally, comparisons were completed between acalabrutinib versus zanubrutinib or pirtobrutinib, and acalabrutinib demonstrated a higher risk of Afib than zanubrutinib (RR 1.316, CI 1.122-1.365) but no increased risk when compared to pirtobrutinib. Lastly, a final comparison between zanubrutinib and pirtobrutinib demonstrated no statistically significant outcomes.
Conclusions: In this real-world retrospective multi-cohort analysis, we provided refined insights into the cardiotoxicity profiles associated with BTKi use in CLL. As these treatment options diversify and treatment populations expand, continued evaluation remains necessary to guide personalized therapy selection.
