Cardiotoxicity and safety of zanubrutinib versus chemoimmunotherapy in chronic lymphocytic leukemia: a real-world retrospective cohort study using the TriNetX registry

Background Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults in the Western countries. Ibrutinib, a first-generation Bruton’s tyrosine kinase (BTK) inhibitor, is commonly used for relapsed/refractory CLL but is associated with cardiovascular adverse effects such as atrial fibrillation (AF) and hypertension (HTN). Zanubrutinib, a second-generation BTK inhibitor, was developed with greater BTK selectivity to reduce off-target toxicity. However, comparative data on zanubrutinib versus chemoimmunotherapy in CLL remain limited. Methods This retrospective cohort study used the TriNetX platform to compare patients treated with zanubrutinib versus those receiving chemoimmunotherapy. Propensity score matching was performed to balance demographic and clinical characteristics. Primary outcomes included all-cause mortality and cardiovascular events: AF/atrial flutter, HTN, acute heart failure, ventricular arrhythmias, and bleeding. There was no ethical or IRB approval required for this study. Proportional-hazards assumptions were assessed using Schoenfeld residuals, and pre-specified sensitivity and severity-surrogate analyses were performed. Results After matching (1,231 per cohort), all-cause mortality was similar between zanubrutinib and chemoimmunotherapy (HR 0.99; p = 0.95). Zanubrutinib showed significantly fewer cardiotoxic events (HR 0.77; p = 0.001) and lower incident atrial fibrillation/flutter (HR 0.65; p = 0.04). Rates of hypertension, heart failure, ventricular arrhythmias, and bleeding were comparable (all p > 0.20). Predictors of bleeding included anticoagulant use, chronic kidney disease, and liver disease. The proportional-hazards assumption was not violated for atrial fibrillation/flutter (Schoenfeld p = 0.92), and sensitivity analyses showed directionally consistent results. Procedural and pharmacologic severity surrogates were also comparable between groups. Conclusions In this propensity-matched real-world analysis, zanubrutinib was associated with similar 2-year mortality and lower observed cardiotoxicity, particularly incident atrial fibrillation/flutter, compared with B-CIT. These findings suggest a potentially favorable cardiovascular safety profile for zanubrutinib, although residual confounding, treatment-selection bias, and limitations of EHR-based outcome capture preclude causal inference. Prospective comparative studies are warranted.