Cardiac Adverse Events in Patients With Chronic Lymphocytic Leukemia Treated With First‐Line Ibrutinib–Venetoclax

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BACKGROUND: Fixed-duration combination of ibrutinib and venetoclax (IV) has emerged as a highly effective first-line treatment for chronic lymphocytic leukemia (CLL). However, the cardiac safety profile of this regimen has not been comprehensively characterized. We conducted a systematic review and meta-analysis to evaluate the incidence and relative risk of cardiac adverse events associated with frontline IV-based therapy. METHODS: PubMed, Embase, and major hematology conference proceedings (2014-2025) were searched for prospective studies evaluating first-line IV-based regimens in CLL/SLL. Two analyses were performed: (1) pooled incidence of cardiac events across prospective trials and (2) comparative meta-analysis of randomized controlled trials (RCTs) comparing IV-based therapy with chemoimmunotherapy (CIT). The primary outcome was summed cardio-vascular events (SCE). Secondary outcomes included atrial fibrillation/flutter (AF), hypertension (HTN), ventricular arrhythmias, and cardiac mortality. RESULTS: Fourteen publications comprising 1522 patients were included in the pooled analysis, and four RCTs were included in the comparative analysis. The pooled incidence of SCE was 18.0% (95% CI 12.8-23.9), while grade ≥ 3 SCE occurred in 6.6% (95% CI 4.6-8.8). AF/flutter occurred in 10.8% (95% CI 8.6-13.3), with grade ≥ 3 AF in 3.6% (95% CI 2.6-4.9). HTN was reported in 19.0% (95% CI 12.5-26.8), with grade ≥ 3 HTN in 8.3% (95% CI 5.6-11.4). Ventricular arrhythmias/cardiac arrest and cardiac mortality were uncommon, occurring in 0.78% and 0.89% of patients, respectively. Compared with CIT, IV-based therapy was associated with significantly higher risks of SCE (RR 3.61, 95% CI 2.32-5.62), grade ≥ 3 SCE (RR 6.86, 95% CI 3.05-15.43), AF (RR 5.50, 95% CI 2.68-10.10), grade ≥ 3 AF (RR 9.82, 95% CI 2.69-35.84), HTN (RR 3.73, 95% CI 2.14-6.50), and grade ≥ 3 HTN (RR 4.91, 95% CI 2.06-11.67). CONCLUSIONS: Frontline IV-based therapy is associated with a clinically meaningful increase in cardiac toxicity, particularly AF and HTN, compared with CIT. Nevertheless, ventricular arrhythmias and cardiac mortality remain rare. Careful cardiovascular risk assessment and monitoring should accompany the use of IV-based regimens in clinical practice.

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