Cardiac Adverse Events in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib and Venetoclax Combination: A Systemic Review and Meta-Analysis
Authors: Hofstetter Liron , Gafter-Gvili Anat , Sternbach Neta , Raanani Pia , Itchaki Gilad 
Published: December 2024

Introduction
Targeted therapies have significantly improved the survival of patients with chronic lymphocytic leukemia (CLL). The combination of ibrutinib and venetoclax (I+V) has a synergistic effect, leading to high rates of undetectable minimal residual disease, thus enabling a time-limited, all-oral therapy in CLL. However, its potential cardiac toxicity has raised concerns, with several trials reporting high-grade cardiac adverse events (CAEs), including sudden death. This meta-analysis aims to evaluate the cardiac safety of the I+V regimen and identify moderating factors associated with increased risk.
Methods
We conducted a comprehensive search of the PubMed and EMBASE databases for prospective trials of I+V in CLL, including abstracts presented at conferences preceding July 2024. Eligible studies included all prospective phase 2 and 3 trials assessing adult patients (aged &gt;18 years) treated with I+V in any line of therapy. The search terms used were (“chronic lymphocytic leukemia” AND “ibrutinib” AND “venetoclax”). One author (L.H.) screened all references identified, and another reviewer (G.I.) independently assessed each abstract and applied inclusion criterion. Discrepancies were resolved by obtaining and independently reviewing the full articles.
We collected demographic and clinical data from the publications, specifically focusing on CAE. The primary outcome was any cardiac event of any grade. Secondary outcomes included grade 3-4 cardiac events, hypertension (any grade and grade 3-4), atrial fibrillation or flutter (AF) (any grade and grade 3-4), ventricular arrhythmia, cardiac arrest, and death from any cardiac cause. The aggregated effect size, representing the weighted average proportion of patients for each event was pooled. We further examined the moderating roles of gender, age, and performance status (PS 0-1) using meta-regression analysis, adjusting for sample size. Individual patient data was not available.
Results
Out of 403 published articles, 12 trials met the inclusion criteria, encompassing 1484 patients. Eight trials included CLL patients with first line treatment, and four involved relapsed/refractory disease. The median number of treatment cycles varied from 7 to 27, with a median of 15 months in half of the trials. Cardiac events of any grade were reported in 11.50% of patients (95% CI: 9.92% - 13.09%). Heterogeneity analysis revealed significant variability among studies (Q = 67.195, p &lt; 0.001; I² = 83.63%), likely due to differences in study populations, methodologies, or other factors. None of the examined moderators significantly influenced the effect size for any cardiac event.
Grade 3-4 cardiac events were reported in 8 studies, including 1237 patients, with an aggregated effect of 2.84% (95% CI: 1.86% - 3.82%) and major variability (I² = 54.22%). No significant effect of the examined moderators was observed. AF of any grade and grade 3-4 were reported in 8.24% (95% CI: 6.85% - 9.64%) and 2.68% (95% CI: 1.85% - 3.51%) of patients, respectively. Heterogeneity analysis revealed no significant variability among the studies (I²= 0%) thus moderator's effect was not tested. Ventricular arrhythmia/cardiac arrest and death from any cardiac cause including sudden death had effect sizes of 0.0% and 0.80% (n=11/1336), respectively. Hypertension of any grade and grade 3-4 was reported in 11.17% (95% CI: 9.53% - 12.80%) and 4.17% (95% CI: 3.15% - 5.18%) of patients, respectively. Heterogeneity analysis revealed no significant variability for these CAEs.
Conclusion
The I+V combination is associated with considerable cardiac toxicity in CLL patients. Although high-grade (3-5) adverse events are uncommon, they remain a clinical concern. The added effect of venetoclax on ibrutinib-induced cardiac toxicity could not be assessed from these data. In our analysis, age, gender, or PS were not associated with increased cardiovascular risk.