Comparative Bayesian Network Meta-Analysis of BTKi-Specific Adverse Events in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia

OBJECTIVES: Bruton kinase inhibitors (BTKi) are effective treatments for relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Recent findings suggest that they may increase the risk of cardiovascular adverse events, including hypertension, atrial fibrillation, and bleeding. This study aimed to compare the cardiovascular risk of BTKis with other anti-leukemic therapies in R/R CLL patients.

METHODS: A comprehensive systematic review was conducted in medical databases (MEDLINE, Embase, and The Cochrane Library) and other sources to identify randomized clinical trials for R/R CLL (PROSPERO: CRD42022304330). Safety outcomes were extracted and analyzed using Bayesian network meta-analysis (NMA). The results of the NMA were presented as risk ratios with 95% credible intervals and SUCRA values. All statistical analyses were performed using R software (GeMTC package).

RESULTS: From the systematic search, 14 studies for safety outcomes were identified, nine of which reported at least one cardiovascular outcome of interest. The NMA revealed that ibrutinib significantly increased the risk of atrial fibrillation compared to next-generation BTKis (acalabrutinib: 1.73 [1.09; 2,83], zanubrutinib: (2.70 [1.55; 4.95]) and other therapies (bendamustine+rituximab: 6.77 [1.09; 193.56], idelalisib+rituximab: 4.20 [1.38; 15.13], ofatumumab: 33.46 [6.04; 945.8]). A significant risk of grade ≥3 atrial fibrillation was noted only in comparison with ofatumumab. Acalabrutinib and zanubrutinib showed similar risks of atrial fibrillation (0.64 [0.30; 1.35]), comparable to bendamustine+rituximab. Acalabrutinib also demonstrated a lower risk of bleeding and hypertension compared to ibrutinib (0.74 [0.61; 0.89] and 0.38 [0.23; 0.53]) and zanubrutinib (0.72 [0.55; 0.94] and 0.34 [0.19; 0.58]). Although the risks of major hemorrhage and grade ≥3 bleeding were similar across therapies, differences in grade ≥3 hypertension remained significant. SUCRA values indicated the lowest atrial fibrillation probability for ofatumumab (0.96) and the lowest bleeding and hypertension probability for bendamustine+rituximab (0.88 and 0.96).

CONCLUSIONS: The results of the NMAs suggest significant differences between BTKi therapies in R/R CLL patients regarding cardiovascular events.