Background: Next-generation Bruton tyrosine kinase inhibitors (BTKi), including acalabrutinib, zanubrutinib, and pirtobrutinib, were developed to improve tolerability compared with first-generation BTKi in chronic lymphocytic leukemia (CLL).
Methods: Systematic review and meta-analysis of randomized phase II/III clinical trials identified through PubMed/MEDLINE, Embase, Cochrane CENTRAL, and major hematology conference proceedings. Outcomes included atrial fibrillation/flutter, hypertension, grade ≥3 adverse events, and treatment discontinuation due to adverse events.
Results: Four randomized trials (ELEVATE-RR, ALPINE, BRUIN CLL-321, and BRUIN CLL-313) involving 1,674 patients were included. Next-generation BTKi significantly reduced atrial fibrillation/flutter and treatment discontinuation due to adverse events. No significant overall reduction in hypertension was observed, while grade ≥3 adverse events showed a trend toward reduction with substantial heterogeneity.
Conclusions: Next-generation BTKi demonstrate an improved cardiovascular tolerability profile and lower treatment discontinuation compared with comparator regimens in randomized CLL trials.