Bruton Tyrosine Kinase Inhibitor-Based Therapy Versus Rituximab-Containing Regimens for Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Bruton tyrosine kinase (BTK) inhibitors have increasingly replaced rituximab-based chemoimmunotherapy in chronic lymphocytic leukemia (CLL), but the magnitude of benefit across treatment settings and whether it extends to overall survival remains uncertain. Therefore, we compared BTK inhibitor-based therapy with rituximab-containing regimens in randomized controlled trials (RCTs). PubMed/MEDLINE and the Cochrane Central Register of Controlled Trials were searched from inception to August 2, 2026, for RCTs enrolling adults with CLL or small lymphocytic lymphoma that compared a BTK inhibitor-based strategy with a rituximab-containing comparator and reported progression-free survival (PFS), overall survival (OS), or overall response rate (ORR). Two reviewers independently screened records, extracted data, and assessed risk of bias using RoB 2. Hazard ratios (HRs) were pooled using the generic inverse-variance method and risk ratios (RRs) using the Mantel-Haenszel method, both under random-effects models; heterogeneity was quantified using I². The review followed PRISMA 2020. Eight RCTs comprising 2,781 participants were included, spanning treatment-naive, relapsed or refractory, and covalent BTK inhibitor-pretreated disease. Five trials were at low overall risk of bias, and three raised some concerns. BTK inhibitor-based therapy was associated with significantly longer PFS (eight trials; pooled HR, 0.42; 95% confidence interval (CI): 0.24-0.73; P=0.002), with substantial heterogeneity (I²=93%). Overall response occurred in 440 of 543 patients (81.0%) receiving BTK inhibitor-based therapy versus 350 of 491 (71.3%) receiving rituximab-containing regimens, a nonsignificant difference (four trials; RR: 1.18; 95% CI: 0.98-1.42; P=0.08; I²=86%). OS favored BTK inhibitor-based therapy without reaching statistical significance (six trials; HR: 0.67; 95% CI: 0.40-1.11; P=0.12; I²=48%). Publication bias could not be formally assessed because fewer than 10 trials contributed to any outcome. BTK inhibitor-based therapy was associated with significantly longer PFS compared with rituximab-containing regimens, whereas the evidence for OS and ORR remained inconclusive. Very high heterogeneity indicates that the pooled PFS estimate represents an average across clinically distinct treatment questions rather than a uniform class effect, and treatment selection should remain individualized.