Targeted combination therapies for untreated chronic lymphocytic leukemia: A network meta-analysis of randomized trials.

7048 Background: Treatment options for previously untreated chronic lymphocytic leukemia (CLL) have expanded to include both fixed-duration venetoclax-based combinations and continuous Bruton tyrosine kinase (BTK) inhibitor therapy. While both approaches improve outcomes compared with chemoimmunotherapy, their relative benefits and risks have not been well defined. We performed a network meta-analysis to compare the efficacy and safety of these frontline targeted strategies. Methods: We searched MEDLINE, Embase, PubMed, the Cochrane Library, Web of Science, and major oncology conference proceedings from inception through November 2025. Phase II–III randomized trials enrolling treatment-naïve adults with CLL and evaluating venetoclax-based combinations or continuous BTK inhibitor–based regimens were included. A frequentist random-effects network meta-analysis was conducted. Treatment effects were summarized using hazard ratios (HRs) for progression-free survival (PFS) and risk ratios (RRs) for grade ≥3 adverse events. Results: Eight randomized trials including 3,056 patients and five treatment regimens were analyzed. All targeted therapy–based regimens significantly improved PFS compared with chlorambucil plus obinutuzumab. The greatest PFS benefit was observed with ibrutinib plus obinutuzumab (HR 0.41; 95% CI, 0.29–0.59), followed by venetoclax plus ibrutinib and venetoclax plus obinutuzumab. Acalabrutinib plus obinutuzumab also significantly reduced the risk of progression (HR 0.52; 95% CI, 0.41–0.67). No significant inconsistency was detected across the treatment network. Safety outcomes varied by regimen, reflecting differences in treatment duration and mechanism of action. Conclusions: In previously untreated CLL, fixed-duration venetoclax-based combinations achieve PFS outcomes comparable to continuous BTK inhibitor–based therapy, with distinct safety and treatment exposure profiles. These findings support personalized frontline treatment selection based on patient comorbidities, tolerability, and preference for time-limited therapy.