First-Line Treatment of IGHV-Unmutated Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Targeted and Chemoimmunotherapy Regimens.

Immunoglobulin heavy chain variable region-unmutated (IGHV-U) chronic lymphocytic leukemia (CLL) represents a biologically aggressive subgroup with limited responsiveness to chemoimmunotherapy (CIT). To clarify the comparative effectiveness of available frontline options, we conducted a comprehensive Bayesian network meta-analysis of randomized clinical trials including more than 4500 IGHV-U patients. Targeted therapies consistently outperformed CIT backbones, confirming the minimal benefit of cytotoxic approaches in this population. Acalabrutinib-based regimens, either as monotherapy or combined with obinutuzumab, emerged as the most effective strategies for progression-free survival, followed by other BTK inhibitors and venetoclax-based combinations. Chlorambucil- and Fludarabine-containing regimens ranked lowest. The fixed-duration venetoclax-obinutuzumab regimen also demonstrated strong efficacy, though estimates were less precise due to a smaller evidence base. Overall, heterogeneity was low, model fit was robust, and no statistical evidence was detected. These findings support targeted agents as the preferred first-line treatment for IGHV-U CLL and provide a quantitative framework to guide regimen selection while highlighting the need for head-to-head trials and long-term follow-up to optimize treatment sequencing.