BRAF Alterations in Chronic Lymphocytic Leukemia: Genomic Landscape, Co-Mutation Patterns, and Clinical Relevance

BRAF alterations are uncommon in chronic lymphocytic leukemia (CLL), yet increasing use of broad genomic profiling has identified them as a recurrent component of MAPK-pathway dysregulation. This revised review summarizes the reported frequency, mutation spectrum, co-mutation patterns, treatment-era associations, and clinical implications of BRAF alterations in adult CLL, with explicit separation of chemoimmunotherapy-dominant cohorts from targeted-therapy-era cohorts.

Across published studies, BRAF mutations are usually detected in approximately 2-6% of unselected CLL cohorts, with higher frequencies in biologically enriched or treatment-selected populations. In chemoimmunotherapy-dominant cohorts, the clinically relevant signals are more often seen in treatment-timing endpoints such as time to first treatment, treatment-free survival, or time to next treatment than in overall survival alone. In targeted-therapy-era studies, including phase II and real-world cohorts, BRAF alterations recur as part of MAPK-pathway-driven clonal evolution at relapse after BTK-, PI3K-, or BCL2-directed therapy. Small pathology-based series also suggest that BRAF V600E is more frequent in Richter transformation than in untransformed CLL. By contrast, direct evidence for BRAF inhibitors in CLL is very limited, and available preclinical data do not support routine single-agent BRAF inhibition for the predominantly non-V600E lesions seen in CLL. Current evidence supports interpreting BRAF-mutated CLL within the broader RAS-RAF-MAPK-ERK signaling context rather than as a classical V600E-driven entity. At present, BRAF is best viewed as a biologic and resistance-relevant annotation rather than an established standalone prognostic biomarker or routine therapeutic target. Its clinical relevance appears greatest in trisomy 12-enriched disease, genomically complex cases, Richter transformation with V600E lesions, and treatment-exposed relapse where pathway-directed strategies may become increasingly important.