Mapping the Remarkable Complexity of Chronic Lymphocytic Leukemia

Clinical subtypes of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are characterized by immunoglobulin heavy chain variable gene (IGHV) mutation status, fluorescent in situ hybridization (FISH) and standard cytogenetics, and TP53 gene mutation status. Investigators now report a comprehensive genomic, transcriptomic, and epigenetic analysis of CLL/SLL and monoclonal B lymphocytosis, a prodromal phase of CLL. The molecular data were correlated with clinical outcomes to identify new prognostic models and potentially targetable anomalies.

The 1095 CLL/SLL samples in the multinational study were from patients under observation and without prior therapy (n=680), patients post treatment (n=52), and clinical trial enrollees who were treatment naïve (n=371) or had relapsed/refractory disease (n=45). The investigators identified 109 potential new driver mutations and confirmed other known CLL drivers. Distinct molecular differences were apparent between IGHV-mutated (n=512) versus IGHV-unmutated (n=459) subtypes, with significantly higher genetic heterogeneity — including driver mutations and cytogenetic structural variants — in the latter. Several new prognostic subgroups could be defined via patterns of gene expression.