B04 | Intraclonal diversification in immunoglobulin light chain genes refines prognostication in early-stage chronic lymphocytic leukemia

Introduction:The mutational status of immunoglobulin heavy chain variable region (IGHV) genes represents one of the most robust biomarkers in chronic lymphocytic leukemia (CLL). Recently, the 99% identity cut-off for light chain genes further refined the prognostic value of IGHV. Intraclonal diversification (ID), characterized by the accumulation of somatic hypermutation (SHM) within immunoglobulin genes, affects IGHV genes and identifies a subset of mutated CLL patients with high-ID levels and improved clinical outcome (Vit et al., Leukemia. 2025). ID may also extend to light chain genes, but its impact on a large consecutive cohort of CLL patients has not yet been reported.Methods:A total of 665 CLL patients were investigated for ID levels in both heavy and light chain genes using an amplicon-based next-generation sequencing. SHMs were assessed within FR1–FR3 regions of the V domain and the inverse Simpson Index (iSI) was applied to quantify ID.Results: A total of 610 patients were analyzed for IGHV ID and 493 patients were analyzed for light chain ID. Patient characteristics were consistent with a real-world cohort of unselected, consecutive CLL. The median follow-up was 11.8 years. Considering the mutational status of both heavy and light chain genes, varying levels of iSI were observed across mutated and unmutated cases. U-IGHV patients exhibited significantly higher iSI levels than M-IGHV patients (p