Clinical impact of immunoglobulin light chain rearrangements in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adult patients in the western world and is a highly heterogeneous disease. Some patients have an indolent disease and may never require treatment, whereas others have an aggressive disease and eventually transform into aggressive lymphoma, namely Richter syndrome (RS). This study aims to investigate the clinical impact of immunoglobulin light chain (IGL) rearrangements in CLL patients. Using a training-validation approach with two independent cohorts, it explores the prognostic significance of IGLV mutational status and their association with time to first treatment (TTFT), aiming to refine prognostic models for early-stage CLL. The training cohort included 573 unselected CLL patients, while the validation cohort consisted of 343 Rai 0 CLL patients. The study identifies that 99% sequence identity to the germline serves as an optimal cut-off for defining IGLV mutational status. Patients with unmutated (UM) IGLV genes had a significantly shorter TTFT compared to those with mutated (M) IGLV genes, a finding consistent across both cohorts, confirming that UM-IGLV was associated with poorer prognosis, with a 10-year treatment-free probability of 32.4% in the training cohort versus 73.2% for M-IGLV patients. Similar results were validated, with a 7-year treatment-free probability of 42.0% versus 73.7% for UM and M-IGLV patients, respectively. Additionally, the study evaluated the combined mutational status of IGHV and IGLV genes, finding that concordant UM status for both genes predicted the poorest TTFT outcomes, while concordant M status showed the best outcomes. The findings suggest that integrating IGLV mutational status with existing prognostic markers, such as IGHV status, provides a more refined risk stratification model. This study highlights the role of IGLV mutational status in early treatment decisions for CLL patients, offering a robust biomarker for clinical practice.