The ABCs of IGHV Testing in Chronic Lymphocytic Leukaemia: Current Recommendations, Ongoing Challenges, and Future Directions.

Chronic lymphocytic leukemia (CLL) is the most common low-grade B-cell neoplasm worldwide. While diagnostic criteria are well established, prognostication and management of this disease are an evolving field, owing to the biological and clinical heterogeneity of CLL. Molecular, cytogenetic, and immunogenetic workup are key in the management of CLL, and include evaluation for specific gene variants, copy number variants (CNVs), and detailed analysis of the immunoglobulin heavy chain variable region (IGHV) with respect to somatic hypermutation (SHM) status and the presence of recurrent stereotyped IGHV subsets. IGHV status has significant prognostic, predictive, and therapeutic implications in CLL and has been incorporated into multiple risk stratification systems. The advent of both next-generation sequencing (NGS) and novel targeted therapies has added further complexity to immunogenetic analysis in CLL. Owing to the necessity and growing complexity of IGHV analysis, the European Research Initiative on CLL (ERIC) developed guidelines to standardize methods for immunogenetic analysis and provide recommendations for interpretation of challenging cases (including multiple productive IGHV clones and discordant SHM status) and has published multiple updates, revising recommendations and raising new questions. This review discusses the biology and clinical significance of IGHV status in CLL as well as laboratory methodology in immunogenetic analysis, the evolution of the ERIC recommendations leading into the era of NGS, and recent advances and emerging strategies in this field.