![]() Unsurprisingly, therefore, IGHV gene SHM status has been included in various prognostic tools/models/scores for TTFT, e.g., the CLL international prognostic index (CLL-IPI), the CLL1 prognostic model, the International Prognostic Score for Early-stage CLL(IPS-E) and the CLL WithOut Need of Treatment (CLL-WONT) risk score. Indeed, this biomarker may assist in predicting how soon patients will require treatment after the initial diagnosis, in other words, it can discriminate patients with shorter versus longer time-to-first-treatment (TTFT). Since then, many studies have confirmed these findings, rendering the analysis of IGHV gene SHM status an invaluable and non-dispensable tool for prognostication in CLL, regarding any relevant outcome measure. The prognostic value of SHM within the clonotypic rearranged IGHV genes was first recognized in 1999, when it was shown that patients with no or limited SHM (‘unmutated’ CLL, U-CLL) usually experience an aggressive form of CLL, while those with a significant SHM load (‘mutated’ CLL, M-CLL) follow more indolent disease courses. This is reflected in the guidelines of the International Workshop on CLL (iwCLL) indicating that this biomarker should be assessed prior to treatment in all patients with CLL, i.e., in both general practice and clinical trials and, it has now been translated into clinical recommendations by many professional scientific societies worldwide, such as the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO). On these grounds, it becomes apparent that robust immunogenetic characterization has an important role in the proper management of patients with CLL. Moreover, this biomarker remains stable over time, thus contrasting other, “cell-intrinsic” biomarkers, such as genomic aberrations, that are enriched in patients with advanced and/or relapsed/refractory disease. Of clinical relevance, the somatic hypermutation (SHM) status of the rearranged immunoglobulin heavy variable (IGHV) gene has emerged as key to accurate risk stratification in CLL. Restrictions in the BcR IG gene repertoire, culminating in the existence of subsets with stereotyped BcR IG, strongly implicate antigen selection in CLL pathogenesis. Immunogenetic studies have offered strong evidence for the central role of the B cell receptor immunoglobulin (BcR IG) in the natural history of chronic lymphocytic leukemia (CLL). Here, we present an overview of the clinical utility of immunogenetics in CLL and update our analytical recommendations with the aim to assist in the refined management of patients with CLL. That said, these recommendations apply to Sanger sequencing, which is increasingly being superseded by next generation sequencing (NGS), further underscoring the need for an update. Recommendations for robust immunogenetic analysis exist thanks to dedicated efforts by ERIC, the European Research Initiative on CLL, covering all test phases, from the pre-analytical and analytical to the post-analytical, pertaining to the analysis, interpretation, and reporting of the findings. ![]() All of the above highlights the relevance of immunogenetic analysis in CLL, which is considered a cornerstone for accurate risk stratification and clinical decision making. Patients in certain stereotyped subsets display consistent biology, clinical presentation, and outcome that are distinct from other patients, even with concordant IGHV gene SHM status. Moreover, immunogenetic analysis in CLL has revealed that different patients may express (quasi)identical, stereotyped B cell receptor immunoglobulin (BcR IG) and are classified into subsets based on this common feature. Importantly, independent studies have documented that IGHV SHM status is also a predictor of responses to therapy, including both chemoimmunotherapy (CIT) and novel, targeted agents. The somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is a critical biomarker for assessing the prognosis of patients with chronic lymphocytic leukemia (CLL).
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