IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) has high biological and clinical heterogeneity. A few prognostic factors are used in clinical practice, including immunoglobulin heavy-chain variable (IGHV) gene somatic hypermutation (SHM) status, chromosome aberrations, and gene mutations, which remain insufficient for personalized patient management. Recent studies have shown that expression of the immunoglobulin lambda light chain IGLV3-21R110 gene carrying an SHM-derived G>C mutation changing the glycine at position 110 to an arginine (IGLV3-21 R110 ) defines a subset of CLL with an intermediate epigenetic profile and an aggressive clinical course. When occurring on the IGLV3-21*01 or *04 alleles, the R110 mutation allows homotypic B-cell receptor (BCR) interactions, triggering cell-autonomous BCR signaling and/or facilitating T-cell–independent engagement with superantigen. IGLV3-21 has been detected in up to 6.5% of patients with CLL at diagnosis and in up to 25% of patients enrolled in clinical trials. We and others have shown that all CLL cases belonging to aggressive stereotyped subset #2 carried the IGLV3-21 R110 . Nonetheless, approximately half of IGLV3-21 R110 CLL are not classified as stereotyped subset #2 but seem to have a similar clinical outcome, 5,6 suggesting that the conventional stereotyped subset #2 classification might not completely recognize this clinically aggressive subgroup of CLL. In addition, IGLV3-21 R110 seems to have a prognostic value independent of the IGHV gene SHM status and methylation–based epigenetic subtypes. However, further studies in independent cohorts are needed to support its application in clinical practice. The aim of this study was to assess the prognostic value of IGLV3-21 R110 in large and independent population-based cohorts of patients with CLL.