The signs of negative selection in IGHV framework regions are associated with worse overall survival of chronic lymphocytic leukemia patients

Abstract

The mutational status of the variable region of the immunoglobulin heavy chain (IGHV) genes remains the most significant prognostic factor in chronic lymphocytic leukemia (CLL) patients. However, the groups of mutated (M) and unmutated (UM) patients are also heterogeneous, and additional markers are used for a more accurate prognosis. The aim of our work was to determine the prognostic value of the signs of antigen selection determined by BASELINe statistics in M IGHV sequences of CLL patients. Clinical data, IGHV gene configuration, TP53, NOTCH1, SF3B1 mutations were analyzed in 127 CLL patients with M IGHV sequences. The median OS of patients with negative selection in the framework regions (FWRs) of IGHV genes was 120 months compared to 202 month in other CLL patients (P = 0.016). In multivariate Cox regression analysis Binet stage C vs A + B (P < 0.0001), SF3B1 mutations (P < 0.0001), negative selection in the FWRs (HR P = 0.007), and age ≥65 years (P = 0.034) were powerful adverse prognostic factors for OS in CLL patients with M IGHV genes. These preliminary data suggest that the signs of antigen-driven selection may be used as a prognostic factor in CLL patients with M IGHV genes in combination with other markers.

Keywords: Antigen-driven selection; Chronic lymphocytic leukemia; Immunoglobulin variable heavy chain (IGHV) gene; Mutational status.