CLL-132: Mutational Status of IGVH in Correlation with Genetic Abnormalities of Patients with Chronic Lymphocytic Leukemia in Macedonia - A Single-Centre Experience

Abstract

Context B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease. One of the most important molecular predictors, the immunoglobulin VH gene mutational status, divides CLL into two prognostic groups, where unmutated U-CLL is associated with remarkably worse prognosis than mutated M-CLL. In many studies, multiple recurring chromosomal aberrations appear to be effective prognostic markers in CLL. Objective The aim of the study was first-time evaluation of rearrangement of IG genes and genetic abnormalities in Macedonian CLL patients. Design Prospective study of Macedonian patients with CLL at early and advanced stage of disease in a period of time from January 2011 to January 2019. The median follow-up was 48 months (1-96 months). Setting Mutational status and configuration of IGHV-IGHD-IGHJ rearrangements in 90 treatment-naive CLL patients were analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing methodology. We used multiplex ligation-dependent probe amplification (MLPA) for detection of most common genetic abnormalities. Interventions We introduced prognostic markers like cytogenetic aberrations, and mutational status of immunoglobulin heavy chain in prognostic stratification of Macedonian patients with CLL. Results Our evaluation has shown that 54.7% patients belonged to the U-CLL subset, whereas 45.3% belonged to the M-CLL subset. The most frequently expressed IGHV subgroup was IGHV3 (40%), followed by IGHV4 (29%), IGHV1(27%), and IGHV5 (3%). The most frequent subgroup with 8% were IGHV1-69*13 and IGHV4-34*0. In the IGHD and IGHJ sets, most frequently expressed genes were IGHD3 (59.7%) and IGHJ6(53.1%), respectively. We found that 80% of IGHV1, 65.6% of IGHD3, and 83.3% of IGHJ6 genes were U-CLL (p=0.0005). Frequency of genetic aberrations by MLPA were 13q14 deletion (20%) followed by 11q deletion (14%), then trisomy 12 (13%) and 17p deletion (6.6%), multiple mutations (6.7%), and NOTCH mutation (5.3%). Conclusions Our evaluation of mutational status on IGVH, IGDH, and IGJH genes in Macedonian CLL patients resulted with data that are consubstantial to those from the Mediterranean area. Novel mutations discovered in this study must be validated through large cohort studies and may offer clues to the mechanisms underlying the difference in CLL survival. In the future, therapeutic strategies targeting these genes should be evaluated and considered.