Chronic Lymphocytic Leukemia (CLL) with Borderline Immunoglobulin Heavy Chain Mutational Status, a Rare Subgroup of CLL with Variable Disease Course

Abstract

Chronic lymphocytic leukemia (CLL) exhibits substantial variability in disease course. The mutational status of the B-cell receptor immunoglobulin heavy variable (IGHV) chain is a critical prognostic factor, categorizing patients into mutated (M-IGHV) and unmutated (U-IGHV) groups. Recently, a third subgroup with borderline mutational status (BL-IGHV) has been identified, comprising approximately 5% of CLL cases. This study retrospectively analyzes the outcomes of 30 BL-IGHV mutated patients among a cohort of 653 CLL patients, focusing on time to first treatment (TTFT) and overall survival (OS). BL-IGHV patients had a short TTFT similar to U-IGHV patients (median 30.2 vs. 34 months; p = 0.9). Conversely, the OS of BL-IGHV patients resembled M-IGHV patients (median NR vs. 258 months; p = 1). Despite a similar incidence in unfavorable prognostic factors, the TTFT was shorter compared to other published cohorts. However, striking similarities with other experiences suggest that BL-IGHV mutated patients share common biological characteristics, biased IGHV gene usage and BCR subset frequency. These findings also underscore the need for multicentric efforts aggregating data on BL-IGHV CLL in order to elucidate its disease course and optimize therapeutic approaches for this rare subgroup. Until then, predicting outcomes and optimal management of BL-IGHV CLL will remain challenging.

Spotlight on borderline-IGHV mutational status in chronic lymphocytic leukemia

“…Regarding the IGHV subgroups in patients with BL-IGHV, IGHV4–34 was the most frequently detected, followed by IGHV4–39, IGHV1–18, and IGHV1–2 ( Figure 1 ). Interestingly, none of the BL-IGHV patients in our study was assigned to a BCR-subset, using the ARResT online database ( 10 ), which is different from previous studies showing an enrichment in subset #2 ( 8 ). In fact, in our previous study only 6% of Lebanese patients with CLL could be assigned to a specific stereotyped subset, which is relatively lower than the data reported from other countries ( 9 ), and thus potentially suggesting the presence of population-specific alterations.…”

“…In a recent paper, Angotzi et al. reported data on 30 BL-CLL cases showing similarities and discrepancies with previously published studies, and yet they were unable to resolve the outcome of BL-IGHV CLL patients ( 8 ).…”