Outcomes of patients with CLL and borderline IGHV mutational status: a systematic review and meta analysis

The immunoglobulin heavy chain variable region (IGHV) mutational status is a major prognostic factor in chronic lymphocytic leukemia (CLL). While patients are conventionally classified as mutated (M-IGHV) or unmutated (U-IGHV) using a 98% germline identity cutoff, increasing interest has focused on patients with IGHV identity values close to this threshold, defined as having a borderline IGHV mutational status (BL-IGHV) whose clinical significance remains controversial. We conducted a systematic review and meta-analysis to clarify the prognostic impact of BL-IGHV in CLL. Following PRISMA guidelines, we identified studies comparing time to first treatment (TTFT) in BL-IGHV patients with M-IGHV and U-IGHV cohorts. A secondary endpoint was the prevalence of B-cell receptor (BCR) stereotyped subset #2. Overall, 122 BL-IGHV patients from 3 studies were included. BL-IGHV patients exhibited a significantly shorter TTFT compared with M-IGHV patients (HR 2.28; 95% CI 1.20–4.35), and a non-significant trend toward longer TTFT compared with U-IGHV patients. Median TTFT for BL-IGHV was intermediate between M-IGHV and U-IGHV groups, and BL-IGHV cases were markedly enriched for BCR stereotyped subset #2. In conclusion, BL-IGHV identifies a clinically and biologically distinct CLL subgroup with intermediate outcomes, supporting its systematic reporting and potential relevance for risk stratification.