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

Abstract

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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40364-026-00913-3.

To the editor,

The mutational status of the immunoglobulin heavy chain variable region (IGHV) is a cornerstone prognostic marker in chronic lymphocytic leukemia (CLL). Based on the identity of the IGHV gene to its germline sequence, patients are conventionally classified as mutated (M-IGHV; identity < 98%), and unmutated (U-IGHV; identity ≥ 98%), with the latter associated with shorter time to first treatment (TTFT) and early disease progression [1]. Increasing attention has recently been focused toward a third, less well-defined category of patients whose IGHV identity lies close to the 98% cutoff. This “borderline” IGHV mutational status (BL-IGHV), variably defined by a germline identity between 97.00% and 97.99% or 98.99% [2, 3], accounts for approximately 5% of CLL, and its biological and clinical significance has remained controversial due to conflicting results from previous studies [2–4].

To address this uncertainty, we performed a systematic review and random-effects meta-analysis of published studies evaluating the outcomes of BL-IGHV CLL. The primary endpoint was TTFT in BL-IGHV versus M-IGHV and U-IGHV groups, using hazard ratio (HR) as the outcome measure. To estimate TTFT, pooled Kaplan-Meier curves were also reconstructed for the analysis of the primary endpoint according to the DerSimonian-Laird method [5]. The secondary endpoint was the prevalence of B-cell receptor (BCR) stereotype subset #2, which confers an adverse prognosis and has been suggested to be enriched among BL-IGHV cases [2–4, 6], with odds ratio (OR) as the outcome measure. Extended methodology is reported in the supplementary materials. This meta-analysis was registered in PROSPERO (ID: CRD420251208370).

A total of 2130 records were identified, of which 965 underwent screening after duplicates removal, and 3 met the inclusion criteria (Fig. 1, Table S1-2). Two additional studies were incorporated in a sensitivity analysis, as they compared BL-IGHV exclusively with M-IGHV patients [7, 8].

Fig. 1.

PRISMA literature search flow diagram

The aggregated cohort comprised 122 patients with BL-IGHV, 1274 with M-IGHV, and 760 with U-IGHV status. BL-IGHV patients demonstrated a significantly shorter TTFT than M-IGHV (HR: 2.28; 95% CI: 1.20–4.35; I²: 81.4%) and a non-significant trend toward a longer TTFT compared with U-IGHV (HR: 0.55, 95% CI: 0.30–1.03; I²: 80.6%) (Fig. 2).

Fig. 2.

Forest-plots of TTNT for BL-IGHV patients vs. M-IGHV (A) and U-IGHV (B)

These results were confirmed in two sensitivity analyses for BL-IGHV vs. M-IGHV: one evaluating the 97-97.99% threshold for BL-IGHV by Davis et al., and another one encompassing 2 more studies for a total of 212 BL-IGHV patients (Figure S1-2). Estimated median TTFT from pooled Kaplan-Meier curves was 91.1 months for BL-IGHV versus not reached for M-IGHV (p = 0.003) and 41.1 months for U-IGHV (p < 0.001) (Figure S3). Interestingly, BL-IGHV TTFT mirrors that of intermediate-CLL (i-CLL), a subtype defined by epigenomic profiling and characterized by an IGHV identity close to the 98% cutoff [9]. BL-IGHV patients were markedly enriched in BCR stereotype subset #2 relative to both M-IGHV (OR: 8.56; 95% CI: 3.79–19.33; I²: 11.1%) and U-IGHV (OR: 6.76; 95% CI: 2.45–18.65; I²: 36.5%) (Figure S4). This finding corroborates prior single-study observations and aligns with the preferential usage of IGHV3-21, IGHV3-23 and IGHV3-74 genes among BL-IGHV CLL [2–4]. The enrichment in subset #2, together with the frequent presence of the IGLV3-21*R110 mutation and SOX11 upregulation, may be the contributing factors driving lower TTFT in BL-IGHV patients [10–12]. Indeed, in a sensitivity analysis excluding subset #2 patients, the statistically significant difference between BL-IGHV and M-IGHV patients in terms of TTFT was lost, suggesting a contribution of subset #2 in driving lower outcomes (Figure S5).

Several limitations merit discussion. All included studies were retrospective and carried a moderate risk of bias, with substantial heterogeneity across analyses. The limited number of studies and inconsistent reporting of variables precluded evaluation of enrichment in other clinical/biological characteristics, overall survival, or responses to modern targeted therapies. Moreover, the study by Davies et al. both employed different IGHV cutoffs to define BL-IGHV CLL and reported TTFT outcomes excluding subset #2 patients which together could have influenced results [2].

Despite these limitations, this meta-analysis - the first to date in BL-IGHV CLL – supports that these patients may follow a distinct clinical trajectory, with lower outcomes driven in part by higher prevalence of subset #2, and that may represent a group with shared immunogenetic and epigenomic backgrounds. Accordingly, systematic reporting of BL-IGHV status along with BCR subsets, as recommended by the European Research Initiative on CLL, remains clinically relevant [1].

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

IGHV

Immunoglobulin heavy chain variable region

CLL

Chronic Lymphocytic Leukemia

M-IGHV

Mutated IGHV mutational status

U-IGHV

Unmutated IGHV mutational status

TTFT

Time to first treatment

BL-IGHV

Borderline IGHV mutational status

BCR

B-cell receptor

i-CLL

Intermediate CLL

Author contributions

FA performed the literature review, statistical analysis, created figures and tables and wrote the manuscript; AB, AS, ND, AC, GL, MD, EP, FF, MF, FP, LT gave intellectual input and reviewed the manuscript; AV conceptualized the study, gave intellectual input and reviewed the manuscript.

Funding

This study was supported by Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.) IG-25024 to LT, Progetti di Rilevanza Nazionale PRIN PNRR (P2022PSMX4) to AV, Ricerca per Credere nella Vita (RCV) odv, Padua Italy.

Data availability

Original data from the studies included in this work are available as dictated by each author in the relevant manuscripts.

Declarations

Ethics approval and consent to participate

Ethics committee approval and informed consent were not required since no individual patient’s data were analyzed.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.