Résumé
The outcome of patients with chronic lymphocytic leukemia (CLL) is known to be influenced by the mutational status of the immunoglobulin heavy-chain variable (IGHV) region [1]. In the past decade, it has been shown that a large part of CLL share B-cell receptor (BCR) sequence homologies, defining subsets of patients with similar clinical outcome [2]. The CLL Subset#2 (S#2), defined by the presence of the stereotyped IGHV3-21-derived rearrangement, with a short third complementarity-determining region (CDR3), has been linked to unfavorable prognosis. This translates in shorter time to first treatment, independently of other prognostic factors such as IGHV mutational status or genetic alterations [3, 4]. Despite S#2 being the most prevalent subset, few studies have investigated treatment responses and progression-free survival (PFS) in this context. Chemoimmunotherapy (CIT) is unsatisfactory in this group of patients [5, 6], but responses to targeted therapies (TT) have not been investigated. The aim of this study was to evaluate the outcome of patients with S#2 compared to patients with other IGHV3-21 subsets in the era of TT.
A retrospective multicentric study was conducted across 31 French Innovative Leukemia Organization (FILO-CLL) affiliated centers in France, including patients diagnosed between 1998 and 2023. The study was declared to the Health data Hub according to French legislation. Patients identified with a productive IGHV3-21 rearrangement, available clinical and survival data, and no opposition to the study, were included. S#2, not-Subset#2 (nS#2) and IGHV mutational status were categorized according to the recommendations of the European Research Initiative on CLL (ERIC) [7]. Treatment strategies were CIT, Bruton Tyrosine Kinase inhibitors (BTKi), and B-Cell Lymphoma 2 inhibitors (BCL2i). Survival analysis, according to ERIC recommendations [7], considered borderline IGHV status as mutated. Time to first treatment (TTFT) and subsequent PFS analysis were performed using Kaplan-Meier estimation and log-rank test (R software, CRAN). Potential confounders, including age, sex, mutated (mIGHV) and unmutated (uIGHV) status, complex karyotype (CK) (≥3 abnormalities), high-CK (HCK) (≥5 abnormalities) and TP53