IGHV mutational status and BCR stereotypy in chronic lymphocytic leukemia: A Turkish cohort analysis

Immunoglobulin heavy chain variable region (IGHV) mutational status and B-cell receptor (BCR) stereotypy are established prognostic markers in chronic lymphocytic leukemia (CLL). However, immunogenetic data from Türkiye and surrounding regions are scarce. We evaluated IGHV mutational status, BCR stereotypy including nearest subset assignment, and their clinical and cytogenetic correlates in a real-world Turkish CLL cohort. We retrospectively analyzed 145 patients with CLL at a tertiary referral center in Türkiye. IGHV mutational status was determined by next-generation sequencing (98% germline homology cutoff). BCR stereotypy was assigned using ARResT/AssignSubsets. Cytogenetic abnormalities were assessed by fluorescence in situ hybridization (FISH). Time-to-first treatment (TTFT), progression-free survival (PFS), and overall survival (OS) were analyzed by Kaplan-Meier method, with multivariate Cox regression for TTFT. Unmutated IGHV was detected in 55.2% of patients, higher than Western reports but consistent with Mediterranean and Middle Eastern cohorts. Unmutated cases showed adverse cytogenetics-del(11q) and multiple concurrent FISH abnormalities-whereas del(13q) predominated in mutated cases. At a median follow-up of 43.0 months unmutated status strongly predicted a profoundly shorter median TTFT compared to mutated cases (17.0 vs. 70.0 months; p < 0.0001). Notably, while an unmutated IGHV status strongly predicted a significantly shorter TTFT, it did not translate into worse PFS or OS compared to mutated cases, reflecting the transformative real-world impact and rescue capacity of modern targeted therapies utilized upon disease progression. Major stereotyped subsets were present in 15.9% of patients; subset #2 was absent, while subset #1 was predominant (39.1%). Subsets #1 and #64B were overrepresented among relapsed cases. Nearest subset #77 showed rapid progression despite mutated IGHV. CLL in Türkiye demonstrates region-specific immunogenetic features while preserving established clinico-biological correlations. Integration of IGHV status, cytogenetics, and BCR stereotypy may improve risk stratification in underrepresented populations.