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Turkish Journal of Medical Sciences

Abstract

Background/aim: Chronic lymphocytic leukemia (CLL) exhibits marked biological heterogeneity, and immunoglobulin heavy chain variable (IgHV) mutation status remains a key prognostic biomarker. We evaluated patient IgHV status via RNA sequencing (RNA-seq) and examined real-life clinical outcomes in a retrospective CLL cohort.

Materials and methods: Eighty-seven adults diagnosed with CLL between 2020 and 2022 at three centers were included. Total RNA from peripheral blood underwent anchored multiplex polymerase chain reaction with the Immunoverse BCR-IGH IGKL v1.0 kit (Integrated DNA Technologies) and was sequenced on the MiSeq platform (Illumina). IgHV mutation status was determined according to ERIC 2022 guidelines, specifically regarding classification of “challenging” double-rearranged cases, with discordant productive rearrangements (one mutated, one unmutated) categorized as unmutated (u-IgHV) to ensure prognostic reliability. Clinical characteristics, treatment patterns, and survival outcomes were analyzed and overall survival (OS) was estimated by the Kaplan–Meier method.

Results: Median age at diagnosis was 60 years and 64% of patients were male. RNA-seq identified double IgHV rearrangements in 73% (n = 63) of patients, 63% of whom harbored two productive rearrangements without evidence of biclonality. Unmutated IgHV (u-IgHV) was observed in 53% (n = 46). Compared to mutated IgHV (m-IgHV), patients with u-IgHV more frequently required first-line therapy (66% vs. 34%) and proceeded to second-line treatment more rapidly. Deletion 17p was significantly more common in the u-IgHV group. After median follow-up of 37.5 months, the 3-year OS rate was 91.9%, with no significant difference in OS between the m-IgHV and u-IgHV cohorts.

Conclusion: RNA-seq provided detailed insight into IgHV mutation status and revealed a higher incidence of challenging double-rearranged cases. These real-life findings underscore the clinical utility of RNA-based IgHV profiling and support its use. Prospective studies comparing RNA- and DNA-based assays are warranted to validate concordance and inform risk-adapted management strategies in the treatment of CLL.

Author ORCID Identifier

FATMA ARIKAN: 0000-0002-4059-1250

PINAR ATA: 0000-0002-2399-2888

ŞENOL DEMİR: 0000-0002-8374-0359

MERAL ULUKÖYLÜ MENGÜÇ: 0000-0002-4303-9488

FAHİR ÖZKALEMKAŞ: 0000-0001-9710-134X

BEDRETTİN ORHAN: 0000-0003-3970-2344

ÖZGÜR MEHTAP: 0000-0002-5603-1178

ARDA BAYAR: 0000-0002-4586-3809

ASU FERGÜN YILMAZ: 0000-0001-5118-6894

AYŞE TÜLİN TUĞLULAR: 0000-0003-3232-7545

IŞIK ATAGÜNDÜZ: 0000-0002-7876-6896

TAYFUR TOPTAŞ: 0000-0002-2690-8581

DOI

10.55730/1300-0144.6357

Keywords

Chronic lymphocytic leukemia, RNA sequencing, somatic hypermutation

First Page

1133

Last Page

1140

Publisher

The Scientific and Technological Research Council of Türkiye (TÜBİTAK)

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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