Introduction: Patients with CLL and mutated immunoglobulin heavy variable (IGHV) genes (M-CLL) are clinically heterogeneous. While genomic aberrations contribute to adverse outcomes in certain M-CLL subgroups, they do not fully account for M-CLL heterogeneity, suggesting the need for further research.

Methods: This is a retrospective, observational study aiming to identify factors associated with shorter overall survival (OS) after first-line (1L) treatment in M-CLL. The study included patients diagnosed with M-CLL between 2000-2022 in 26 centers with a follow-up >6 months after 1L treatment. Special attention was given to immunogenetic features, including BcR stereotypy. Besides, we developed a novel immunogenetic metric that considers the amino acid composition of the germline IGHV genes, following the IMGT physicochemical classification table. Each aligned position across the IGHV gene sequences was assigned different scores based on the relation between the assessed amino acids: 0 if identical, 1 if in the same physicochemical group, and 2 if in different groups. This scoring system enabled the generation of a distance matrix for all IGHV genes, which was then used as input for hierarchical clustering, leading to the creation of 15 clusters. Univariable (UVA) and multivariable (MVA) analyses were performed to identify risk factors associated with shorter OS. The variables assessed in the UVA were age at 1L initiation, biological sex, type of 1L treatment, TP53 mutations, FISH aberrations, and karyotype.

Results: 1933 patients from 26 centers in 12 countries were evaluated. The median age at 1L treatment was 69 years (IQR: 62-76). Most patients were males (1184, 61.3%) and 1249 (64.7%) were alive at last follow up. The median follow-up from 1L treatment was 4.6 years (IQR: 1.8-8.1). Before 1L treatment, 623/1090 (57.2%), 195/1077 (18.1%), 107/1342 (8%) and 103/1240 (8.3%) carried del(13q), trisomy 12, del(17p) and del(11q) detected by FISH, respectively. TP53 mutations were detected in 118/1012 (11.7%) cases and karyotype with ≥3 and ≥5 (CK5) aberrations in 82/610 (13.4%) and 17/610 (2.8%) cases, respectively. The most common stereotyped subsets were #2 (59/1112, 5.3%) and #4 (11/1112, 1%). Most patients (1346, 69.8%) received 1 line of treatment, while 344 (17.8%), 138 (7.2%) and 101 (5.2%) received 2, 3, and ≥4 lines, respectively. FCR was the most common 1L treatment (395, 20.8%) followed by chlorambucil (Chl) monotherapy (320, 16.9%). BTK inhibitors (BTKis) were used in 241 cases [12.5%; ibrutinib: 162 (8.3%), acalabrutinib 65 (3.4%), zanubrutinib: 10 (0.5%), pirtobrutinib 4 (0.2%)]. BR, Chl-rituximab and Chl-obinutuzumab were used in 185 (9.8%), 126 (6.6%) and 98 (5.2%) cases, respectively. Finally, 70 (3.6%) received venetoclax-obinutuzumab 1L treatment and 33 (1.7%) received ibrutinib-venetoclax. The median OS was 11 years (95% CI: 10.4-11.8). In UVA, older age at 1L, male sex, TP53 aberrations (TP53-abs), del(11q) and CK5 were associated with shorter OS (p<0.001, p=0.03, p<0.001, p<0.001, p=0.001, respectively). Compared to FCR/BR, targeted treatments led to a similar OS (p=0.3), while other non-targeted treatments resulted in shorter OS (p<0.001). Regarding the new immunogenetic metric, clusters 13 (IGHV1-24 and IGHV1-69-2 genes), 4 (IGHV2 genes) and 8 (IGHV3-13) associated with shorter OS (p=0.07, p=0.02, and p=0.002, respectively). To assess the relevance of this finding, we scanned our immunogenetic database consisting of 42,154 M-CLL IG rearrangements. While the IGHV1-24, IGHV1-69-2 and IGHV3-13 genes were very rare (0.6%), IGHV2 gene rearrangements represented a sizeable M-CLL subgroup (1969 cases, 4.7%). In MVA, only age at 1L and CK5 retained statistical significance for OS (HR: 1.08, 95% CI: 1.04-1.3, p<0.001, HR: 2.5, 95% CI: 1.04-6.2, p=0.04, respectively).

In patients <70 years, older age at 1L, TP53-abs, del(11q), and clusters 4 and 8 were associated with shorter OS (p<0.001, p=0.01, p=0.007, p=0.01, and p=0.01, respectively). The type of treatment effect was similar to the whole cohort. In MVA, age at 1L andTP53-absretained statistical significance (HR:1.07, 95% CI:1.02-1.11, p=0.003, HR:1.9, 95% CI:1.02-3.5, p=0.04, respectively).

Conclusion: Older age, CK5 and TP53 aberrations are independent high-risk factors for shorter OS in M-CLL. Utilization of IGHV2 subgroup genes emerged as adverse-prognostic for OS and merits further evaluation.

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2025
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