Parker, H, Carr, L, Norris, K, Nilsson-Takeuchi, A, Stevens, B, Amarasinghe, H, Kadalayil, L, Else, M, Clifford, R, Pettitt, A 
ORCID: 0000-0002-0907-8950 et al (show 9 more authors)
(2026)
High-risk molecular features may eclipse genomic complexity in predicting chronic lymphocytic leukemia outcomes; UK clinical trial insights
LEUKEMIA, 40 (4).
pp. 816-826.
ISSN 0887-6924, 1476-5551
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Text
Parker et al, Leukemia 2026.pdf - Author Accepted Manuscript Available under License Creative Commons Attribution. Download (1MB) | Preview |
Abstract
High genomic complexity (HGC) is linked to poor prognosis in CLL, but its independent prognostic value remains uncertain amid emerging biomarkers. We analysed copy number alterations (CNA) in 495 untreated patients from (immuno)chemotherapy trials (CLL4, ADMIRE, ARCTIC), incorporating IGHV status, telomere length (TL), targeted sequencing and DNA-methylation subtypes. Patients harboured low (LGC, ≤2 CNAs; n = 334), intermediate (IGC, 3–4 CNAs; n = 97), or high (HGC, ≥5 CNAs; n = 64) genomic complexity. HGC associated with U-CLL (81%, p < 0.001), TP53-aberration (36%, p < 0.001), short TL (TL-S; 61%, p < 0.05), del13q (50%, p < 0.001) and del11q (22%, p < 0.05). IGC was enriched for biallelic ATM disruption and BIRC3 deletions (p < 0.001). Trisomy 12 and NOTCH1 mutations were enriched in LGC (p < 0.001). HGC associated with shorter progression-free and overall survival in univariate models but only remained independent for OS in CLL4 (HR = 1.61, p = 0.02). Independent prognostic factors included TP53 aberration, U-CLL, TL-S and n-CLL. Of 64 HGC patients, 23 had TP53-aberration; 92% of TP53 wild-type cases had other high-risk features (TL-S, U-CLL, or n-CLL). HGC may reflect a convergence of high-risk features rather than represent an independent biomarker. The interplay of telomere attrition, IGHV status and DNA methylation subtype necessitates further validation in targeted therapy cohorts to enhance risk assessment in prognostic models.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Prognosis, Genomics, DNA Methylation, Mutation, Aged, Female, Male, Leukemia, Lymphocytic, Chronic, B-Cell, DNA Copy Number Variations, Biomarkers, Tumor, United Kingdom |
| Divisions: | Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology (T&R Staff) Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Molecular & Clinical Cancer Medicine |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 16 Mar 2026 09:47 |
| Last Modified: | 05 Jul 2026 03:03 |
| DOI: | 10.1038/s41375-026-02906-5 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3197523 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
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