High genomic complexity is linked to poor prognosis in chronic lymphocytic leukaemia (CLL), but its independent prognostic value remains uncertain amid emerging biomarkers.

We analysed copy number alterations (CNA) in 495 treatment-naïve patients from three randomized trials (CLL4, ADMIRE, ARCTIC), incorporating IGHV status, telomere length (TL), targeted sequencing, and DNA-methylation subtypes. Patients harboured low (LGC, 0–2 CNAs; n=334), intermediate (IGC, 3–4 CNAs; n=97), or high (HGC, ≥5 CNAs; n=64) genomic complexity.

U-CLL (81%, p<0.001) and short TL (61%, p<0.05) were enriched in HGC, and TL inversely correlated with CNA burden (τ = –0.147, p<0.001). 62% of HGC patients were n-CLL. TP53 dysfunction was associated with HGC (36%, p<0.001). Trisomy 12 and NOTCH1 mutations, were enriched in LGC (p<0.001). HGC predicted shorter progression-free and overall survival in all univariate models but only remained independently prognostic for OS only in CLL4 (HR=1.61, p=0.02). Of 64 HGC patients, 23 had TP53 dysfunction; 92% of TP53 wild-type cases had other high-risk features (TL-S, U-CLL, or n- CLL).

HGC is associated with adverse outcomes but may reflect underlying biological risk rather than serve as an independent biomarker. Its interplay with telomere attrition, immunogenetics, and epigenetic subtype warrants further validation in targeted therapy-treated cohorts.

The authors have declared no competing interest.

This study was funded by funded by Bloodwise (11052, 12036), the Kay Kendall Leukaemia Fund (873), Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087, and programme C2750/A23669) and the Bournemouth Leukaemia Fund. The LRF CLL4 trial was funded by a core grant from Leukaemia and Lymphoma Research. Patient material was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Blood Cancer UK. ME acknowledges the support by The Arbib Charitable Fund. LC received a PhD studentship funded by Cancer Research UK and the Medical Research Council. The Baird lab is funded by Cancer Research UK programme C17199/A29202.

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