Clinical significance of DNA methylation in chronic lymphocytic leukaemia patients: results from three UK clinical trials

CLL patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemo-immunotherapy (CIT). DNA methylation profiling can sub-divide early stage patients into naive B cell-like (n-CLL), memory B cell-like (m-CLL) and int...

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Bibliographic Details
Published in:Blood Advances
Main Authors: Wojdacz, Tomasz, Amarasinghe, Harindra E., Kadalayil, Latha, Beattie, Alice, Forster, Jade, Blakemore, Stuart, Parker, Helen, Bryant, Dean, Larrayoz, Marta, Clifford, Ruth, Robbe, Pauline, Davis, Zadie, Else, Monica, Howard, Dena R., Stamatopoulos, Basile, Steele, Andrew, Rosenquist, Richard, Collins, Andrew, Pettitt, Andrew, Hillmen, Peter, Plass, Christoph, Schuh, Anna, Catovsky, Daniel, Oscier, David G, Rose-Zerilli, Matthew, Oakes, Christopher C., Strefford, Jonathan
Format: Article in Journal/Newspaper
Language:English
Published: 2019
Subjects:
Arctic
Online Access:https://eprints.soton.ac.uk/431916/
https://eprints.soton.ac.uk/431916/1/2019_Wojdacz_Manuscript_BloodAdvs_11062019.pdf
https://eprints.soton.ac.uk/431916/2/2474.full.pdf
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Summary:CLL patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemo-immunotherapy (CIT). DNA methylation profiling can sub-divide early stage patients into naive B cell-like (n-CLL), memory B cell-like (m-CLL) and intermediate CLL (i-CLL) with differing times to first treatment and overall survival. However, whether DNA methylation can identify patients destined to respond favourably to CIT has not been ascertained. We classified treatment-naïve patients (n=605) randomized to three UK chemo and chemo-immunotherapy clinical trials into the three epigenetic subgroups using pyrosequencing and microarray analysis, and performed expansive survival analysis. The n-CLL, i-CLL and m-CLL signatures were found in 80% (n=245/305), 17% (53/305), and 3% (7/305) of IGHV-unmutated (IGHV-U) cases, respectively; and in 9%, (19/216), 50% (108/216) and 41%, (89/216) of IGHV-M cases, respectively. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for OS (HR 0.46 (95% CI: 0.24-0.87), p=0.018) in CLL4, and for PFS (HR 0.25 (95% CI: 0.10-0.57), p=0.002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into three first-line UK CLL trials, identifies m-CLL as an independent marker of prolonged survival and may aid in the identification of patients destined to demonstrate prolonged survival after CIT.

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