Clinical significance of DNA methylation in chronic lymphocytic leukemia patients: results from 3 UK clinical trials

<jats:title>Abstract</jats:title> <jats:p>Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemoimmunotherapy (CIT). DNA methylation profiling can subdivide earl...

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Bibliographic Details
Published in:Blood Advances
Main Authors: Wojdacz, TK, Amarasinghe, HE, Kadalayil, L, Beattie, A, Forster, J, Blakemore, SJ, Parker, H, Bryant, D, Larrayoz, M, Clifford, R, Robbe, P, Davis, ZA, Else, M, Howard, DR, Stamatopoulos, B, Steele, AJ, Rosenquist, R, Collins, A, Pettitt, AR, Hillmen, P, Plass, C, Schuh, A, Catovsky, D, Oscier, DG, Rose-Zerilli, MJJ, Oakes, CC, Strefford, JC
Other Authors: Else, Monica
Format: Article in Journal/Newspaper
Language:English
Published: American Society of Hematology 2019
Subjects:
Arctic
Online Access:https://repository.icr.ac.uk/handle/internal/3471
https://doi.org/10.1182/bloodadvances.2019000237
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Summary:<jats:title>Abstract</jats:title> <jats:p>Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemoimmunotherapy (CIT). DNA methylation profiling can subdivide early-stage patients into naive B-cell–like CLL (n-CLL), memory B-cell–like CLL (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 favorably to CIT has not been ascertained. We classified treatment-naive patients (n = 605) from 3 UK chemo and CIT clinical trials into the 3 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 2% (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 overall survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.87; P = .018) in CLL4, and for progression-free survival (HR, 0.25; 95% CI, 0.10-0.57; P = .002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into 3 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.</jats:p>

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