Clinical significance of DNA methylation in chronic lymphocytic leukemia patients: results from 3 UK clinical trials
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Date
2019-08-27ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
<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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Research team
Biology of Childhood Leukaemia
Language
eng
License start date
2019-08-27
Citation
Blood Advances, 2019, 3 (16), pp. 2474 - 2481
Publisher
American Society of Hematology