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

par Wojdacz, Tomasz Kazimierz;Amarasinghe, Harindra H.E.;Kadalayil, Latha;Beattie, Alice;Forster, Jade;Blakemore, Stuart S.J.;Parker, Helen;Bryant, Dean;Larrayoz, Marta;Clifford, Ruth;Robbe, Pauline;Davis, Zadie Z.A.;Else, Monica;Howard, Dena D.R.;Stamatopoulos, Basile ;Steele, Andrew;Rosenquist, Richard;Collins, Andrew;Pettitt, Andrew A.R.;Hillmen, Peter;Plass, Christoph;Schuh, Anna;Catovsky, Daniel;Oscier, David Graham;Rose-Zerilli, Matthew M.J.J.;Oakes, Christopher C.C.;Strefford, Jonathan J.C.
Référence Blood Advances, 3, 16, page (2474-2481)
Publication Publié, 2019-08-01

Article révisé par les pairs

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Résumé :

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 5 605) 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 5 245/305), 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 5 .018) in CLL4, and for progression-free survival (HR, 0.25; 95% CI, 0.10-0.57; P 5 .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.