Clinical significance of DNA methylation in chronic lymphocytic leukemia patients: results from 3 UK clinical trials
Tomasz K Wojdacz, Harindra E Amarasinghe, Latha Kadalayil, Alice Beattie, Jade Forster, Stuart J Blakemore, Helen Parker, Dean Bryant, Marta Larrayoz, Ruth Clifford, Pauline Robbe, Zadie A Davis, Monica Else, Dena R Howard, Basile Stamatopoulos, Andrew J Steele, Richard Rosenquist, Andrew Collins, Andrew R Pettitt, Peter Hillmen, Christoph Plass, Anna Schuh, Daniel Catovsky, David G Oscier, Matthew J J Rose-Zerilli, Christopher C Oakes, Jonathan C Strefford
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.
CITATION Blood Adv. 2019 Aug 27;3(16):2474-2481. doi: 10.1182/bloodadvances.2019000237.