TY - JOUR
T1 - Clinical significance of DNA methylation in chronic lymphocytic leukemia patients
T2 - Results from 3 UK clinical trials
AU - Wojdacz, Tomasz K.
AU - Amarasinghe, Harindra E.
AU - Kadalayil, Latha
AU - Beattie, Alice
AU - Forster, Jade
AU - Blakemore, Stuart J.
AU - Parker, Helen
AU - Bryant, Dean
AU - Larrayoz, Marta
AU - Clifford, Ruth
AU - Robbe, Pauline
AU - Davis, Zadie A.
AU - Else, Monica
AU - Howard, Dena R.
AU - Stamatopoulos, Basile
AU - Steele, Andrew J.
AU - Rosenquist, Richard
AU - Collins, Andrew
AU - Pettitt, Andrew R.
AU - Hillmen, Peter
AU - Plass, Christoph
AU - Schuh, Anna
AU - Catovsky, Daniel
AU - Oscier, David G.
AU - Rose-Zerilli, Matthew J.J.
AU - Oakes, Christopher C.
AU - Strefford, Jonathan C.
N1 - Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019/8/27
Y1 - 2019/8/27
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85071580517
U2 - 10.1182/bloodadvances.2019000237
DO - 10.1182/bloodadvances.2019000237
M3 - Article
C2 - 31434681
AN - SCOPUS:85071580517
SN - 2473-9529
VL - 3
SP - 2474
EP - 2481
JO - Blood Advances
JF - Blood Advances
IS - 16
ER -
