期刊
BLOOD ADVANCES
卷 3, 期 16, 页码 2474-2481出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2019000237
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资金
- Bloodwise [11052, 12036]
- Kay Kendall Leukaemia Fund [873]
- Cancer Research UK [C34999/A18087, ECMC C24563/A15581]
- Bournemouth Leukaemia Fund
- Leukaemia and Lymphoma Research
- Leuka Charity John Goldman Fellowship for Future Science [2016/JGF/0003]
- Arbib Charitable Fund
- Swedish Cancer Society
- Swedish Research Council
- Science for Life Laboratory
- Uppsala University
- Uppsala University Hospital
- Lion's Cancer Research Foundation, Uppsala
- United Kingdom's National Institute for Health Research
- Faculty of Natural and Environmental Sciences, University of Southampton
- Polish National Agency for Academic Exchange
- Aarhus Institute of Advanced Studies
Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemo immunotherapy (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.
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