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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Tomasz K. Wojdacz
  • Harindra E. Amarasinghe, University of Southampton
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  • Latha Kadalayil, University of Southampton
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  • Alice Beattie, University of Southampton
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  • Jade Forster, University of Southampton
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  • Stuart J. Blakemore, University of Southampton, University of Cologne
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  • Helen Parker, University of Southampton
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  • Dean Bryant, University of Southampton
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  • Marta Larrayoz, University of Southampton, University of Navarra
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  • Ruth Clifford, Oxford University, Oxford, UK.
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  • Pauline Robbe, Oxford University, Oxford, UK.
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  • Zadie A. Davis, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
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  • Monica Else, Institute of Cancer Research
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  • Dena R. Howard, Leeds University
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  • Basile Stamatopoulos, Université Libre de Bruxelles
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  • Andrew J. Steele, University of Southampton
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  • Richard Rosenquist, Karolinska Institutet
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  • Andrew Collins, University of Southampton
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  • Andrew R. Pettitt, University of Liverpool
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  • Peter Hillmen, Leeds University
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  • Christoph Plass, German Cancer Research Center, Heidelberg
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  • Anna Schuh, Oxford University, Oxford, UK.
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  • Daniel Catovsky, Institute of Cancer Research
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  • David G. Oscier, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
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  • Matthew J.J. Rose-Zerilli, University of Southampton
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  • Christopher C. Oakes, The Ohio State University
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  • Jonathan C. Strefford, University of Southampton

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.

Original languageEnglish
JournalBlood Advances
Volume3
Issue16
Pages (from-to)2474-2481
Number of pages8
ISSN2473-9529
DOIs
Publication statusPublished - 27 Aug 2019

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