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Clinical significance of DNA methylation in chronic lymphocytic leukaemia patients: results from three UK clinical trials

Clinical significance of DNA methylation in chronic lymphocytic leukaemia patients: results from three UK clinical trials
Clinical significance of DNA methylation in chronic lymphocytic leukaemia patients: results from three UK clinical trials
CLL 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 sub-divide early stage patients into naive B cell-like (n-CLL), memory B cell-like (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 favourably to CIT has not been ascertained. We classified treatment-naïve patients (n=605) randomized to three UK chemo and chemo-immunotherapy clinical trials into the three 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 3% (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 OS (HR 0.46 (95% CI: 0.24-0.87), p=0.018) in CLL4, and for PFS (HR 0.25 (95% CI: 0.10-0.57), p=0.002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into three 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.
2473-9529
2474-2481
Wojdacz, Tomasz
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Amarasinghe, Harindra E.
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Kadalayil, Latha
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Beattie, Alice
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Forster, Jade
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Blakemore, Stuart
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Parker, Helen
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Larrayoz, Marta
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Clifford, Ruth
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Robbe, Pauline
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Davis, Zadie
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Else, Monica
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Howard, Dena R.
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Stamatopoulos, Basile
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Collins, Andrew
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Hillmen, Peter
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Plass, Christoph
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Wojdacz, Tomasz
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Amarasinghe, Harindra E.
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Kadalayil, Latha
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Beattie, Alice
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Forster, Jade
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Blakemore, Stuart
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Parker, Helen
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Bryant, Dean
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Larrayoz, Marta
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Clifford, Ruth
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Else, Monica
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Howard, Dena R.
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Stamatopoulos, Basile
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Steele, Andrew
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Rosenquist, Richard
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Collins, Andrew
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Pettitt, Andrew
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Hillmen, Peter
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Plass, Christoph
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Schuh, Anna
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Catovsky, Daniel
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Oscier, David G
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Rose-Zerilli, Matthew
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Oakes, Christopher C.
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Wojdacz, Tomasz, Amarasinghe, Harindra E., Kadalayil, Latha, Beattie, Alice, Forster, Jade, Blakemore, Stuart, Parker, Helen, Bryant, Dean, Larrayoz, Marta, Clifford, Ruth, Robbe, Pauline, Davis, Zadie, Else, Monica, Howard, Dena R., Stamatopoulos, Basile, Steele, Andrew, Rosenquist, Richard, Collins, Andrew, Pettitt, Andrew, Hillmen, Peter, Plass, Christoph, Schuh, Anna, Catovsky, Daniel, Oscier, David G, Rose-Zerilli, Matthew, Oakes, Christopher C. and Strefford, Jonathan (2019) Clinical significance of DNA methylation in chronic lymphocytic leukaemia patients: results from three UK clinical trials. Blood Advances, 3 (16), 2474-2481. (doi:10.1182/bloodadvances.2019000237).

Record type: Article

Abstract

CLL 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 sub-divide early stage patients into naive B cell-like (n-CLL), memory B cell-like (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 favourably to CIT has not been ascertained. We classified treatment-naïve patients (n=605) randomized to three UK chemo and chemo-immunotherapy clinical trials into the three 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 3% (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 OS (HR 0.46 (95% CI: 0.24-0.87), p=0.018) in CLL4, and for PFS (HR 0.25 (95% CI: 0.10-0.57), p=0.002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into three 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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Accepted/In Press date: 15 June 2019
e-pub ahead of print date: 21 August 2019
Published date: 27 August 2019

Identifiers

Local EPrints ID: 431916
URI: http://eprints.soton.ac.uk/id/eprint/431916
ISSN: 2473-9529
PURE UUID: 05fc58bc-97e6-4bb9-afa2-cb68f35fa9c9
ORCID for Helen Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for Andrew Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for Andrew Collins: ORCID iD orcid.org/0000-0001-7108-0771
ORCID for Matthew Rose-Zerilli: ORCID iD orcid.org/0000-0002-1064-5350
ORCID for Jonathan Strefford: ORCID iD orcid.org/0000-0002-0972-2881

Catalogue record

Date deposited: 21 Jun 2019 16:30
Last modified: 10 Jan 2022 02:57

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Contributors

Author: Tomasz Wojdacz
Author: Harindra E. Amarasinghe
Author: Latha Kadalayil
Author: Alice Beattie
Author: Jade Forster
Author: Stuart Blakemore
Author: Helen Parker ORCID iD
Author: Dean Bryant
Author: Marta Larrayoz
Author: Ruth Clifford
Author: Pauline Robbe
Author: Zadie Davis
Author: Monica Else
Author: Dena R. Howard
Author: Basile Stamatopoulos
Author: Andrew Steele ORCID iD
Author: Richard Rosenquist
Author: Andrew Collins ORCID iD
Author: Andrew Pettitt
Author: Peter Hillmen
Author: Christoph Plass
Author: Anna Schuh
Author: Daniel Catovsky
Author: David G Oscier
Author: Christopher C. Oakes

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