Wojdacz, Tomasz K., Amarasinghe, Harindra E., Kadalayil, Latha, Beattie, Alice, Forster, Jade, Blakemore, Stuart J., Parker, Helen, Bryant, Dean, Larrayoz, Marta, Clifford, Ruth, Robbe, Pauline, Davis, Zadie A., Else, Monica, Howard, Dena R., Stamatopoulos, Basile, Steele, Andrew J., Rosenquist, Richard, Collins, Andrew ORCID: 0000-0001-7108-0771, Pettitt, Andrew R., Hillmen, Peter, Plass, Christoph, Schuh, Anna, Catovsky, Daniel, Oscier, David G., Rose-Zerilli, Matthew J. J., Oakes, Christopher C. and Strefford, Jonathan C. (2019). Clinical significance of DNA methylation in chronic lymphocytic leukemia patients: results from 3 UK clinical trials. Blood Adv., 3 (16). S. 2474 - 2482. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 2473-9537

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wojdacz, Tomasz K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amarasinghe, Harindra E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kadalayil, LathaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beattie, AliceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Forster, JadeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blakemore, Stuart J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parker, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bryant, DeanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larrayoz, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clifford, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robbe, PaulineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Davis, Zadie A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Else, MonicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Howard, Dena R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stamatopoulos, BasileUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steele, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenquist, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collins, AndrewUNSPECIFIEDorcid.org/0000-0001-7108-0771UNSPECIFIED
Pettitt, Andrew R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hillmen, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plass, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuh, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Catovsky, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oscier, David G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rose-Zerilli, Matthew J. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oakes, Christopher C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strefford, Jonathan C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-143895
DOI: 10.1182/bloodadvances.2019000237
Journal or Publication Title: Blood Adv.
Volume: 3
Number: 16
Page Range: S. 2474 - 2482
Date: 2019
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 2473-9537
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CLL PATIENTS; CYCLOPHOSPHAMIDE; FLUDARABINE; MUTATIONS; SURVIVAL; FCR; RITUXIMAB; GENE; PROGRESSION; REMISSIONSMultiple languages
HematologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14389

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