CLINICAL IMPORTANCE OF DNA METHYLATION SIGNATURES IN CHRONIC LYMPHOCYTIC LEUKAEMIA PATIENTS TREATED WITH CHEMO-IMMUNOTHERAPY
Author(s): ,
Jonathan Strefford
Affiliations:
Cancer Sciences Unit, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Harindra Amarasinghe
Affiliations:
Cancer Sciences Unit, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Tomasz Wojdacz
Affiliations:
Cancer Sciences Unit, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Alice Beattie
Affiliations:
Cancer Sciences Unit, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Jade Forster
Affiliations:
Cancer Sciences Unit, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Latha Kadalayil
Affiliations:
4Human Development and Health,University of Southampton,Southampton,United Kingdom
,
Stuart Blakemore
Affiliations:
Cancer Sciences Unit, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Helen Parker
Affiliations:
Cancer Sciences Unit, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Marta Larrayoz
Affiliations:
Cancer Sciences Unit, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Ruth Clifford
Affiliations:
Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology,University of Oxford,Oxford,United Kingdom
,
Zadie Davis
Affiliations:
Department of Pathology,Royal Bournemouth Hospital,Bournemouth,United Kingdom
,
Monica Else
Affiliations:
The Institute of Cancer Research,The Institute of Cancer Research,Sutton,United Kingdom
,
Dena Cohen
Affiliations:
Leeds Institute of Clinical Trials Research,University of Leeds,Leeds,United Kingdom
,
Andrew Steele
Affiliations:
Cancer Sciences Unit, Faculty of Medicine,University of Southampton,Southampton,United Kingdom
,
Richard Rosenquist
Affiliations:
Department of Molecular Medicine and Surgery,Karolinska Institutet,Stockholm,Sweden
,
Andrew Collins
Affiliations:
Human Development and Health,University of Southampton,Southampton,United Kingdom
,
Andrew Pettitt
Affiliations:
Department of Molecular and Clinical Cancer Medicine,University of Liverpool,Liverpool,United Kingdom
,
Peter Hillmen
Affiliations:
Leeds Institute of Clinical Trials Research,University of Leeds,Leeds,United Kingdom
,
Christoph Plass
Affiliations:
Division of Epigenomics and Cancer Risk Factors,The German Cancer Research Center,Heidelberg,Germany
,
Anna Schuh
Affiliations:
Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology,University of Oxford,Oxford,United Kingdom
,
Daniel Catovsky
Affiliations:
The Institute of Cancer Research,The Institute of Cancer Research,Sutton,United Kingdom
,
David Oscier
Affiliations:
Department of Pathology,Royal Bournemouth Hospital,Bournemouth,United Kingdom
Christopher Oakes
Affiliations:
Division of Hematology,The Ohio State University,Columbus,United States
(Abstract release date: 05/17/18) EHA Library. Strefford J. 06/17/18; 214580; S1571
J.C. Strefford
J.C. Strefford
Contributions
Abstract

Abstract: S1571

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 08:15 - 08:30

Location: Room A6

Background

Even in the era of the targeted therapies, there remains clinical value in exploring the impact of disease characteristics in chemo-immunotherapy (CIT) trials, namely to identify features that contribute most to long-term outcomes, thereby pinpointing patients destined to benefit from these therapies. One such feature is the CLL DNA methylome, that recapitulates normal B cell maturation, with IGHV mutated (M-CLL) and unmutated CLL (U-CLL) retaining an imprint of the DNA methylation signature of memory (m-CLL) and naive B cells (n-CLL), respectively, with a third intermediate epigenetic subgroup (i-CLL) with borderline mutation status. The pyrosequencing analysis of 5 CpG sites can divide CLL into these three subgroups, each with different clinico-biological features.

Aims

To validate the clinical utility of the epigenetic subgroups in patients entering clinical trials.

Methods

We classified 605 treatment-naïve patients randomized to one chemotherapy (CLL4) and two CIT (ARCTIC and ADMIRE) trials, into the three epigenetic subgroups using pyrosequencing and confirmatory Infinium HumanMethylation450 analysis (n=60, 96% concordance between technologies).

Results
We identified n-, i- and m-CLL in 49.5% (n=298), 32.0% (n=195) and 18.5% (n=112) of our patients, respectively (Fig1I). Fewer m-CLL patients were identified in our study compared to published data, reflecting the progressive nature of our cohort, with 80% (n=245/305, P<0.001) of U-CLL cases exhibited the n-CLL signature (i-CLL: 17% and m-CLL: 3%). For M-CLL cases 9%, 50% and 41% exhibited the n-, i- and m-CLL epigenetic signature, respectively. In 359 CLL4 patients, n-, i- and m-CLL patients exhibited a median PFS of 23, 35 and 33, and OS of 63, 66 and 106 months, respectively (Fig1IIa and b). n-CLL showed significantly shorter PFS than i-CLL (HR 0.64, p<0.001) and m-CLL (HR 0.52, p<0.001), and had the shortest OS, again compared to i-CLL (HR 0.73, p=0.01) and m-CLL (HR 0.33, p<0.001). The epigenetic signature was associated with long-term survival (>10 years OS), with n-CLL accounting for only 14% of this subgroup (P<0.001, FigIIe). In IGHV-M patients, the m-CLL subgroup showed 104 months of median OS compared to 79 and 84 months in n- and i-CLL subgroups (FigIId). Multivariate Cox proportional analysis, controlling for confounding variables (inc. clinical features, IGHV status, TP53, NOTCH1 and SF3B1) in 278 patients showed that m-CLL was an independent prognostic factor for OS (HR 0.46, p<0.01), but not PFS. In univariate analysis, in 247 patients randomized to ARCTIC and ADMIRE, the i- (HR:0.57, p=0.05) and m-CLL (HR:0.3, p=0.002) subgroups displayed longer PFS (Fig1IIc). In a multivariate model, including TP53 lesions and IGHV status (239 patients), the m-CLL subgroup retained its independent prognostic significance (HR:0.25, p<0.001). 

Conclusion
In conclusion, we report the first analysis of the clinical utility of epigenetic subgroup signatures in patients entered into first-line chemotherapy and CIT trials and identified m-CLL as an independent marker of survival in both our CLL4 and ARCTIC/ADMIRE cohorts. This provides important evidence that DNA methylation analysis may aid in the identification of patients destined to demonstrate durable remissions when treated with these agents.

Session topic: 5. Chronic lymphocytic leukemia and related disorders – Biology & Translational Research

Keyword(s): Chronic Lymphocytic Leukemia, DNA methylation, prognosis

Abstract: S1571

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 08:15 - 08:30

Location: Room A6

Background

Even in the era of the targeted therapies, there remains clinical value in exploring the impact of disease characteristics in chemo-immunotherapy (CIT) trials, namely to identify features that contribute most to long-term outcomes, thereby pinpointing patients destined to benefit from these therapies. One such feature is the CLL DNA methylome, that recapitulates normal B cell maturation, with IGHV mutated (M-CLL) and unmutated CLL (U-CLL) retaining an imprint of the DNA methylation signature of memory (m-CLL) and naive B cells (n-CLL), respectively, with a third intermediate epigenetic subgroup (i-CLL) with borderline mutation status. The pyrosequencing analysis of 5 CpG sites can divide CLL into these three subgroups, each with different clinico-biological features.

Aims

To validate the clinical utility of the epigenetic subgroups in patients entering clinical trials.

Methods

We classified 605 treatment-naïve patients randomized to one chemotherapy (CLL4) and two CIT (ARCTIC and ADMIRE) trials, into the three epigenetic subgroups using pyrosequencing and confirmatory Infinium HumanMethylation450 analysis (n=60, 96% concordance between technologies).

Results
We identified n-, i- and m-CLL in 49.5% (n=298), 32.0% (n=195) and 18.5% (n=112) of our patients, respectively (Fig1I). Fewer m-CLL patients were identified in our study compared to published data, reflecting the progressive nature of our cohort, with 80% (n=245/305, P<0.001) of U-CLL cases exhibited the n-CLL signature (i-CLL: 17% and m-CLL: 3%). For M-CLL cases 9%, 50% and 41% exhibited the n-, i- and m-CLL epigenetic signature, respectively. In 359 CLL4 patients, n-, i- and m-CLL patients exhibited a median PFS of 23, 35 and 33, and OS of 63, 66 and 106 months, respectively (Fig1IIa and b). n-CLL showed significantly shorter PFS than i-CLL (HR 0.64, p<0.001) and m-CLL (HR 0.52, p<0.001), and had the shortest OS, again compared to i-CLL (HR 0.73, p=0.01) and m-CLL (HR 0.33, p<0.001). The epigenetic signature was associated with long-term survival (>10 years OS), with n-CLL accounting for only 14% of this subgroup (P<0.001, FigIIe). In IGHV-M patients, the m-CLL subgroup showed 104 months of median OS compared to 79 and 84 months in n- and i-CLL subgroups (FigIId). Multivariate Cox proportional analysis, controlling for confounding variables (inc. clinical features, IGHV status, TP53, NOTCH1 and SF3B1) in 278 patients showed that m-CLL was an independent prognostic factor for OS (HR 0.46, p<0.01), but not PFS. In univariate analysis, in 247 patients randomized to ARCTIC and ADMIRE, the i- (HR:0.57, p=0.05) and m-CLL (HR:0.3, p=0.002) subgroups displayed longer PFS (Fig1IIc). In a multivariate model, including TP53 lesions and IGHV status (239 patients), the m-CLL subgroup retained its independent prognostic significance (HR:0.25, p<0.001). 

Conclusion
In conclusion, we report the first analysis of the clinical utility of epigenetic subgroup signatures in patients entered into first-line chemotherapy and CIT trials and identified m-CLL as an independent marker of survival in both our CLL4 and ARCTIC/ADMIRE cohorts. This provides important evidence that DNA methylation analysis may aid in the identification of patients destined to demonstrate durable remissions when treated with these agents.

Session topic: 5. Chronic lymphocytic leukemia and related disorders – Biology & Translational Research

Keyword(s): Chronic Lymphocytic Leukemia, DNA methylation, prognosis

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies