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MOLECULAR PREDICTORS OF RESPONSE TO AZACITIDINE THERAPY: THE RESULTS OF THE UK TRIALS ACCELERATION PROGRAMME RAVVA STUDY
Author(s): ,
Charles Craddock
Affiliations:
Centre for Clinical Haematology, University of Birmingham,University of Birmingham,Birmingham,United Kingdom
,
Lynn Quek
Affiliations:
Haematology,Weatherall Institute of Molecular Medicine,Oxford,United Kingdom
,
Aimee Houlton
Affiliations:
Cancer Research UK Clinical Trials Unit,University of Birmingham,Birmingham,United Kingdom
,
Paul Ferguson
Affiliations:
Haematology,Centre for Clinical Haematology, Queen Elizabeth Hospital,Birmingham,United Kingdom
,
Emma Gbandi
Affiliations:
Cancer Research UK Clinical Trials Unit,University of Birmingham,Birmingham,United Kingdom
,
Corran Roberts
Affiliations:
Haematology,Oxford,Oxford,United Kingdom
,
Marlen Metzner
Affiliations:
Haematology,Weatherall Institute of Molecular Medicine,Oxford,United Kingdom
,
Keith Wheatley
Affiliations:
CRCTU,University of Birmingham,Birmingham,United Kingdom
,
Shamyla Siddique
Affiliations:
CRCTU,University of Birmingham,Birmingham,United Kingdom
,
Srinivas Pillai
Affiliations:
Haematology,University Hospital of North Staffordshrire,Stoke on Trent,United Kingdom
,
Michael Dennis
Affiliations:
Haematology,The Christie NHS Foundation Trust,Manchester,United Kingdom
,
Jamie Cavenagh
Affiliations:
Department of Haemato-Oncology,St Bartholomews Hospital,London,United Kingdom
Paresh Vyas
Affiliations:
MRC Molecular Haematology Unit,Weatherall Institute of Molecular Medicine,Oxford,United Kingdom
(Abstract release date: 05/18/17) EHA Library. Craddock C. 06/25/17; 182078; S791
Prof. Charles Craddock
Prof. Charles Craddock
Contributions
Abstract

Abstract: S791

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:30 - 08:45

Location: Room N101

Background

Azacitidine (AZA) represents an important therapeutic advance in patients with acute myeloid leukaemia (AML) and high risk myelodysplasia (MDS) ineligible for intensive chemotherapy. However disease progression appears inevitable and a number of strategies aimed at improving outcome, including co-administration of histone deacetylase inhibitors such as vorinostat (VOR), have been proposed. Leukaemic stem/progenitor cells (LSC) have been postulated to represent a reservoir of resistant disease but the impact of AZA based therapy on LSC numbers has not been studied. An additional factor limiting the rational use of AZA based therapy in AML and MDS is imprecision in the identification of patients likely to achieve a significant clinical benefit and molecular predictors of outcome would improve the rational utilisation of thsi important new agent. 

Aims

We wished to study the impact of AZA based therapy on LSC numbers aswell as identify molecular predictors of outcome in patients treated on the recently completed UK Trials Acceleration Programme RAVVA randomised Phase II trial which compared AZA monotherapy with AZA/VOR combination therapy.

Methods

The RAVVA trial randomized 259 adults with AML (n=217) and MDS (n=42) to receive AZA monotherapy (AZA (75 mg/m2) x 7 days every 28 days) or AZA combined with VOR (300 mg bd days 3-9) po for a minimum of 6 cycles. Next generation sequencing was performed on 42 genes commonly mutated in AML and MDS in 250 patients treated on the RAVVA trial and correlated with response. Separately serial immunophenotypic quantitation of leukaemic stem/progenitor cells (LSC) was performed in 44 patients. 

Results
Co-administration of VOR did not increase overall survival (OS) (1 year OS AZA 43% versus 41% p=0.32) as previously reported (Blood 2016 Absract No 1065). The mean number of mutations per patient in the 250 genotyped patients was 3.4. The presence of mutations in CDKN2A (p=0.0001), IDH1 (p=0.004) and TP53 (p=0.003), NPM1 (p=0.037) and FLT3-ITD (p=0.04) were associated with reduced OS in univariate analysis. In multivariate analysis adjusted for all clinical variables mutations in CDKN2A, IDH1 and TP53 remained predictive of decreased OS. No mutations were associated with improved OS. The presence of ASXL1 (p=0.035) and ETV6 (p=0.033) mutations were found to be associated with a reduced duration of response. AZA based therapy had no significant impact on LSC numbers in patients who failed to achieve a CR. LSC numbers were reduced but not eradicated in patients achieving a CR and observed to expand at relapse.

Conclusion
In this, the largest such study reported to date, the demonstration that mutations in CDKN2A, IDH1 and TP53 are associated with a decreased OS in patients treated with AZA not only can inform patient risk stratification but also provides insights into the mechanism of action of AZA. Specifically, the observation that mutations in the cell cycle regulator CDKN2A was associated with a markedly decreased overall survival is consistent with the hypothesis that induction of cell cycle arrest represents at least one of the mechanisms by which AZA exerts an anti-tumour activity. Furthermore our data identify serial quantitation of LSC populations as a potentially important biomarker of response to AZA based therapies which may assist in the evaluation of novel treatment combinations.  

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Molecular markers, Hypomethylation, Epigenetic

Abstract: S791

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:30 - 08:45

Location: Room N101

Background

Azacitidine (AZA) represents an important therapeutic advance in patients with acute myeloid leukaemia (AML) and high risk myelodysplasia (MDS) ineligible for intensive chemotherapy. However disease progression appears inevitable and a number of strategies aimed at improving outcome, including co-administration of histone deacetylase inhibitors such as vorinostat (VOR), have been proposed. Leukaemic stem/progenitor cells (LSC) have been postulated to represent a reservoir of resistant disease but the impact of AZA based therapy on LSC numbers has not been studied. An additional factor limiting the rational use of AZA based therapy in AML and MDS is imprecision in the identification of patients likely to achieve a significant clinical benefit and molecular predictors of outcome would improve the rational utilisation of thsi important new agent. 

Aims

We wished to study the impact of AZA based therapy on LSC numbers aswell as identify molecular predictors of outcome in patients treated on the recently completed UK Trials Acceleration Programme RAVVA randomised Phase II trial which compared AZA monotherapy with AZA/VOR combination therapy.

Methods

The RAVVA trial randomized 259 adults with AML (n=217) and MDS (n=42) to receive AZA monotherapy (AZA (75 mg/m2) x 7 days every 28 days) or AZA combined with VOR (300 mg bd days 3-9) po for a minimum of 6 cycles. Next generation sequencing was performed on 42 genes commonly mutated in AML and MDS in 250 patients treated on the RAVVA trial and correlated with response. Separately serial immunophenotypic quantitation of leukaemic stem/progenitor cells (LSC) was performed in 44 patients. 

Results
Co-administration of VOR did not increase overall survival (OS) (1 year OS AZA 43% versus 41% p=0.32) as previously reported (Blood 2016 Absract No 1065). The mean number of mutations per patient in the 250 genotyped patients was 3.4. The presence of mutations in CDKN2A (p=0.0001), IDH1 (p=0.004) and TP53 (p=0.003), NPM1 (p=0.037) and FLT3-ITD (p=0.04) were associated with reduced OS in univariate analysis. In multivariate analysis adjusted for all clinical variables mutations in CDKN2A, IDH1 and TP53 remained predictive of decreased OS. No mutations were associated with improved OS. The presence of ASXL1 (p=0.035) and ETV6 (p=0.033) mutations were found to be associated with a reduced duration of response. AZA based therapy had no significant impact on LSC numbers in patients who failed to achieve a CR. LSC numbers were reduced but not eradicated in patients achieving a CR and observed to expand at relapse.

Conclusion
In this, the largest such study reported to date, the demonstration that mutations in CDKN2A, IDH1 and TP53 are associated with a decreased OS in patients treated with AZA not only can inform patient risk stratification but also provides insights into the mechanism of action of AZA. Specifically, the observation that mutations in the cell cycle regulator CDKN2A was associated with a markedly decreased overall survival is consistent with the hypothesis that induction of cell cycle arrest represents at least one of the mechanisms by which AZA exerts an anti-tumour activity. Furthermore our data identify serial quantitation of LSC populations as a potentially important biomarker of response to AZA based therapies which may assist in the evaluation of novel treatment combinations.  

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Molecular markers, Hypomethylation, Epigenetic

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