Contributions
Abstract: S791
Type: Oral Presentation
Presentation during EHA22: On Sunday, June 25, 2017 from 08:30 - 08:45
Location: Room N101
Background
Aims
Methods
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
Aims
Methods
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