DNMT3A,   IDH1/2,  General AML,  FLT3,  NPM1,  TET2

Response to HMAs in AML patients harboring mutations in DNMT3, IDH1/2 and/or TET2 – Retrospective analysis of a MSKCC/MCC cohort

Response to HMAs in AML patients harboring mutations in DNMT3A, IDH1/2 and/or TET2 – Retrospective analysis of a MSKCC/MCC cohort

Evidence from small retrospective studies suggests that harbor mutations in genes affecting DNA-methylation may have therapeutic implications in de novo Acute Myeloid Leukemia (AML). Following on from these findings C. C. Coombs, et al., conducted a dual institution (MSKCC and MCC) retrospective study in order to ascertain the relationship between the response to hypomethylating agents (HMAs) in patients with AML with respect to the presence or absence of mutations in DNMT3A, IDH1/2 and/or TET2.

The retrospective study was conducted in two parts, first, a MSKCC and MCC combined cohort was analyzed. Then, this combined cohort was compared with previously published cohorts. Patients treated in a frontline setting with DNMT3A mutation status, with IDH1/2 mutation status, and with TET2 mutation status were reviewed in this second analysis. To date, this is believed to be the largest dataset assembled to evaluate the impact of mutations in epigenetic modifiers in AML patients treated with HMAs. The results were published in Haematologica in July 2016.

Key results from the MSKCC and MCC cohort n= 83:
  • DNMT3A mutation: of the 83 patients, 45 patients were treated in a frontline setting, and there was a 60% CR (CR + CRi) rate in patients with the DNMT3A mutation compared to a 33% CR rate in patients with wild-type DNMT3A. However, these values were not statistically significant owing to the sample size.
  • IDH1/2 mutation: patients with IDH1/2 mutations had a higher CR rate compared to patients with wild-type IDH1/2 (60% vs 29%, Odds Ratio [OR] 3.67; p= 0.08).
  • TET2 mutation: no correlation was observed between TET2 mutation status and response to treatment (18% CR rate in TET2 mutants vs 41% in wild-type TET2, OR 0.33; p= 0.195)

There were not any statistically significant associations observed for all the 83 patients in the frontline versus relapsed refractory settings 

Key results from the pooled analyses of the MSKCC/MCC cohort and previously published cohorts n= 588
  • Presence of DNMT3A mutation was significantly associated with achievement of a CR (57% vs 29%, OR 3.12 [1.63-5.94] with P = 0.001) in the 1st-line setting.
  • There was a higher CR rate in 1st line and in R/R patients with mutations in both DNMT3A and NPM1 compared to patients without the co-mutation; 73% compared to 21% respectively (OR 2.82 [1.33-6.00] with P = 0.007).

In conclusion, despite the heterogeneity of the assembled data sets, it is clear that there was a significantly higher CR rate in AML patients harboring DNMT3A mutations treated with HMAs in the frontline setting.

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  1. Coombs C.C, et al. Mutational Correlates of Response to Hypomethylating Agent Therapy in Acute Myeloid Leukemia. Haematologica. 2016 Jul 14. DOI: 10.3324/haematol.2016.148999. [Epub ahead of print]
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