| Summary: | Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). <i>DNMT3A</i> mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of <i>DNMT3A</i> status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for <i>NPM1</i>-mutated AML in two French institutions were analyzed retrospectively. <i>DNMT3A</i> status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of <i>FLT3-ITD</i> patients reached ≥ 4log MRD1 reduction compared to 47.5% in <i>FLT3</i>wt cases. A 4log reduction of <i>NPM1</i> MRD was associated with a better outcome, even in <i>FLT3-ITD</i> mutated patients, independent of the allelic ratio. <i>DNMT3A</i> negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23; <i>p</i> < 0.001). However, postinduction <i>NPM1</i> MRD1 reduction was not predictive of OS and LFS in <i>DNMT3A</i>mut patients. These results confirm that post-induction <i>NPM1</i> MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of <i>DNMT3A</i> also identifies a subgroup of patients at high risk of relapse.
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