| Summary: | Recently, a new subset of acute myeloid leukemia (AML) presenting a direct partial tandem duplication (PTD) of the <i>KMT2A</i> gene was described. The consequences of this alteration in terms of outcome and response to treatment remain unclear. We analyzed retrospectively a cohort of <i>KMT2A-PTD</i>-mutated patients with newly diagnosed AML. With a median follow-up of 3.6 years, the median overall survival was 12.1 months. <i>KMT2A-PTD</i>-mutated patients were highly enriched in mutations affecting epigenetic actors and the <i>RTK/RAS</i> signaling pathway. Integrating <i>KMT2A-PTD</i> in ELN classification abrogates its predictive value on survival suggesting that this mutation may overcome other genomic marker effects. In patients receiving intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) significantly improved the outcome compared to non-transplanted patients. In the multivariate analysis, only HSCT at any time in complete remission (HR = 2.35; <i>p</i> = 0.034) and <i>FLT3-ITD</i> status (HR = 0.29; <i>p</i> = 0.014) were independent variables associated with overall survival, whereas age was not. In conclusion, our results emphasize that <i>KMT2A-PTD</i> should be considered as a potential adverse prognostic factor. However, as <i>KMT2A-PTD</i>-mutated patients are usually considered an intermediate risk group, upfront HSCT should be considered in first CR due to the high relapse rate observed in this subset of patients.
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