Although FLT3 internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) confer an adverse prognosis, co-occurrence with a nucleophosphomin (NPM1) mutation partially improves response and survival outcomes. In contrast, simultaneous NPM1 and FLT3 tyrosine kinase domain (TKD) mutations were reported to improve response over that of an isolated NPM1 mutation in one as yet unverified report. To validate this, we explored the impact of the co-occurrence of FLT3-TKD and NPM1 mutations on clinical outcomes. Study populations included 21 patients (8%) with FLT3-TKD1NPM11 mutated, 18 patients (7%) with FLT3-TKD-only-mutated, 117 patients (44%) with NPM1-only-mutated, and 107 patients (41%) with FLT3-ITD1NPM1-mutated AML. Compared with NPM11-only-mutated AML, FLT3-TKD/NPM1 double mutation status was associated with a significantly superior relapse-free survival (median, not reached vs 18.3 months; P 5 .03) and a trend toward improved overall survival (OS). The presence of FLT3-TKD/NPM1 double mutation status was an independent positive predictor in multivariable analysis. Allogeneic stem cell transplant did not improve outcomes in the FLT3-TKD/NPM1 cohort. Consistent with historical data, the co-mutation status defined a highly favorable prognostic group characterized by high response rates and prolonged disease-free and OS. These study findings substantiate previous data describing this intriguing paradoxical cooperative effect. Our results emphasize the need for elucidating the mechanistic links between FLT3-TKD and NPM1 in future molecular and murine model studies.
|Original language||English (US)|
|Number of pages||5|
|State||Published - Aug 22 2017|
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