Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group

Abstract

Although <i>FLT3</i> internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) confer an adverse prognosis, co-occurrence with a nucleophosphomin (<i>NPM1</i>) mutation partially improves response and survival outcomes. In contrast, simultaneous <i>NPM1</i> and <i>FLT3</i> tyrosine kinase domain (TKD) mutations were reported to improve response over that of an isolated <i>NPM1</i> mutation in one as yet unverified report. To validate this, we explored the impact of the co-occurrence of <i>FLT3</i>-TKD and <i>NPM1</i> mutations on clinical outcomes. Study populations included 21 patients (8%) with <i>FLT3</i>-TKD⁺<i>NPM1</i>^<i>+</i> mutated, 18 patients (7%) with <i>FLT3</i>-TKD-only-mutated, 117 patients (44%) with <i>NPM1</i>-only-mutated, and 107 patients (41%) with <i>FLT3</i>-ITD⁺<i>NPM1</i>-mutated AML. Compared with <i>NPM1</i>^<i>+</i> -only-mutated AML, <i>FLT3</i>-TKD/<i>NPM1</i> double mutation status was associated with a significantly superior relapse-free survival (median, not reached vs 18.3 months; <i>P</i> = .03) and a trend toward improved overall survival (OS). The presence of <i>FLT3</i>-TKD/<i>NPM1</i> double mutation status was an independent positive predictor in multivariable analysis. Allogeneic stem cell transplant did not improve outcomes in the <i>FLT3</i>-TKD/<i>NPM1</i> 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 <i>FLT3</i>-TKD and <i>NPM1</i> in future molecular and murine model studies.