Fludarabine, High-Dose Cytarabine and Idarubicin-Based Induction May Overcome the Negative Prognostic Impact of FLT3-ITD in NPM1 Mutated AML, Irrespectively of FLT3-ITD Allelic Burden

SIMPLE SUMMARY: The prognostic relevance of molecular aberrations in acute myeloid leukemia (AML) has been prevalently tested in patients receiving conventional 3+7 induction. Recently, there has been a renewed interest in intensified inductions, but very few data are available on the impact of the most frequent genetic alterations with these alternative treatments. We analyzed a large multicentric cohort of younger AML patients harboring NPM1 and FLT3-ITD mutations receiving an intensified fludarabine-containing regimen (FLAI). Our data suggest that in NPM1 mut patients, FLAI may overcome the prognostic influence of co-mutated FLT3-ITD. The increased efficacy of this treatment seems to reduce the need for early consolidation with allogeneic transplant in double-mutated patients. Our data strongly support FLAI as an ideal backbone for combination with innovative targeted drugs, in order to further improve patients’ outcome. ABSTRACT: The mutations of NPM1 and FLT3-ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an NPM1 mutation reduces the negative prognostic impact of FLT3-ITD in patients treated with conventional “3+7” induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the NPM1 and/or FLT3-ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both NPM1mut (p < 0.05) and ELN 2017 risk score (p < 0.05) were significant predictors of survival. NPM1-mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant FLT3-ITD (p = 0.372), irrespective of FLT3-ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with NPM1mut and question the role of HSCT in 1st CR in NPM1mut patients with concomitant FLT3-ITD.