Adding midostaurin — a multi-targeted kinase inhibitor — to chemotherapy prolongs overall survival (OS) among patients with newly diagnosed acute myeloid leukemia (AML) and an FLT3 mutation, according to a study published in the New England Journal of Medicine.1

FLT3 mutations are associated with poor outcomes among patients with AML. The purpose of this trial was to determine if midostaurin plus chemotherapy can improve outcomes.

The multicenter, double-blind, phase 3 RATIFY trial ( Identifier: NCT00651261) randomly assigned 717 patients aged 18 to 59 with newly diagnosed AML with an FTL3 mutation to receive chemotherapy plus midostaurin or placebo.

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The chemotherapy regimen included induction with daunorubicin and cytarabine, and consolidation with high-dose cytarabine. Patients who achieved complete remission after consolidation therapy received maintenance therapy with midostaurin or placebo.

The median age at baseline was 47.9, 68.6% of patients had normal risk disease, and 19% had intermediate II risk disease according to the Modified European LeukemiaNet classification. FLT3 mutations were located within the tyrosine kinase domain (TKD) in 22.6% of patients, or was an internal tandem duplication with low or high allelic ratio in 47.6% and 29.8%, respectively.

The addition of midostaurin significantly prolonged median OS at 74.7 months (95% CI, 31.5-not reached) compared with 25.6 months (95% CI, 18.6-42.9) with placebo (hazard ratio [HR], 0.78; 95% CI, 0.63-0.96; one-sided P = .009), resulting in 4-year OS rates of 51.4% and 44.3%, respectively.

Event-free survival was also significantly longer, at 8.2 months (95% CI, 5.4-10.7) with midostaurin compared with 3.0 months (95% CI, 1.9-5.9) with placebo (HR, 0.78; 95% CI, 0.66-0.93; one-sided P = .002). The midostaurin and placebo arms demonstrated 4-year EFS rates of 28.2% and 20.6%, respectively.

There was, however, no significant difference in the proportion of patients who achieved complete remission between the midostaurin and placebo groups (59% vs. 54%; P = .15).

During the trial, 57% of patients underwent allogeneic transplantation. Benefit with midostaurin “was observed among those who underwent transplantation during first remission, but not among those who underwent transplantation at a later time,” the authors wrote.

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Adverse events that occurred more frequently with midostaurin compared with placebo were anemia and rash or desquamation.

According to the authors, the results of this study suggest that midostaurin improved outcomes “among younger adults with AML and a FLT3 mutation, a population with a poor prognosis that represents about one-fourth of all patients with AML.”


  1. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017 Jun 23. doi: 10.1056/NEJMoa1614359 [Epub ahead of print]