ORLANDO ­– The addition of midostaurin, a multi-targeted small molecular FLT3 inhibitor, to standard chemotherapy and for 1 year of maintenance therapy significantly improved event-free and overall survival in patients with internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutant FLT3 acute myeloid leukemia (AML).1

“Activating mutations of FLT3 are detectable in about 30% of AML cases at diagnosis,” Mark J. Levis, MD, PhD, of Johns Hopkins School of Medicine in Baltimore, MD, said during his introduction of Stone et al’s plenary session presentation. “There is growing consensus to consolidate with allogeneic stem cell transplantation.”

“Midostaurin is a multi-kinase inhibitor, which probably limits its potency against FLT3, but it is active against both ITD and TKD mutations,” Dr Levis noted.

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“Midostaurin 50 mg orally twice daily given for 14 days was safely combined with chemotherapy in patients with newly diagnosed AML in a phase 1/2 trial, which provided encouraging results,” Richard M. Stone, hematologist/medical oncologist at Dana-Farber Cancer Institute in Boston, MA, said during the plenary session at the American Society of Hematology (ASH) 57th Annual Meeting

For the global phase 3 RATIFY trial, researchers sought to evaluate whether adding midostaurin to induction and consolidation therapy followed by 1 year of maintenance would improve overall survival compared with standard chemotherapy in younger adults with activating FLT3 mutations. Researchers enrolled 717 previously untreated patients with AML and randomly assigned them to midostaurin or placebo plus chemotherapy. Of those, 81% were FLT3-positive. Arms were well-balanced for age and FLT3 mutation subtype.

Results showed that the complete remission rate was 59% with midostaurin and 53% with placebo (P = .15). Median overall survival was 74.7 months (95% CI, 31.7 – not attainable) with midostaurin vs 25.6 months (95% CI, 18.6 – 42.9) with placebo (HR, 0.77; P = .0074). Median 5-year event-free survival was 8.0 months (95% CI, 5.1 – 10.6) and 3.0 months (95% CI, 1.9 – 5.8), respectively (HR, 0.79; P = .0025).

Researchers observed a consistent effect by midostaurin on overall survival and event-free survival by FLT3 mutation status.

“Overall survival and event-free survival benefit was consistent in uncensored as well as censored analyses, despite high stem cell transplantation rate,” Dr Stone noted.

In regard to safety, there was no statistically significant difference in the overall rate of grade 3 or higher hematologic or non-hematologic adverse events between the 2 treatment arms. There was a higher incidence of rash in the midostaurin arm, however.

”Midostaurin…improves overall survival when added to standard chemo with 1-year maintenance in newly diagnosed patients aged 18 to 60 years with ITD and TKD FLT3 mutant AML and represents a new standard of care,” Dr Stone concluded. “The drug should be tested beyond the FLT3 mutant patients.”


1. Stone RM, Mandrekar S, Sanford BL, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations (muts): An international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL.