June 23, 2017
3 min read

Midostaurin extends survival in acute myeloid leukemia with FLT3 mutation

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The addition of midostaurin to standard chemotherapy improved OS and EFS among patients with acute myeloid leukemia and FLT3 mutation, according to results of the RATIFY clinical trial.

Based in part on these results — published in The New England Journal of Medicine to coincide with the European Hematology Association Congress in Madrid — the FDA approved midostaurin (Rydapt, Novartis) as part of combination treatment for adults with newly diagnosed FLT3–positive AML in April.

Richard M. Stone

“We determined that midostaurin, a multitargeted kinase inhibitor, led to improved outcomes among younger adults with AML and a FLT3 mutation, a population with a poor prognosis that represents approximately one fourth of all patients with AML,” Richard M. Stone, MD, clinical director of the adult leukemia program at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, and colleagues wrote.

Midostaurin — a small molecule FLT3 inhibitor originally developed as a protein kinase C inhibitor for the treatment of solid tumors — showed efficacy in phase 1 trials when added during courses of induction and consolidation chemotherapy, especially among patients with FLT3 mutation.

Approximately 8% of patients with newly diagnosed AML harbor a FLT3 mutation in the tyrosine kinase domain.

Stone and colleagues sought to determine whether the addition of midostaurin to standard therapy would improve OS in younger adult patients with FLT3–mutated AML.

The researchers screened 3,277 patients aged 18 to 59 years with previously untreated AML from 225 clinical sites for FLT3 mutation. Of these, 896 had FLT3 mutation, 717 (median age, 47.9 years; range, 18-60.9) of whom researchers enrolled in the trial.

Researchers stratified patients according to FLT3 mutation subtype, defined by point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) with high or low ratio of mutant to wild-type alleles (FLT3 ITD-low, n = 341; FLT3 ITD-high, n = 214; FLT3 TKD, n = 162).

Patients received induction chemotherapy with IV daunorubicin (60 mg/m2 on days 1-3) and cytarabine (200 mg/m2 on days 1-7) plus 50 mg midostaurin (n = 360) or placebo (n = 357) twice daily on days 8 through 22.

Age, race and FLT3 subtype appeared comparable in the midostaurin and placebo groups. However, the midostaurin arm contained fewer women (51.7% vs. 59.4%; P = .04).

More patients in the placebo group received a second course of induction therapy (n = 101 vs. n = 81).


Thirty-eight patients discontinued treatment immediately after achieving complete remission due to receipt of alternative therapy, early disease progression, adverse event, patient withdrawal from trial or other reasons.

More patients in the midostaurin group received a maintenance regimen (n = 120) than patients in the placebo group (n = 85); 120 patients overall received a full 12 cycles (midostaurin, n = 69; placebo, n = 51).

Median follow-up for surviving patients was 59 months.

Patients assigned midostaurin achieved longer median OS than the placebo group (74.7 months vs. 25.6 months; HR for death = 0.78; 95% CI, 0.63-0.96).

Researchers reported rates of 4-year OS of 51.4% in the midostaurin group and 44.3% in the placebo group.

A total 536 events occurred — 298 failures to achieve complete remission, 181 relapses and 57 deaths without relapse.

Patients assigned midostaurin demonstrated longer median EFS (8.2 months vs. 3 months) and appeared 21.6% less likely to experience an event (HR = 0.78; 95% CI, 0.66-0.93).

The OS and EFS benefit of midostaurin extended across all FLT3 subgroups in the primary analysis and an analysis that censored data from patients who underwent transplantation.

The occurrence of adverse events appeared similar between the groups. More patients in the midostaurin group experienced grade 3 to grade 5 anemia (92.7% vs. 87.8%; P = .03) and rash (14.1% vs. 7.6%; P = .008), but nausea occurred in more patients in the placebo group (9.6% vs. 5.6%; P = .05).

“It remains unclear whether agents with different target profiles, including more specific FLT3 inhibitors, would also improve outcomes if they were added to usual therapy for younger adults with AML and a FLT3 mutation and whether chemotherapy plus midostaurin might be beneficial for older adults or those with wild-type FLT3,” the researchers wrote. – by Melinda Stevens

Disclosure: Stone reports personal fees and other support from AbbVie, Agios, Amgen, Argenix, Arog, Astellas, Bristol-Myers Squibb, Celator, Celgene, Cornerstone, Daichi Sankyo, Fujifilm, Jazz Pharmaceuticals, Jannssen, Juno, Karyopharm, Merck, Novartis, Ono, Orsenix, Pfizer, Seattle Genetics, Sumitomo and Sunesis. Please see the full study for a list of all other researchers relevant financial disclosures.