For FLT3-Mutated AML Patients, Midostaurin Added to Chemotherapy Improved Survival

Patients with FLT3-mutated acute myeloid leukemia (AML) have poor prognosis, a high chance of relapse, and a limited number of treatment options. Research presented at this year’s ASH Annual Meeting suggests that adding the investigational FLT3 inhibitor midostaurin to standard, “7+3” chemotherapy, followed by one year of maintenance therapy, improves event-free survival (EFS) and overall survival (OS), compared with standard chemotherapy alone.

“This trial is the first step in applying the theories of personalized medicine to patients with AML,” said Richard M. Stone, MD, from the Department of Medical Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts. Patients with the FLT3 mutation, he added, “are likely to benefit from the addition of this targeted agent, midostaurin, to standard chemotherapy.”

In the randomized, phase III RATIFY trial (the largest clinical trial in FLT3-mutated AML conducted to date), 717 patients (median age = 48 years; range = 18-60 years) were randomized to receive either midostaurin (n=360) or placebo (n=357). There were no significant differences between the two groups in terms of age, race, FLT3 subtype, or baseline complete blood cell count.

The induction therapy protocol was: daunorubicin (60 mg/m2) on days 1-3, cytarabine (200 mg/m2) on days 1-7, and either midostaurin or placebo administered orally at a dose of 50 mg twice-daily on days 8-22.

Re-treatment with a second course was allowed if residual AML was noted on a marrow exam performed on day 21, and patients achieving complete remission (CR) received up to four cycles of cytarabine (3 g/m2) every 12 hours on days 1, 3, and 5 plus midostaurin or placebo (50 mg) twice-daily on days eight through 22. Patients then received one year of maintenance therapy with midostaurin or placebo (50 mg) twice-daily.

“The final analysis was to occur after 509 deaths, but given the slow rate of events (359 deaths by April 2015), the trial was amended to change the timing of the OS analysis and promote event-free survival (EFS) as a key secondary endpoint,” Dr. Stone noted. EFS was defined as the earliest of death, relapse, or no CR within 61 days of the start of induction therapy.
After a median follow-up of 57 months, the complete remission rate was 59 percent in the midostaurin group, compared with 54 percent in the placebo group (p=0.18).

Patients receiving midostaurin had significantly longer median OS than those receiving placebo: 74.7 months versus 25.6 months (p=0.0076). As seen in TABLE, midostaurin also more than doubled the median EFS achieved with placebo. However, for both outcomes, medians were exaggerated because survival curves hovered around 50 percent. The five-year event rate was 50.8 percent for those treated with midostaurin and 43.1 percent for those receiving placebo (hazard ratio = 0.77).

The safety profile was similar between both groups; the researchers did not observe a significant difference in the rate of grade ≥3 hematologic or non-hematologic adverse events. Patients experienced a total of 37 grade 5 adverse events (5.3% in the midostaurin group and 5% in the placebo group).

“This is very much a real-world trial,” Dr. Stone commented, with 57 percent of patients undergoing allogeneic hematopoietic cell transplantation (AlloHCT) during the study. The survival rates were similar regardless of AlloHCT (TABLE), suggesting that patients could potentially avoid having a transplant.

The survival curves, however, did not separate until about six months after treatment initiation. Also, complete remission by day 60 was slightly higher among midostaurin-treated patients, but similar between both arms (59% and 53%).

Dr. Stone noted other areas where midostaurin could be investigated, including older patients with AML and younger adults with wild-type FLT3-mutated AML. “Because midostaurin is a multi-kinase inhibitor, it may work in other subsets of patients with AML.”

The trial both proved the concept that targeting FLT3 in AML patients improves survival and that persistence in clinical research pays off. “The trial took 10 years to conceive, conduct, and analyze,” Dr. Stone said. “RATIFY shows that is feasible to do this kind of trial, with a lot of collaboration [between academic and pharmaceutical partners], cooperation, and persistence.”


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]). Abstract #6. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida.

TABLE. Efficacy Outcomes for Midostaurin Versus Placebo
  Arm Median, months (95% CI) p Value 5-Year Event Rate, % (95% CI) HR (95% CI)
Overall survival Midostaurin 74.7 (31.5-NA) 0.007 50.8 (45.4-55.9) 0.77 (0.63-0.95)
Placebo 26.0 (18.5-46.5) 43.1 (37.6-48.4)
Overall survival (Allo–HCT censored) Midostaurin NA 0.047 62.6 (54.6-69.7) 0.77 (0.56-1.05)
Placebo NA (36.9-NA) 54.9 (46.2-62.8)
Event-free survival Midostaurin 8.0 (5.3-10.6) 0.0044 26.7 (22.2-31.5) 0.80 (0.67-0.95)
Placebo 3.0 (1.9-5.8) 19.1 (15.1-23.6)
Event-free survival (Allo–HCT censored) Midostaurin 8.2 (5.5-10.7) 0.025 24.2 (18.9-29.8) 0.84 (0.70-1.00)
Placebo 3.0 (1.9-5.8) 21.8 (16.8-27.3)
NA = Not attained