Enrolled patients were randomly assigned, in a 1:1 ratio, to receive standard chemotherapy plus either midostaurin or placebo. Randomization was performed with a block size of 6 and was stratified according to the subtype of FLT3 mutation: TKD, or ITD with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively).
Therapy consisted of induction therapy with daunorubicin (at a dose of 60 mg per square meter of body-surface area per day, administered by rapid intravenous injection on days 1, 2, and 3) and cytarabine (at a dose of 200 mg per square meter, administered by continuous intravenous infusion on days 1 through 7). Midostaurin or placebo was administered in a double-blind fashion, at a dose of 50 mg orally twice daily, on days 8 through 21. Midostaurin or placebo was not administered if the patient had a corrected QT interval above 500 msec or a grade 3 or 4 non-hematologic toxic effect (for further details, see theSupplementary Appendix ). A missed dose of midostaurin or placebo was not made up. A bone marrow examination was to be performed on day 21. If there was definitive evidence of clinically significant residual leukemia, a second cycle of induction therapy that was identical to the first, including midostaurin or placebo, was administered.
Patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy with high-dose cytarabine (at a dose of 3000 mg per square meter, administered over a period of 3 hours every 12 hours on days 1, 3, and 5). Midostaurin or placebo was administered at a dose of 50 mg orally twice daily on days 8 through 21. Patients who remained in remission after completion of consolidation therapy entered a maintenance phase in which they received midostaurin or placebo, administered at a dose of 50 mg orally twice daily, for twelve 28-day cycles. Complete remission was defined as the presence of less than 5% blasts in the marrow or extramedullary leukemia, an absolute neutrophil count of more than 1000 per microliter, a platelet count of more than 100,000 per microliter, and the absence of blasts in the peripheral blood; in addition, per protocol, the complete remission had to have occurred by day 60. Transplantation was not mandated in the protocol but was performed at the discretion of the investigator.
Therapy consisted of induction therapy with daunorubicin (at a dose of 60 mg per square meter of body-surface area per day, administered by rapid intravenous injection on days 1, 2, and 3) and cytarabine (at a dose of 200 mg per square meter, administered by continuous intravenous infusion on days 1 through 7). Midostaurin or placebo was administered in a double-blind fashion, at a dose of 50 mg orally twice daily, on days 8 through 21. Midostaurin or placebo was not administered if the patient had a corrected QT interval above 500 msec or a grade 3 or 4 non-hematologic toxic effect (for further details, see the
Patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy with high-dose cytarabine (at a dose of 3000 mg per square meter, administered over a period of 3 hours every 12 hours on days 1, 3, and 5). Midostaurin or placebo was administered at a dose of 50 mg orally twice daily on days 8 through 21. Patients who remained in remission after completion of consolidation therapy entered a maintenance phase in which they received midostaurin or placebo, administered at a dose of 50 mg orally twice daily, for twelve 28-day cycles. Complete remission was defined as the presence of less than 5% blasts in the marrow or extramedullary leukemia, an absolute neutrophil count of more than 1000 per microliter, a platelet count of more than 100,000 per microliter, and the absence of blasts in the peripheral blood; in addition, per protocol, the complete remission had to have occurred by day 60. Transplantation was not mandated in the protocol but was performed at the discretion of the investigator.
