Background
Phase III RCT enrolling 717 patients aged 18-59 with newly diagnosed, non-therapy-related AML harboring FLT3 mutation (ITD 77%, TKD 22.7%), randomized 1:1 to test the addition of midostaurin to chemotherapy.
Interventions and follow up
Arm A: 7+3 induction (cytarabine 200mg/m2 IV x7d + daunorubicin 60mg/m2 daily x3d) + midostaurin 50mg PO BID days 8-21; high-dose cytarabine consolidation 3000mg/m2 IV BID days 1,3,5 + midostaurin; then midostaurin maintenance q28d x12 cycles; transplant per investigator discretion
Arm B: Same chemotherapy + placebo
Primary endpoint: Overall survival
mFollow up: 59mo
Arm B: Same chemotherapy + placebo
Primary endpoint: Overall survival
mFollow up: 59mo
Results
mOS: 74.7mo vs 25.6mo, arm A vs B; HR 0.78, 95%CI 0.63–0.96; P=.009
4-yr OS: 51.4% vs 44.3%, arm A vs B
mEFS: 8.2mo vs 3.0mo, arm A vs B; HR 0.78, 95%CI 0.66–0.93; one-sided P=.002
Complete remission (by day 60): 58.9% vs 53.5%, P=.15 (CR defined as BM blasts <5%, ANC>1,000, PLT>100K, no peripheral blasts)
4-yr OS: 51.4% vs 44.3%, arm A vs B
mEFS: 8.2mo vs 3.0mo, arm A vs B; HR 0.78, 95%CI 0.66–0.93; one-sided P=.002
Complete remission (by day 60): 58.9% vs 53.5%, P=.15 (CR defined as BM blasts <5%, ANC>1,000, PLT>100K, no peripheral blasts)
Adverse events
Hematologic/cytopenias: Grade 3-4 anemia 92.7% vs 87.8%, P=.03; median time to ANC recovery 26d vs 26d; median time to PLT recovery 21d vs 21d
Non-hematologic: Grade 3-4 rash 14.1% vs 7.6%, P=.008; nausea 9.6% vs 5.6%, P=.05; midostaurin/placebo withheld if QTc >500ms or grade 3-4 nonhematologic AE
Non-hematologic: Grade 3-4 rash 14.1% vs 7.6%, P=.008; nausea 9.6% vs 5.6%, P=.05; midostaurin/placebo withheld if QTc >500ms or grade 3-4 nonhematologic AE
Conclusions
Adding midostaurin to standard chemotherapy and as maintenance reduced the risk of death by 22% in younger adults with FLT3-mutated AML, establishing FLT3 inhibition as a component of first-line therapy.
Key Limitations
Restricted to patients aged 18-59 (younger fit population); transplant performed at investigator discretion, introducing heterogeneity; trial not powered for FLT3-subtype-specific survival; OS curves influenced by post-trial transplant.
Clinical Context
Led to FDA/EMA approval of midostaurin combined with 7+3 induction/consolidation for newly diagnosed FLT3-mutated AML. ELN guidelines recommend incorporating a FLT3 inhibitor into induction for FLT3-mutated AML; allogeneic transplant remains standard for eligible patients in first remission.