Midostaurin

Mechanism:

A multi-targeted kinase inhibitor that primarily blocks FLT3 (FMS-like tyrosine kinase 3), along with KIT, PDGFR, and VEGFR.

Approval: FDA-approved for:

• FLT3-mutated AML (in combination with chemotherapy for newly diagnosed patients).
• Aggressive systemic mastocytosis (ASM).

Key Features in AML

• Target Population:
• • Newly diagnosed FLT3-mutated AML (both FLT3-ITD and FLT3-TKD).
  • Used in induction, consolidation, and maintenance (with chemotherapy).
• Combination Therapy:
• • Given with standard 7+3 induction (cytarabine + daunorubicin) and high-dose cytarabine consolidation.
  • Continued as maintenance therapy in eligible patients.
• Efficacy:
• • Improves overall survival (OS) and event-free survival (EFS) vs. chemo alone.
  • Landmark trial (RATIFY): Median OS = 74.7 months (vs. 25.6 months with placebo + chemo).

Mechanism of Action

• Inhibits FLT3 signaling → blocks proliferation and survival of leukemia cells.
• Also targets KIT (relevant in core-binding factor AML) and other kinases.

Side Effects

• Myelosuppression (neutropenia, anemia, thrombocytopenia).
• GI effects (nausea, vomiting, diarrhea).
• Pulmonary toxicity (rare but serious; monitor for pneumonitis).

Key Takeaways

• First FLT3 inhibitor approved for AML (now standard of care in FLT3-mutated AML).
• Used with chemotherapy, not as monotherapy.
• Gilteritinib (a next-gen FLT3 inhibitor) is preferred for relapsed/refractory FLT3+ AML