midostaurin — Drug Monograph

Brand names: Rydapt

Drug class: FLT3 Inhibitor

Mechanism of Action

Midostaurin is a multi-targeted kinase inhibitor with activity against FLT3 (both FLT3-ITD and FLT3-TKD mutations), KIT (including D816V), PDGFR-α/β, VEGFR2, and protein kinase C (PKC) isoforms. By inhibiting FLT3-mediated signaling, it suppresses RAS/MAPK and STAT5 pathways in FLT3-mutated AML blast cells. KIT D816V inhibition underlies its activity in systemic mastocytosis, where constitutively activated KIT drives mast cell accumulation in bone marrow and organs.

FDA Indications

• Newly diagnosed FLT3-mutated (ITD or TKD) AML in adults, in combination with standard induction (cytarabine + daunorubicin "7+3") and consolidation chemotherapy — approved Apr 2017 (RATIFY trial)
• Advanced systemic mastocytosis (AdvSM) including aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL) — approved Apr 2017 (CPKC412D2201 trial)

Common Side Effects

• Nausea (~83% in SM)
• Vomiting (~68% in SM)
• Diarrhea (~54% in SM)
• Febrile neutropenia (AML)
• Mucositis / stomatitis
• Headache
• Petechiae
• Upper respiratory infections
• Fatigue
• Edema
• Hyperglycemia
• Elevated LFTs
• QTc prolongation

Clinical Pearl

In the RATIFY trial, midostaurin added to standard 7+3 induction improved 4-year overall survival (51.4% vs 44.3%) in newly diagnosed FLT3-mutated AML, establishing it as a standard component of induction despite its modest single-agent FLT3 inhibitory potency. Unlike second-generation agents, midostaurin is used exclusively in the frontline chemotherapy-combination setting and is not continued as maintenance post-transplant. The 100 mg BID dose for systemic mastocytosis is higher than the AML…

Related Therapies & Mechanisms

• Gilteritinib (Xospata) — FLT3 Inhibitor · Leukemia
• Quizartinib (Vanflyta) — FLT3 Inhibitor · Leukemia
• Acalabrutinib (Calquence) — Leukemia
• Alemtuzumab (Campath) — Leukemia