II. Indications
-
Acute Myelogenous Leukemia (FLT3+ new or advanced/refractory)
- Gilteritinib (Xospata)
- Midostaurin (Rydapt)
- Severe Systemic Mastocytosis
- Midostaurin (Rydapt)
III. Mechanism
- FLT3 Tyrosine Kinase (FMS-like Tyrosine Kinase 3)
- Tyrosine Kinase Receptor
- Regulates the survival and proliferation of hematopoietic stem cells and progenitor cells
- FLT3 Mutations
- FLT3 mutations are found in one third of Acute Myelogenous Leukemia cases
- FLT3 Inhibitors
- FLT3 Inhibitors suppress only peripheral AML progenitor cells (blasts), NOT marrow cells
IV. Medications
- Gilteritinib (Xospata)
- Risk of differentiation syndrome, PRES, Prolonged QTc, Pancreatitis
- Midostaurin (Rydapt)
- Crenolanib
- Orally benzimidazole small molecule agent
- Active against FLT3 (FMS-like Tyrosine Kinase 3)
- Active against Platelet-derived growth factor receptor (PDGFR, alpha and beta)
V. Dosing
- See other references for disease specific dosing protocols
VI. Safety
- Avoid in Lactation
- Avoid Breast Feeding for 2 months after Gilteritinib
- Avoid in pregnancy (all trimesters, pregnancy category X)
- Use reliable Contraception
- Monitoring
VII. Adverse Effects
- Differentiation Syndrome (Gilteritinib)
- Life threatening condition, rapid myeloid cell proliferation and differentiation
- May present with acute respiratory distress, Acute Kidney Injury, fever, edema
- Onset in the first 10 weeks of therapy requiring prompt initiation of Corticosteroids
- Posterior Reversible Encephalopathy Syndrome or PRES (Gilteritinib)
- Prolonged QTc (Gilteritinib, Midostaurin)
- Acute Pancreatitis (Gilteritinib)
- Interstitial Lung Disease (Midostaurin)
- Other reported adverse effects
- Hepatotoxicity
- Rash
- Vomiting
VIII. Drug Interactions
- Strong CYP3A4 Inhibitor and Inducers
- Avoid with Gilteritinib and Midostaurin
-
Medication Causes of QTc Prolongation
- Avoid with Gilteritinib and Midostaurin