II. Indications

  1. Acute Myelogenous Leukemia (FLT3+ new or advanced/refractory)
    1. Gilteritinib (Xospata)
    2. Midostaurin (Rydapt)
  2. Severe Systemic Mastocytosis
    1. Midostaurin (Rydapt)

III. Mechanism

  1. FLT3 Tyrosine Kinase (FMS-like Tyrosine Kinase 3)
    1. Tyrosine Kinase Receptor
    2. Regulates the survival and proliferation of hematopoietic stem cells and progenitor cells
  2. FLT3 Mutations
    1. FLT3 mutations are found in one third of Acute Myelogenous Leukemia cases
  3. FLT3 Inhibitors
    1. FLT3 Inhibitors suppress only peripheral AML progenitor cells (blasts), NOT marrow cells

IV. Medications

  1. Gilteritinib (Xospata)
    1. Risk of differentiation syndrome, PRES, Prolonged QTc, Pancreatitis
  2. Midostaurin (Rydapt)
    1. Risk of Interstitial Lung Disease, QTc Prolongation
  3. Crenolanib
    1. Orally benzimidazole small molecule agent
    2. Active against FLT3 (FMS-like Tyrosine Kinase 3)
    3. Active against Platelet-derived growth factor receptor (PDGFR, alpha and beta)

V. Dosing

  1. See other references for disease specific dosing protocols

VI. Safety

  1. Avoid in Lactation
    1. Avoid Breast Feeding for 2 months after Gilteritinib
  2. Avoid in pregnancy (all trimesters, pregnancy category X)
    1. Use reliable Contraception
  3. Monitoring
    1. Complete Blood Count
    2. Electrocardiogram (for QTc Prolongation)

VII. Adverse Effects

  1. Differentiation Syndrome (Gilteritinib)
    1. Life threatening condition, rapid myeloid cell proliferation and differentiation
    2. May present with acute respiratory distress, Acute Kidney Injury, fever, edema
    3. Onset in the first 10 weeks of therapy requiring prompt initiation of Corticosteroids
  2. Posterior Reversible Encephalopathy Syndrome or PRES (Gilteritinib)
  3. Prolonged QTc (Gilteritinib, Midostaurin)
  4. Acute Pancreatitis (Gilteritinib)
  5. Interstitial Lung Disease (Midostaurin)
  6. Other reported adverse effects
    1. Hepatotoxicity
    2. Rash
    3. Vomiting

VIII. Drug Interactions

  1. Strong CYP3A4 Inhibitor and Inducers
    1. Avoid with Gilteritinib and Midostaurin
  2. Medication Causes of QTc Prolongation
    1. Avoid with Gilteritinib and Midostaurin

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Related Studies

Ontology: fms-Like Tyrosine Kinase 3 (C0287186)

Definition (MSH) A receptor tyrosine kinase that is involved in HEMATOPOIESIS. It is closely related to FMS PROTO-ONCOGENE PROTEIN and is commonly mutated in acute MYELOID LEUKEMIA.
Concepts Receptor (T192) , Amino Acid, Peptide, or Protein (T116)
MSH D051941
German Fetale Leberkinase 3, Fetale Leberkinase 2, FMS-Like Tyrosine Kinase 3, FMS-Like Tyrosin Kinase 3, FLT3, Antigene, CD135-, CD135-Antigene, CD135-Antigen, Fetale Leber-Kinase 2, Fetale Leber-Kinase 3, Stammzell-Tyrosin-Kinase 1, fms-ähnliche Tyrosin-Kinase 3
Swedish fms-lik-tyrosinkinas 3
English ANTIGENS CD 135, CD 135 ANTIGENS, FMS LIKE TYROSINE KINASE 003, fms-Like Tyrosine Kinase 3 [Chemical/Ingredient], Stem Cell Tyrosine Kinase 1, Antigen, CD135, Antigens, CD135, CD135 Antigens, CD135 Antigen, Fetal Liver Kinase 2, Fetal Liver Kinase 3, Fetal Liver Kinase-2, Fetal Liver Kinase-3, fms Like Tyrosine Kinase 3, fms-Like Tyrosine Kinase 3
Czech antigeny CD135, tyrosinkinasa 3 podobná fms
Portuguese Tirosina Quinase 3 Semelhante a fms, Tirosinoquinase 3 Similar a fms, Tirosina Quinase 3 fms-Like, Tirosinoquinase 3 fms-Like, Tirosina Quinase 3 fms-Similar, Tirosinoquinase 3 fms-Similar, Tirosina Quinase 3 Similar a fms, Tirosinoquinase 3 Semelhante a fms, Tirosina Quinase 3 fms-Semelhante, Tirosinoquinase 3 fms-Semelhante, Antígenos CD135
Spanish Tirosina Quinasa 3 Similar a fms, Tirosina-Cinasa 3 Similar a fms, Tirosina-Quinasa 3 Similar a fms, Tirosincinasa 3 Similar a fms, Antígenos CD135
Finnish Fms:n kaltainen tyrosiinikinaasi 3
Russian FMS-PODOBNAIA TIROZIN-KINAZA 3, ANTIGENY CD135, TIROZINKINAZA 3 FMS-PODOBNAIA, FMS-ПОДОБНАЯ ТИРОЗИН-КИНАЗА 3, АНТИГЕНЫ CD135, ТИРОЗИНКИНАЗА 3 FMS-ПОДОБНАЯ
French Protéine FLT3, Tyrosine kinase-3 des cellules souches, fms-Like Tyrosine Kinase 3, Kinase-3 de foie foetal, Protéine FLT-3, Kinase-2 de foie foetal, Tyrosine kinase des cellules souches de type 3, CD135, Antigène CD135
Polish Kinaza 3 tyrozynowa fms-podobna
Japanese CD135抗原
Italian Tirosina chinasi 3 fms-simile

Ontology: crenolanib (C1831982)

Definition (NCI) An orally bioavailable benzimidazole targeting the platelet-derived growth factor receptor (PDGFR) subtypes alpha and beta and FMS-related tyrosine kinase 3 (Flt3), with potential antineoplastic activity. Upon oral administration, crenolanib binds to and inhibits both wild-type and mutated forms of PDGFR and Flt3, which may result in the inhibition of PDGFR- and Flt3-related signal transduction pathways. This results in inhibition of tumor angiogenesis and tumor cell proliferation in PDGFR and/or Flt3 overexpressing tumor cells. PDGFR and Flt3, class III receptor tyrosine kinases, are upregulated or mutated in many tumor cell types.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C577197
English PDGFR inhibitor CP-868,596, Crenolanib, PDGFR Inhibitor CP-868596, ARO-002, [1-[2-[5-(3-Methyloxetan-3-ylmethoxy)benzimidazol-1-yl]quinolin-8-yl]piperidin-4-yl]amine, 4-Piperidinamine, 1-[2-[5-[(3-methyl-3-oxetanyl)methoxy]-1Hbenzimidazol-1-yl]-8-quinolinyl]-, crenolanib, CRENOLANIB