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
IX. Resources
X. References
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Related Studies
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 |