II. Indications

  1. FDA Approved for Philadelphia Chromosome positive malignancies
    1. Chronic Myelogenous Leukemia with (all BCR-ABL Inhibitors)
    2. Acute Lymphocytic Leukemia (Dasatinib, Ponatinib)
    3. Refractory Systemic Mastocytosis (Imatinib)
    4. Dermatofibrosacroma Protuberans (Imatinib)
    5. Hypereosinophilic symdrome (Imatinib)
    6. Myleodysplastic syndrome with growth factor receptor mutation (Imatinib)
  2. Off-Label Use
    1. Gastrointestinal Stromal Tumors or GIST (Dasatinib, Nilotinib, Imatinib)
    2. Desmoid Tumors (Imatinib)
    3. Melanoma (Imatinib)
    4. C-KIT mutated tumors (Imatinib)

III. Contraindications

  1. QT Prolongation
    1. Also avoid in significant Electrolyte abnormalities until corrected (Hypomagnesemia, Hypokalemia)
    2. Avoid with other Medication Causes of QTc Prolongation

IV. Mechanism

  1. Philadelphia Chromosome (Ph+)
    1. Chimeric Chromosome formed by translocation between Chromosome 9 and 22
    2. Encodes the fusion Protein BCR-ABL at the junction of the combined Chromosomes
  2. BCR-ABL
    1. Tyrosine Kinase that triggers cancer growth by inhibiting ABL Kinase
  3. BCR-ABL Inhibitors
    1. Tyrosine Kinase Inhibitors of BCR-ABL
    2. Prone to mutations within the drug binding sites, rendering the tumors resistant (esp. with Imatinib)

V. Medications

  1. Bosutinib (Bosulif)
    1. Synthetic Quinolone derivative
    2. Targets both Abl and Src kinases (less prone to resistance than Imatinib)
    3. Risk of edema, Prolonged QT, myelosuppression, Pancreatitis, Steven Johnson Syndrome, decreased bone density
    4. Avoid with moderate-strong CYP3A Inhibitors and Inducers, and with Proton Pump Inhibitors (decreased serum levels)
  2. Dasatinib (Sprycel)
    1. Targets both Abl and Src kinases (less prone to resistance than Imatinib)
    2. Risk of edema (Pleural Effusion, CHF), Prolonged QT, myelosuppression, bleeding, Steven Johnson Syndrome, HepB reactivation
    3. Avoid with moderate-strong CYP3A Inhibitors and Inducers
    4. Avoid with PPI, H2 Blockers or within 2 hours of other Antacids
    5. Also approved in children for CML and ALL (Philadelphia Chromosome positive)
  3. Nilotinib (Tasigna)
    1. Binds and stabilizes inactive ABL Protein kinase, with greater potency and less resistance than Imatinib
    2. Also a Platelet-derived growth factor receptor Antagonist (PDGF-R inhibitor) and c-KIT Inhibitor
    3. Risk of Prolonged QT, myelosuppression, Hemorrhage, Pneumonia, Pancreatitis, Peripheral Arterial Disease progression
    4. Avoid with moderate-strong CYP3A Inhibitors and Inducers
    5. Take on empty Stomach (increased absorption and toxicity risk with food)
  4. Ponatinib (Iclusig)
    1. Ponatinib is associated with serious cardiovascular events (CVA, MI, PVD) in 20-30%, mortality in 1% (black box warning)
    2. Ponatinib also has a black box warning for hepatotoxicity
    3. Ponatinib inhibits both unmutated and mutated forms of Bcr-Abl, including highly drug resistant mutations
    4. Inhibits other Tyrosine Kinases
      1. Vascular Endothelial Growth Factor Receptor Antagonist (VEGFR Inhibitor)
      2. Fibroblast Growth Factor ReceptorAntagonist (FGFR Inhibitor)
      3. FMS-related Tyrosine Kinase Receptor-3 (FLT3 Inhibitor)
      4. TIE2 Inhibitor
  5. Imatinib mesylate (Gleevec)
    1. BCR-ABL Inhibitor and also a Stem Cell Factor (SCF) and c-KIT Inhibitor (Tyrosine Kinase KIT Gene Inhibitor)
    2. Also a Platelet-derived growth factor inhibitor (PDGF Inhibitor)
    3. Risk of edema, Tumor Lysis Syndrome, myelosuppression, hepatotoxicity, bleeding, Stevens Johnson Syndrome, pseudoporphyria
    4. Avoid with moderate-strong CYP3A Inhibitors and Inducers
    5. Increases Warfarin levels and INR, and increases Acetaminophen levels
    6. Also approved in children for ALL (Philadelphia Chromosome positive)
    7. Decreased dosing in renal dysfunction

VI. Dosing

  1. See other references for disease specific dosing protocols
  2. Decrease Imatinib dosing in renal dysfunction

VII. Adverse Effects

  1. Gastrointestinal side effects (Nausea, Vomiting, Diarrhea)
  2. Edema such as Pericardial Effusions, Pleural Effusions, CHF (Bosutinib, Dasatinib, Imatinib)
  3. Myelosuppression (Bosutinib, Dasatinib, Imatinib )
  4. Bleeding (Dasatinib, Nilotinib, Imatinib)
  5. Acute Pancreatitis (Bosutinib, Nilotinib)
  6. Prolonged QTc (Bosutinib, Dasatinib, Nilotinib)
  7. Acute vascular Occlusion and thrombosis such as MI, CVA, Mesenteric Ischemia or Peripheral Arterial Disease (Ponatinib, Nilotinib)
  8. Hepatotoxicity (Ponatinib, Imatinib)
  9. Decreased Bone Mineral Density (Bosutinib)
  10. Steven Johnson Syndrome (Bosutinib, Dasatinib, Imatinib)
  11. Pulmonary Hypertension (Dasatinib)
  12. Hepatitis B Reactivation (Dasatinib, Nilotinib, Imatinib)
  13. Tumor Lysis Syndrome (Imatinib)

VIII. Safety

  1. Avoid in Lactation
  2. Avoid in pregnancy (all trimesters, pregnancy category X)
    1. Use reliable Contraception
  3. Monitoring
    1. Weight (edema risk with most BCR-ABL Inhibitor)
    2. Complete Blood Count with Platelets (most agents)
    3. Liver Function Tests (Dasatinib, Nilotinib, Imatinib)
    4. Serum Lipase (Bosutinib, Nilotinib)
    5. Electrocardiogram (QT Prolongation)

IX. Drug Interactions

  1. Moderate to Strong CYP3A Inhibitors and inducers
    1. Bosutinib
    2. Dasatinib
    3. Nilotinib
    4. Imatinib
  2. Proton Pump Inhibitors (decreases agent serum levels)
    1. Bosutinib
    2. Dasatinib
  3. Warfarin
    1. Imatinib increases INR
  4. Medication Causes of QTc Prolongation
    1. Avoid with Bosutinib, Dasatinib, Nilotinib

Images: Related links to external sites (from Bing)

Related Studies

Cost: Medications

sprycel (on 4/6/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
SPRYCEL 100 MG TABLET $510.80 each
imatinib (on 6/22/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
IMATINIB MESYLATE 100 MG TAB Generic $0.81 each
IMATINIB MESYLATE 400 MG TAB Generic $2.46 each

Ontology: imatinib (C0935989)

Definition (NCI) An antineoplastic agent that inhibits the Bcr-Abl fusion protein tyrosine kinase, an abnormal enzyme produced by chronic myeloid leukemia cells that contain the Philadelphia chromosome. Imatinib also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF)/c-kit; the SCF/c-kit receptor tyrosine kinase is activated in gastrointestinal stromal tumor (GIST). This agent inhibits proliferation and induces apoptosis in cells that overexpress these oncoproteins.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C097613
SnomedCT 391634008, 414460008
English 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide, imatinib (medication), imatinib [Chemical/Ingredient], imatinib, alpha-(4-methyl-1-piperazinyl)-3'-((4-(3-pyridyl)-2-pyrimidinyl)amino)-p-tolu-p-toluidide, IMATINIB, Imatinib (product), Imatinib, Imatinib (substance)
Spanish imatinib (producto), imatinib, imatinib (sustancia)

Ontology: Imatinib mesylate (C0939537)

Definition (NCI_NCI-GLOSS) A drug used to treat different types of leukemia and other cancers of the blood, gastrointestinal stromal tumors, skin tumors called dermatofibrosarcoma protuberans, and a rare condition called systemic mastocytosis. It is also being studied in the treatment of other types of cancer. Imatinib mesylate blocks the protein made by the bcr/abl oncogene. It is a type of tyrosine kinase inhibitor.
Definition (NCI) The mesylate salt of imatinib, a tyrosine kinase inhibitor with antineoplastic activity. Imatinib binds to an intracellular pocket located within tyrosine kinases (TK), thereby inhibiting ATP binding and preventing phosphorylation and the subsequent activation of growth receptors and their downstream signal transduction pathways. This agent inhibits TK encoded by the bcr-abl oncogene as well as receptor TKs encoded by the c-kit and platelet-derived growth factor receptor (PDGFR) oncogenes. Inhibition of the bcr-abl TK results in decreased proliferation and enhanced apoptosis in malignant cells of Philadelphia-positive (Ph+) hematological malignancies such as CML and ALL; effects on c-kit TK activity inhibit mast-cell and cellular proliferation in those diseases overexpressing c-kit, such as mastocytosis and gastrointestinal stromal tumor (GIST).
Definition (PDQ) The mesylate salt of an antineoplastic agent that inhibits the Bcr-Abl fusion protein tyrosine kinase, an abnormal enzyme produced by chronic myeloid leukemia cells that harbor the Philadelphia chromosome. Imatinib also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF)/c-kit; the SCF/c-kit receptor tyrosine kinase is activated in gastrointestinal stromal tumor (GIST). This agent inhibits proliferation and induces apoptosis in cells that overexpress these oncoproteins. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=37862&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=37862&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C1687" NCI Thesaurus)
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C097613
SnomedCT 129558005
LNC LP97866-5, MTHU035097
English 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide Monomethanesulfonate, Imatinib mesilate, IMATINIB MESYLATE, imatinib (as imatinib mesylate), Imatinib mesylate, Imatinib mesylate (substance), imatinib mesylate, Imatinib Mesylate
Spanish imanitib mesilato, mesilato de imanitib (sustancia), mesilato de imanitib

Ontology: dasatinib (C1455147)

Definition (NCI_NCI-GLOSS) A drug used to treat certain types of chronic myeloid leukemia and acute lymphoblastic leukemia. BMS-354825 is also being studied in the treatment of certain other blood diseases and types of cancer. BMS-354825 binds to and blocks BCR-ABL and other proteins that help cancer cells grow. It is a type of tyrosine kinase inhibitor.
Definition (NCI) An orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib binds to and inhibits the growth-promoting activities of these kinases. Apparently because of its less stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations. SRC-family protein-tyrosine kinases interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways; tumorigenic forms can occur through altered regulation or expression of the endogenous protein and by way of virally-encoded kinase genes.
Definition (PDQ) An orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib binds to and inhibits the growth-promoting activities of these kinases. Apparently because of its less stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations. SRC-family protein-tyrosine kinases interact with variety of cell-surface receptors and participate in intracellular signal transduction pathways; tumorigenic forms can occur through altered regulation or expression of the endogenous protein and by way of virally-encoded kinase genes. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=315885&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=315885&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C38713" NCI Thesaurus)
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C488369
SnomedCT 423658008, 422756008
English DASATINIB, Dasatinib, Dasatinib (product), Dasatinib (substance), dasatinib (medication), dasatinib [Chemical/Ingredient], N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide, dasatinib
Spanish dasatinib, dasatinib (sustancia), dasatinib (producto)

Ontology: nilotinib (C1721377)

Definition (NCI_NCI-GLOSS) A drug used to treat certain types of chronic myelogenous leukemia (CML). It is used in patients who have not gotten better after treatment with other anticancer drugs or who are not able to take imatinib mesylate. It is also being studied in the treatment of other types of cancer. Nilotinib blocks a protein called BCR/ABL which is made in CML cells that contain the Philadelphia chromosome (an abnormal chromosome 22 that has part of chromosome 9 attached). It is a type of tyrosine kinase inhibitor.
Definition (NCI) An orally bioavailable aminopyrimidine-derivative Bcr-Abl tyrosine kinase inhibitor with antineoplastic activity. Designed to overcome imatinib resistance, nilotinib binds to and stabilizes the inactive conformation of the kinase domain of the Abl protein of the Bcr-Abl fusion protein, resulting in the inhibition of the Bcr-Abl-mediated proliferation of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) cells. This agent also inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs). With a binding mode that is energetically more favorable than that of imatinib, nilotinib has been shown to have an approximately 20-fold increased potency in kinase and proliferation assays compared to imatinib.
Definition (PDQ) An orally available aminopyrimidine with antineoplastic activity. Designed to overcome imatinib resistance, nilotinib is a tyrosine kinase inhibitor that binds to and inhibits the Bcr-Abl fusion protein, an abnormal chimeric tyrosine kinase expressed in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) cells. This agent also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and for c-kit, a receptor tyrosine kinase activated in gastrointestinal stromal tumor (GIST). Nilotinib interrupts phosphorylation of these tyrosine kinases and their downstream signaling targets, resulting in decreased cellular proliferation and the induction of apoptosis. This agent is more potent than imatinib against Ph+ CML cells. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=435988&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=435988&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C48375" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C498826
SnomedCT 428468009, 427941004
English 4-Methyl-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)-N-(5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide, nilotinib, Nilotinib, Nilotinib (product), Nilotinib (substance), NILOTINIB
Spanish nilotinib (sustancia), nilotinib, nilotinib (producto)

Ontology: bosutinib (C1831731)

Definition (NCI) A synthetic quinolone derivative and dual kinase inhibitor that targets both Abl and Src kinases with potential antineoplastic activity. Unlike imatinib, bosutinib inhibits the autophosphorylation of both Abl and Src kinases, resulting in inhibition of cell growth and apoptosis. Because of the dual mechanism of action, this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors. Abl kinase is upregulated in the presence of the abnormal Bcr-abl fusion protein which is commonly associated with chronic myeloid leukemia (CML). Overexpression of specific Src kinases is also associated with the imatinib-resistant CML phenotype.
Definition (PDQ) A synthetic quinolone derivative and dual kinase inhibitor that targets both Abl and Src kinases with potential antineoplastic activity. Unlike imatinib, bosutinib inhibits the autophosphorylation of both Abl and Src kinases, resulting in inhibition of cell growth and apoptosis. Because of the dual mechanism of action, this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors. Abl kinase is upregulated in the presence of the abnormal Bcr-abl fusion protein which is commonly associated with chronic myeloid leukemia (CML). Overexpression of specific Src kinases is also associated with the imatinib-resistant CML phenotype. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=467222&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=467222&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C60809" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C471992
SnomedCT 703586005, 703128001
English 4-Anilino-3-quinolinecarbonitrile, 4-Anilinobenzo(g)quinoline-3-carbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, bosutinib, chemotherapeutics bosutinib, bosutinib (medication), Bosutinib, Bosutinib (product), Bosutinib (substance), BOSUTINIB

Ontology: Bcr-Abl Tyrosine Kinase Inhibitors [MoA] (C2267122)

Concepts Molecular Function (T044)
English Bcr-Abl Tyrosine Kinase Inhibitor, Bcr-Abl Tyrosine Kinase Inhibitors, Bcr-Abl Tyrosine Kinase Inhibitors [MoA]