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

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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