II. Indications
- FDA Approved for Philadelphia Chromosome positive malignancies
- Chronic Myelogenous Leukemia with (all BCR-ABL Inhibitors)
- Acute Lymphocytic Leukemia (Dasatinib, Ponatinib)
- Refractory Systemic Mastocytosis (Imatinib)
- Dermatofibrosacroma Protuberans (Imatinib)
- Hypereosinophilic symdrome (Imatinib)
- Myleodysplastic syndrome with growth factor receptor mutation (Imatinib)
- Off-Label Use
- Gastrointestinal Stromal Tumors or GIST (Dasatinib, Nilotinib, Imatinib)
- Desmoid Tumors (Imatinib)
- Melanoma (Imatinib)
- C-KIT mutated tumors (Imatinib)
III. Contraindications
-
QT Prolongation
- Also avoid in significant Electrolyte abnormalities until corrected (Hypomagnesemia, Hypokalemia)
- Avoid with other Medication Causes of QTc Prolongation
IV. Mechanism
-
Philadelphia Chromosome (Ph+)
- Chimeric Chromosome formed by translocation between Chromosome 9 and 22
- Encodes the fusion Protein BCR-ABL at the junction of the combined Chromosomes
- BCR-ABL
- Tyrosine Kinase that triggers cancer growth by inhibiting ABL Kinase
- BCR-ABL Inhibitors
- Tyrosine Kinase Inhibitors of BCR-ABL
- Prone to mutations within the drug binding sites, rendering the tumors resistant (esp. with Imatinib)
V. Medications
- Bosutinib (Bosulif)
- Synthetic Quinolone derivative
- Targets both Abl and Src kinases (less prone to resistance than Imatinib)
- Risk of edema, Prolonged QT, myelosuppression, Pancreatitis, Steven Johnson Syndrome, decreased bone density
- Avoid with moderate-strong CYP3A Inhibitors and Inducers, and with Proton Pump Inhibitors (decreased serum levels)
- Dasatinib (Sprycel)
- Targets both Abl and Src kinases (less prone to resistance than Imatinib)
- Risk of edema (Pleural Effusion, CHF), Prolonged QT, myelosuppression, bleeding, Steven Johnson Syndrome, HepB reactivation
- Avoid with moderate-strong CYP3A Inhibitors and Inducers
- Avoid with PPI, H2 Blockers or within 2 hours of other Antacids
- Also approved in children for CML and ALL (Philadelphia Chromosome positive)
- Nilotinib (Tasigna)
- Binds and stabilizes inactive ABL Protein kinase, with greater potency and less resistance than Imatinib
- Also a Platelet-derived growth factor receptor Antagonist (PDGF-R inhibitor) and c-KIT Inhibitor
- Risk of Prolonged QT, myelosuppression, Hemorrhage, Pneumonia, Pancreatitis, Peripheral Arterial Disease progression
- Avoid with moderate-strong CYP3A Inhibitors and Inducers
- Take on empty Stomach (increased absorption and toxicity risk with food)
- Ponatinib (Iclusig)
- Ponatinib is associated with serious cardiovascular events (CVA, MI, PVD) in 20-30%, mortality in 1% (black box warning)
- Ponatinib also has a black box warning for hepatotoxicity
- Ponatinib inhibits both unmutated and mutated forms of Bcr-Abl, including highly drug resistant mutations
- Inhibits other Tyrosine Kinases
- Vascular Endothelial Growth Factor Receptor Antagonist (VEGFR Inhibitor)
- Fibroblast Growth Factor ReceptorAntagonist (FGFR Inhibitor)
- FMS-related Tyrosine Kinase Receptor-3 (FLT3 Inhibitor)
- TIE2 Inhibitor
- Imatinib mesylate (Gleevec)
- BCR-ABL Inhibitor and also a Stem Cell Factor (SCF) and c-KIT Inhibitor (Tyrosine Kinase KIT Gene Inhibitor)
- Also a Platelet-derived growth factor inhibitor (PDGF Inhibitor)
- Risk of edema, Tumor Lysis Syndrome, myelosuppression, hepatotoxicity, bleeding, Stevens Johnson Syndrome, pseudoporphyria
- Avoid with moderate-strong CYP3A Inhibitors and Inducers
- Increases Warfarin levels and INR, and increases Acetaminophen levels
- Also approved in children for ALL (Philadelphia Chromosome positive)
- Decreased dosing in renal dysfunction
VI. Dosing
- See other references for disease specific dosing protocols
- Decrease Imatinib dosing in renal dysfunction
VII. Adverse Effects
- Gastrointestinal side effects (Nausea, Vomiting, Diarrhea)
- Edema such as Pericardial Effusions, Pleural Effusions, CHF (Bosutinib, Dasatinib, Imatinib)
- Myelosuppression (Bosutinib, Dasatinib, Imatinib )
- Bleeding (Dasatinib, Nilotinib, Imatinib)
- Acute Pancreatitis (Bosutinib, Nilotinib)
- Prolonged QTc (Bosutinib, Dasatinib, Nilotinib)
- Acute vascular Occlusion and thrombosis such as MI, CVA, Mesenteric Ischemia or Peripheral Arterial Disease (Ponatinib, Nilotinib)
- Hepatotoxicity (Ponatinib, Imatinib)
- Decreased Bone Mineral Density (Bosutinib)
- Steven Johnson Syndrome (Bosutinib, Dasatinib, Imatinib)
- Pulmonary Hypertension (Dasatinib)
- Hepatitis B Reactivation (Dasatinib, Nilotinib, Imatinib)
- Tumor Lysis Syndrome (Imatinib)
VIII. Safety
- Avoid in Lactation
- Avoid in pregnancy (all trimesters, pregnancy category X)
- Use reliable Contraception
- Monitoring
- Weight (edema risk with most BCR-ABL Inhibitor)
- Complete Blood Count with Platelets (most agents)
- Liver Function Tests (Dasatinib, Nilotinib, Imatinib)
- Serum Lipase (Bosutinib, Nilotinib)
- Electrocardiogram (QT Prolongation)
IX. Drug Interactions
- Moderate to Strong CYP3A Inhibitors and inducers
- Bosutinib
- Dasatinib
- Nilotinib
- Imatinib
-
Proton Pump Inhibitors (decreases agent serum levels)
- Bosutinib
- Dasatinib
-
Warfarin
- Imatinib increases INR
-
Medication Causes of QTc Prolongation
- Avoid with Bosutinib, Dasatinib, Nilotinib
X. Resources
- Bosutinib (DailyMed)
- Dasatinib (DailyMed)
- Nilotinib (DailyMed)
- Ponatinib (DailyMed)
- Imatinib (DailyMed)
Images: Related links to external sites (from Bing)
Related Studies
| 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 |