Pharmacological Class
- Tyrosine kinase inhibitor (TKI)
- Targets BCR-ABL (Philadelphia chromosome fusion protein) and SRC family kinases
Mechanism of Action
- Inhibits the BCR-ABL tyrosine kinase, thereby blocking downstream signaling that drives proliferation and survival in Ph+ CML.
- Also inhibits SRC kinases, contributing to antileukemic activity.
Indications (FDA-approved)
- Chronic Myeloid Leukemia (CML), Philadelphia chromosome-positive (Ph+):
Dosing
- Newly diagnosed chronic phase CML:
- 400 mg orally once daily with food.
- Previously treated CML:
- 500 mg orally once daily with food.
- Dose adjustments based on toxicity, renal impairment, and hepatic impairment.
Common Adverse Effects
- GI toxicity: diarrhea (very common), nausea, vomiting, abdominal pain
- Hepatotoxicity: elevated AST/ALT, bilirubin
- Myelosuppression: thrombocytopenia, neutropenia, anemia
- Rash, fatigue, headache
- Rare but serious: pleural effusion, QT prolongation
Boxed Warning
- Hepatotoxicity
- Monitor LFTs monthly for the first 3 months, then as clinically indicated.
Monitoring
- CBC: baseline, then monthly (risk of cytopenias)
- LFTs: baseline, monthly for first 3 months, then periodically
- Renal function (dose adjust in renal impairment)
- Electrolytes + ECG in patients at risk for QT prolongation
Drug Interactions
- CYP3A4 substrate
- Avoid strong CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine, St. John’s wort).
- Avoid strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) or reduce bosutinib dose.
- Avoid PPIs (reduce absorption); use H2 antagonists/antacids if needed but separate dosing.
Dose Adjustments
- Renal impairment:
- CrCl ≥60 mL/min: no adjustment.
- CrCl 30–59 mL/min: start 400 mg daily.
- CrCl <30 mL/min: start 300 mg daily.
- Hepatic impairment:
- Start 200 mg daily.
Clinical Pearls
- Compared to other TKIs:
- Useful in patients resistant or intolerant to imatinib.
- Take with food to improve absorption and reduce GI upset.