Introduction
Sprycel (dasatinib) is an oral tyrosine kinase inhibitor developed by Bristol-Myers Squibb for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Approved by the FDA in 2006, it represents a second-generation targeted therapy that has significantly improved outcomes for patients with these hematologic malignancies.
Mechanism of Action
Dasatinib is a multi-targeted kinase inhibitor that potently inhibits BCR-ABL, the abnormal tyrosine kinase responsible for CML pathogenesis. Unlike first-generation inhibitors, dasatinib binds to both active and inactive conformations of the ABL kinase domain. It also inhibits SRC family kinases (SRC, LCK, YES, FYN), c-KIT, PDGFR, and ephrin receptor kinases. This broad kinase inhibition profile contributes to its efficacy in imatinib-resistant cases and allows for once-daily dosing due to its potent BCR-ABL inhibition.
Indications
- Newly diagnosed chronic phase Philadelphia chromosome-positive CML
- Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy including imatinib
- Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy
Dosage and Administration
Standard dosing:- Chronic phase CML: 100 mg orally once daily
- Accelerated/blast phase CML or Ph+ ALL: 140 mg orally once daily
- Administer with or without food
- Tablets should be swallowed whole; do not crush, cut, or break
- Dosing adjustments required for hematologic toxicity, non-hematologic toxicity, and drug interactions
- Hepatic impairment: Reduce dose in patients with hepatic impairment
- Renal impairment: No initial dose adjustment required, but caution advised
- Elderly: Monitor closely due to increased potential for toxicity
Pharmacokinetics
Absorption: Oral bioavailability approximately 25-35%, Tmax 0.5-6 hours Distribution: Volume of distribution ~2500 L, protein binding ~96% Metabolism: Primarily hepatic via CYP3A4 to active and inactive metabolites Elimination: Half-life 3-5 hours, primarily fecal excretion (85%), renal elimination (4%)Contraindications
- Hypersensitivity to dasatinib or any component of the formulation
- Concomitant use with strong CYP3A4 inhibitors when alternatives are unavailable
Warnings and Precautions
Boxed Warning:- Hematologic toxicity: Severe thrombocytopenia, neutropenia, and anemia requiring dose interruption or reduction
- Fluid retention: Including pleural effusion, pericardial effusion, pulmonary edema, and ascites
- QT prolongation: May require monitoring and dose adjustment
- Pulmonary arterial hypertension (PAH)
- Severe dermatologic reactions
- Tumor lysis syndrome
- Embryo-fetal toxicity
- Growth retardation in children
Drug Interactions
Major interactions:- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): Increase dasatinib exposure
- Strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine): Decrease dasatinib exposure
- Gastric acid reducing agents: May decrease dasatinib absorption
- Drugs that prolong QT interval: Additive risk of QT prolongation
Adverse Effects
Very common (≥10%):- Fluid retention (including pleural effusion)
- Diarrhea
- Headache
- Nausea
- Rash
- Fatigue
- Musculoskeletal pain
- Hemorrhage
- Infection
- Febrile neutropenia
- Severe myelosuppression
- Significant bleeding events
- Congestive heart failure
- Pulmonary hypertension
- QT prolongation
- Severe skin reactions
Monitoring Parameters
Baseline assessment:- Complete blood count with differential
- Electrolytes including magnesium and potassium
- Liver function tests
- ECG for QT interval assessment
- Cardiac function assessment in high-risk patients
- CBC weekly for first month, then monthly or as clinically indicated
- Liver function tests monthly or as clinically indicated
- Signs and symptoms of fluid retention
- ECG monitoring for QT prolongation
- Growth monitoring in pediatric patients
Patient Education
- Take medication exactly as prescribed; do not change dose without consulting healthcare provider
- Report signs of infection, unusual bleeding, or bruising immediately
- Monitor for symptoms of fluid retention (shortness of breath, weight gain, swelling)
- Avoid grapefruit and grapefruit juice during treatment
- Inform all healthcare providers about Sprycel use before starting new medications
- Use effective contraception during treatment and for at least 30 days after discontinuation
- Do not breastfeed during treatment and for at least 2 weeks after final dose
- Store at room temperature in original container
References
1. FDA Prescribing Information: Sprycel (dasatinib). 2021 2. Hochhaus A, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007;110(7):2309-2315 3. Kantarjian H, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260-2270 4. Shah NP, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531-2541 5. NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia. Version 3.2022 6. Cortes JE, et al. Safety and efficacy of dasatinib in patients with chronic myeloid leukemia: a phase 3 study. Leukemia. 2018;32(6):1535-1546