Introduction
Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) that represents a significant advancement in the treatment of Philadelphia chromosome-positive leukemias. Originally approved by the FDA in 2006, dasatinib was developed to address resistance and intolerance to first-generation TKIs like imatinib. This oral targeted therapy has transformed the management of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), offering improved response rates and survival outcomes for patients with these hematologic malignancies.
Mechanism of Action
Dasatinib is a potent, multi-targeted inhibitor of BCR-ABL, SRC family kinases, c-KIT, PDGFR, and ephrin receptor kinases. It binds to both active and inactive conformations of the ABL kinase domain, inhibiting the aberrant tyrosine kinase activity of the BCR-ABL fusion protein that drives Philadelphia chromosome-positive leukemias. Dasatinib demonstrates approximately 325-fold greater potency than imatinib against unmutated BCR-ABL in vitro and maintains activity against many imatinib-resistant BCR-ABL mutations, except for T315I and F317L mutations.
Indications
- Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP)
- 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:- CML-CP: 100 mg orally once daily
- CML-AP, CML-BP, or Ph+ ALL: 140 mg orally once daily
- Administer with or without food
- Tablets should be swallowed whole; do not crush, cut, or break
- If a dose is missed, take the next scheduled dose at the regular time
- Hematologic toxicity: May require temporary interruption or dose reduction
- Hepatic impairment: Reduce dose in patients with severe hepatic impairment
- CYP3A4 inhibitors/inducers: Dose adjustments required when co-administered
Pharmacokinetics
Absorption: Rapidly absorbed with time to peak concentration of 0.5-3 hours; oral bioavailability approximately 34% Distribution: Extensive tissue distribution with volume of distribution of 2,505 L; >96% protein bound Metabolism: Primarily metabolized by CYP3A4 to active and inactive metabolites Elimination: Primarily fecal excretion (85%) with terminal half-life of 3-5 hoursContraindications
- Hypersensitivity to dasatinib or any component of the formulation
- Concomitant use with strong CYP3A4 inhibitors when alternative therapies are available
Warnings and Precautions
Boxed Warning:- Hemorrhagic events including severe central nervous system hemorrhage
- Fluid retention (pleural effusion, pericardial effusion, pulmonary edema, ascites)
- Severe cytopenias
- QT prolongation
- Pulmonary arterial hypertension (PAH): Monitor for signs and symptoms
- Cardiac dysfunction: Evaluate patients with cardiac risk factors
- Tumor lysis syndrome: Maintain adequate hydration and monitor uric acid levels
- Embryo-fetal toxicity: Can cause fetal harm; advise women of reproductive potential
Drug Interactions
Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): Increase dasatinib exposure; avoid concomitant use or reduce dasatinib dose Strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine): Decrease dasatinib exposure; avoid concomitant use or increase dasatinib dose Antacids/H2 blockers/PPIs: Reduce dasatinib absorption; separate administration by at least 2 hours Drugs that prolong QT interval: Increased risk of torsades de pointes; monitor ECGAdverse Effects
Very common (>10%):- Fluid retention (including pleural effusion)
- Diarrhea
- Headache
- Fatigue
- Nausea
- Rash
- Musculoskeletal pain
- Hemorrhagic events
- Cytopenias (neutropenia, thrombocytopenia, anemia)
- Severe pleural effusion requiring thoracentesis
- Severe hemorrhage (including CNS hemorrhage)
- Congestive heart failure
- Pulmonary arterial hypertension
- QT prolongation
- Tumor lysis syndrome
Monitoring Parameters
Baseline:- Complete blood count with differential
- Comprehensive metabolic panel
- ECG (baseline QTc)
- Echocardiogram in patients with cardiac risk factors
- Pregnancy test in women of reproductive potential
- CBC weekly for first month, then monthly or as clinically indicated
- Liver function tests monthly for first 3 months, then as clinically indicated
- ECG monitoring for QT prolongation
- Signs/symptoms of fluid retention (weight gain, dyspnea, edema)
- Bleeding events
- Response monitoring with cytogenetic and molecular testing (BCR-ABL levels)
Patient Education
- Take medication exactly as prescribed; do not change dose without medical advice
- Report any signs of bleeding, unusual bruising, or petechiae immediately
- Monitor for fluid retention symptoms: sudden weight gain, swelling, shortness of breath
- Avoid grapefruit and grapefruit juice during treatment
- Inform all healthcare providers about dasatinib use before starting new medications
- Use effective contraception during treatment and for at least 30 days after final dose
- Report any signs of infection (fever, chills) promptly
- Maintain regular follow-up appointments for monitoring
References
1. FDA Prescribing Information: Sprycel (dasatinib) 2. NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia (Version 2023) 3. Shah NP, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531-2541. 4. Kantarjian H, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260-2270. 5. Hochhaus A, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044-1054. 6. Cortes JE, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34(20):2333-2340.