Dasatinib
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Ph+ CML in chronic phase — newly diagnosed | Adults | Monotherapy | FDA Approved |
| Ph+ CML (chronic, accelerated, myeloid or lymphoid blast) — imatinib-resistant or -intolerant | Adults | Monotherapy | FDA Approved |
| Ph+ ALL — resistant or intolerant to prior therapy | Adults | Monotherapy | FDA Approved |
| Ph+ CML in chronic phase | Pediatrics ≥1 year | Monotherapy | FDA Approved |
| Ph+ ALL — newly diagnosed | Pediatrics ≥1 year | Combination with chemotherapy (2-year duration) | FDA Approved |
Dasatinib is a second-generation tyrosine kinase inhibitor approximately 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Its broader kinase inhibition profile — encompassing SRC family kinases (LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ — confers activity against most imatinib-resistant BCR-ABL mutations, with the notable exception of the T315I gatekeeper mutation. In the DASISION trial, dasatinib 100 mg daily achieved faster and deeper molecular responses compared with imatinib 400 mg in newly diagnosed chronic-phase CML, with confirmed complete cytogenetic response rates of 83% versus 79% at 5 years. Dasatinib has a distinctive side-effect profile characterised by pleural effusion (28% at 5 years) and a unique risk of pulmonary arterial hypertension, requiring specific monitoring strategies.
Dosing
Adult Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Ph+ CML — chronic phase (newly diagnosed or imatinib-resistant/intolerant) | 100 mg once daily | 100 mg once daily | 140 mg once daily | Escalate to 140 mg if inadequate hematologic/cytogenetic response With or without food; do not crush/cut tablets |
| Ph+ CML — accelerated phase, myeloid or lymphoid blast phase | 140 mg once daily | 140 mg once daily | 180 mg once daily | Escalate to 180 mg if inadequate response Higher hematologic toxicity expected |
| Ph+ ALL — resistant or intolerant to prior therapy | 140 mg once daily | 140 mg once daily | 180 mg once daily | Escalate to 180 mg for inadequate response |
| With strong CYP3A4 inhibitor (100 mg baseline) | 20 mg once daily | 20 mg once daily | 20 mg/day | For 140 mg baseline → reduce to 40 mg; for 70 mg → reduce to 20 mg Interrupt dasatinib if on 60 mg or 40 mg daily until inhibitor discontinued |
Pediatric Dosing (CML and Ph+ ALL, ≥1 year)
| Body Weight | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| 10 to <20 kg | 40 mg once daily | 40 mg | 50 mg (CML escalation) | Recalculate dose every 3 months based on weight changes. For Ph+ ALL: start on/before Day 15 of induction chemo; continue for 2 years Tablets not recommended for <10 kg |
| 20 to <30 kg | 60 mg once daily | 60 mg | 70 mg | |
| 30 to <45 kg | 70 mg once daily | 70 mg | 90 mg | |
| ≥45 kg | 100 mg once daily | 100 mg | 120 mg |
Dasatinib requires an acidic gastric environment for optimal dissolution and absorption. Co-administration with antacids reduces AUC by 55% and Cmax by 58%; H2 blockers (famotidine) reduce AUC by 61% and Cmax by 63%; PPIs (omeprazole) reduce AUC by 43% and Cmax by 42%. If antacids are needed, administer them at least 2 hours before or after dasatinib. Avoid concomitant H2 blockers and PPIs entirely. This is the most critical practical prescribing consideration for dasatinib and is a major clinical difference from imatinib.
Pharmacology
Mechanism of Action
Dasatinib is a potent, second-generation oral multi-kinase inhibitor that binds to both the active and inactive conformations of the BCR-ABL kinase, unlike imatinib which binds only the inactive conformation. This dual-conformation binding confers approximately 325-fold greater potency against unmutated BCR-ABL and activity against most imatinib-resistant mutations (except T315I). Beyond BCR-ABL, dasatinib is a potent inhibitor of SRC family kinases (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-β. The broader SRC kinase inhibition may contribute to both its enhanced efficacy and its distinctive toxicity profile, particularly the higher incidence of pleural effusion and pulmonary arterial hypertension. Dasatinib is also a weak, time-dependent inhibitor of CYP3A4 and is not an inhibitor of P-glycoprotein in vitro.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid; Tmax 0.5–6 h (typically 0.5–1.5 h); food does not affect extent; pH-dependent solubility — acid-reducing agents dramatically decrease absorption | Can take with or without food; avoid all antacids, H2 blockers, and PPIs (or separate antacids by ≥2 h) |
| Distribution | 96% plasma protein bound; large apparent Vd (~2,505 L); does not meaningfully cross BBB | Extensive tissue distribution; high protein binding |
| Metabolism | Primarily CYP3A4; also FMO-3 and UGT; active metabolite M4 (N-dealkylated, equipotent, ~5% of parent AUC); 19 metabolites identified | Sensitive CYP3A4 substrate: ketoconazole ↑ AUC 5-fold, rifampin ↓ AUC 82%. Dasatinib is also a weak time-dependent CYP3A4 inhibitor |
| Elimination | t½ 3–5 h; ~85% fecal, ~4% urinary; 19% unchanged in feces, 1% in urine | Despite very short half-life, once-daily dosing is effective because transient high peak concentrations drive SRC/ABL inhibition; predominantly hepatic elimination |
Side Effects
Side effect data below are from the DASISION trial (newly diagnosed CP-CML, dasatinib 100 mg QD, N=258 vs imatinib 400 mg QD, N=258, minimum 60 months follow-up; FDA PI Table 6) unless otherwise stated.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Fluid retention (all types) | 38% | Includes pleural effusion 28%, superficial edema 14%, pulmonary hypertension 5%, pericardial effusion 4%. Grade 3/4: 5% |
| Pleural effusion | 28% | Signature dasatinib toxicity; Grade 3/4 in 3%; more common with higher doses and twice-daily dosing; 6% discontinued due to pleural effusion |
| Diarrhea | 22% | Similar to imatinib (23%); Grade 3/4 in 1% |
| Superficial localized edema | 14% | Much lower than imatinib (38%); a key advantage of dasatinib |
| Musculoskeletal pain | 14% | Lower than imatinib (17%) |
| Rash | 14% | Lower than imatinib (18%) |
| Headache | 14% | Higher than imatinib (11%) |
| Abdominal pain | 11% | Higher than imatinib (8%) |
| Fatigue | 11% | Similar to imatinib (12%) |
| Nausea | 10% | Much lower than imatinib (25%); a key tolerability advantage |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hemorrhage (all sites) | 8% | Grade 3/4 in 1%; GI bleeding in 2%; across all CML/ALL studies, Grade 3/4 hemorrhage in 5.8%, Grade 5 in 0.4% |
| Myalgia | 7% | Lower than imatinib (12%) |
| Arthralgia | 7% | Lower than imatinib (10%) |
| Pulmonary hypertension | 5% | Includes PAH; Grade 3/4 in 1%; unique to dasatinib among TKIs; may occur >1 year after initiation |
| Vomiting | 5% | Much lower than imatinib (12%) |
| Muscle spasms | 5% | Much lower than imatinib (21%); a notable tolerability advantage |
| Pericardial effusion | 4% | Grade 3/4 in 1%; monitor echocardiography |
| Cardiac ischemic events | 3.9% | Higher than imatinib (1.6%); includes angina, MI, myocardial ischemia |
| CHF / cardiac dysfunction | 2% | Similar to imatinib (1%); Grade 3/4 in <1% |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Grade 3/4 pleural effusion | 3% (newly diagnosed CP); 5–7% (imatinib-resistant/intolerant) | Can occur at any time; cumulative rate increases with duration | Chest X-ray for dyspnea/dry cough; severe cases require thoracentesis and O2; dose interruption/reduction; diuretics or short-course steroids |
| Grade 3/4 neutropenia | 29% (newly diagnosed CP); 36% (imatinib-resistant CP); 58–79% (AP/BC/lymphoid blast) | First weeks of therapy | Hold until ANC ≥1.0×10&sup9;/L; resume at same dose or reduce per FDA PI Table 3; permanent discontinuation in 2% (newly diagnosed) |
| Grade 3/4 thrombocytopenia | 22% (newly diagnosed CP); 24% (imatinib-resistant CP); 63–85% (AP/BC/lymphoid blast) | First weeks of therapy | Hold until platelets ≥50×10&sup9;/L; resume at same or reduced dose; dasatinib also causes platelet dysfunction in vitro |
| Grade 3/4 hemorrhage (all sites) | 5.8% (all studies); Grade 5: 0.4% | Any time; most associated with severe thrombocytopenia | Avoid concomitant anticoagulants/antiplatelets; CNS hemorrhage <1% including fatalities; evaluate source |
| Pulmonary arterial hypertension (PAH) | 5% all grades; 1% Grade 3/4 (newly diagnosed CP at 60 months) | Any time, including >1 year after initiation | May be reversible on discontinuation; if PAH confirmed, permanently discontinue dasatinib |
| Cardiac ischemic events | 3.9% dasatinib vs 1.6% imatinib (5-year DASISION) | During treatment | Cardiovascular risk assessment; monitor for ischemic symptoms |
| QT prolongation (QTcF >500 ms) | 1% of patients | Variable | Correct hypokalemia/hypomagnesemia before and during treatment; avoid concomitant QT-prolonging drugs; caution with anthracyclines |
| Stevens-Johnson syndrome | Rare (post-marketing) | Variable | Permanently discontinue if no other etiology identified |
| Growth retardation in children | 5.2% (pediatric CML); 1 case Grade 3 | During prolonged treatment (≥2 years) | Monitor bone growth and development; includes delayed epiphyseal fusion, osteopenia, gynecomastia |
Pleural effusion is the most clinically significant and distinctive adverse effect of dasatinib, affecting 28% of newly diagnosed CP-CML patients by 5 years. It is cumulative (10% at 1 year, 28% at 5 years) and was the leading cause of drug discontinuation (6%). Importantly, once-daily dosing produces significantly less pleural effusion than twice-daily dosing, which informed the dose-optimization to 100 mg once daily for chronic phase. Management involves prompt evaluation with chest X-ray for new dyspnea or dry cough, dose interruption, diuretics, and/or short-course steroids. Severe cases may require thoracentesis and supplemental oxygen. Most patients can resume dasatinib at a reduced dose after resolution.
Drug Interactions
Dasatinib is a sensitive CYP3A4 substrate and a weak time-dependent CYP3A4 inhibitor. Its pH-dependent solubility adds a critical non-CYP interaction pathway with acid-reducing agents. Unlike imatinib, dasatinib is not an inhibitor of P-glycoprotein in vitro, but its CYP3A4 interaction vulnerability is much more pronounced, with ketoconazole increasing exposure 5-fold.
Monitoring
- Complete Blood CountEvery 2 weeks × 12 weeks (CP-CML), then Q3 months
RoutineGrade 3/4 neutropenia 29%, thrombocytopenia 22%, anemia 13% in newly diagnosed CP-CML. Much higher in advanced phase. In AP/BC/ALL: weekly × 2 months, then monthly. - Liver FunctionBaseline, then monthly or as indicated
RoutineGrade 3/4 ALT elevation <1% in newly diagnosed CP-CML, but higher in advanced disease. Monitor more frequently when combined with hepatotoxic chemotherapy (pediatric Ph+ ALL). - Chest ImagingIf new dyspnea, dry cough, or pleuritic pain
Trigger-basedPleural effusion affects 28% by 5 years. Promptly evaluate with chest X-ray or CT. Some centres perform baseline and periodic imaging proactively. - Cardiopulmonary Assessment (PAH Screening)Baseline evaluation; if symptoms arise
Trigger-basedEvaluate for underlying cardiopulmonary disease before starting. PAH can occur any time including >1 year post-initiation. Manifestations: dyspnea, fatigue, hypoxia. If PAH confirmed, permanently discontinue dasatinib. - ECG / QTcBaseline; as clinically indicated
RoutineQTcF >500 ms in 1% of patients. Correct electrolytes (K+, Mg2+) before and during treatment. Use caution with congenital long QT or concomitant QT-prolonging drugs. - ElectrolytesBaseline, then periodically
RoutineHypophosphatemia Grade 3/4 in 7%, hypocalcemia in 4%. Supplement as needed. Correct hypokalemia/hypomagnesemia before starting. - Molecular Response (CML)Q3 months until MMR, then Q3–6 months
RoutineBCR-ABL1 transcript levels by qRT-PCR (IS). ELN response milestones apply. Dasatinib achieves faster molecular responses than imatinib. - Growth (Pediatric)Every 3–6 months
RoutineGrowth/development effects in 5.2% of pediatric CML patients after ≥2 years. Monitor height, weight, and bone development.
Contraindications & Cautions
Absolute Contraindications
- None listed in the FDA prescribing information (Section 4). As with imatinib, the absence of formal contraindications reflects the critical nature of the underlying malignancies, but the extensive warnings remain clinically essential.
Relative Contraindications (Specialist Input Recommended)
- Pre-existing pulmonary arterial hypertension or significant cardiopulmonary disease. Dasatinib may increase the risk of PAH. Evaluate patients before initiating and permanently discontinue if PAH is confirmed.
- Pregnancy. Dasatinib can cause fetal harm. Post-marketing reports include hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia. Transplacental transfer demonstrated. Effective contraception required during treatment and for 30 days after the last dose.
- Concomitant use of H2 blockers or PPIs. Dramatically reduces dasatinib absorption; essentially pharmacologically incompatible.
Use with Caution
- QT prolongation risk factors. Hypokalemia, hypomagnesemia, congenital long QT, concomitant QT-prolonging drugs, or cumulative high-dose anthracycline therapy.
- Hepatic impairment. No formal PK studies; dasatinib is primarily hepatically metabolised. Use with caution.
- Concomitant anticoagulants or antiplatelet agents. Dasatinib causes thrombocytopenia and platelet dysfunction in vitro, increasing hemorrhage risk.
- Lactation. Present in rat milk; advise against breastfeeding during treatment and for 2 weeks after the last dose.
Dasatinib may increase the risk of developing pulmonary arterial hypertension (PAH) in adult and pediatric patients, which may occur at any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating dasatinib and during treatment. If PAH is confirmed, permanently discontinue dasatinib (FDA PI Section 5.5).
Based on limited human data, dasatinib can cause fetal harm when administered to a pregnant woman. Adverse pharmacologic effects including hydrops fetalis, fetal leukopenia, and fetal thrombocytopenia have been reported. Transplacental transfer has been measured at concentrations comparable to maternal plasma. Advise females and males with female partners of reproductive potential to use effective contraception during treatment and for 30 days after the last dose (FDA PI Section 5.9).
Patient Counselling
Purpose of Therapy
Dasatinib is a targeted therapy that blocks the abnormal protein (BCR-ABL) driving your leukaemia. It is more potent than imatinib and is effective in many patients whose disease has become resistant to first-line treatment. In newly diagnosed CML, dasatinib achieves deeper and faster responses, which may offer the possibility of treatment-free remission in the future for eligible patients.
How to Take
Take the prescribed dose by mouth once daily, either in the morning or evening, with or without food. Swallow tablets whole — do not crush, break, or chew them. If a dose is missed, take it as soon as remembered unless it is close to the next dose; do not double up.
Sources
- SPRYCEL (dasatinib) Tablets. Full Prescribing Information. Bristol-Myers Squibb. Revised 07/2024. FDA LabelPrimary regulatory source for all dosing, pharmacokinetics, adverse reaction incidence rates, and drug interaction data.
- Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260–2270. DOIDASISION initial results demonstrating faster and deeper molecular responses with dasatinib vs imatinib in newly diagnosed CP-CML.
- Cortes JE, Saglio G, Kantarjian HM, 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. DOIDASISION 5-year final analysis confirming CCyR 83% vs 79% (dasatinib vs imatinib); source for mature safety data including pleural effusion 28%.
- Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008;26(19):3204–3212. DOIDose-optimization study establishing 100 mg once daily as optimal dose for CP-CML with less fluid retention than twice-daily regimens.
- Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531–2541. DOIPhase 1 study establishing dasatinib activity across all phases of CML and Ph+ ALL after imatinib failure.
- Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966–984. DOIELN 2020 CML management guideline positioning dasatinib as a first-line TKI option with specific monitoring recommendations.
- Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47(27):6658–6661. DOIDiscovery paper describing dasatinib’s dual SRC/ABL inhibitory mechanism and 325-fold greater potency vs imatinib.
- Lévêque D, Becker G, Toussaint E, Maloisel F. Clinical pharmacokinetics and pharmacodynamics of dasatinib. Clin Pharmacokinet. 2020;59(7):849–869. DOIComprehensive PK/PD review covering absorption, pH-dependent solubility, drug interactions, and dosing rationale for once-daily administration.
- Porkka K, Koskenvesa P, Lundán T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112(4):1005–1012. DOIEvidence that dasatinib achieves clinically relevant CNS penetration, unlike imatinib, relevant for CNS Ph+ disease.
- Eley T, Luo FR, Agrawal S, et al. Phase I study of the effect of gastric acid pH modulators on the bioavailability of oral dasatinib in healthy subjects. J Clin Pharmacol. 2009;49(6):700–709. DOIKey PK study quantifying the dramatic reduction in dasatinib exposure with antacids, H2 blockers, and PPIs.