Dasatinib: Second Generation Tyrosine Kinase Inhibitor in CML and Ph plus ALL
Dasatinib (trade name Sprycel, Bristol Myers Squibb) is an oral multikinase inhibitor of the second generation, used primarily in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph plus ALL). It was approved in the USA in 2006 and in Europe in 2007, indicated for patients with resistance or intolerance to imatinib, the first line tyrosine kinase inhibitor (TKI).
Dasatinib has significantly higher potency against BCR ABL tyrosine kinase compared to imatinib (approximately 325 fold more potent) and a broader spectrum of activity, making it effective against many imatinib resistant mutations. The only BCR ABL mutation against which dasatinib is ineffective is the T315I mutation, for which ponatinib or asciminib are used. With increasing clinical experience, dasatinib is increasingly being discussed for first line CML therapy.
Mechanism of Action
Dasatinib is a potent inhibitor of multiple tyrosine kinases, particularly BCR ABL (the fusion protein of the Philadelphia translocation t(9;22) in CML and Ph plus ALL), SRC family kinases (SRC, LCK, YES, FYN), c KIT, PDGFR alpha and beta, and ephrin receptors.
In CML, inhibition of the constitutively activated BCR ABL tyrosine kinase leads to apoptosis of leukemic cells. Unlike imatinib, which binds only the inactive conformation of BCR ABL, dasatinib binds both the inactive and active conformations, explaining its higher potency and broader spectrum of activity against mutations.
Pharmacokinetically, dasatinib is orally absorbed with bioavailability of approximately 30 percent, with marked pH dependence. Half life approximately 3 to 5 hours, metabolism via CYP3A4. The short half life allows once daily dosing in CML because the effect on bone marrow persists even after plasma levels decline.
Indications
- Chronic myeloid leukemia (CML) chronic phase: First line or in case of imatinib resistance/intolerance
- CML accelerated phase and blast crisis: Standard therapy
- Philadelphia chromosome positive acute lymphoblastic leukemia (Ph plus ALL): In combination with chemotherapy or as monotherapy for relapse
- Pediatric CML and Ph plus ALL: Approved since 2017 for children from 1 year of age
Dosage and Administration
CML chronic phase: 100 mg once daily orally. CML accelerated phase, blast crisis or Ph plus ALL: 140 mg once daily (adults) or 70 mg twice daily divided.
Pediatric dosage: According to body weight and indication, approximately 60 mg/m² once daily in chronic phase CML.
Administration: With or without food, preferably at the same time each day. Absorption is pH dependent, gastric acid producing agents (antacids, PPI) can reduce bioavailability.
In renal impairment: Generally no dose adjustment required. In moderate to severe hepatic impairment: Dose adjustment necessary.
Adverse Effects
Very common: Bone marrow suppression with neutropenia, thrombocytopenia and anemia; pleural effusion (a characteristic adverse effect of dasatinib); peripheral edema; diarrhea; nausea; rash; fatigue; headache; musculoskeletal pain.
Common: Hepatotoxicity, hyperuricemia, hypocalcemia, hyperglycemia, pleuritis, hypertension.
Serious: Pulmonary arterial hypertension (can be reversible but may persist), QT prolongation with risk of torsade de pointes, severe bleeding (especially gastrointestinal and intracranial), serious infections including hepatitis B reactivation, cardiovascular events including myocardial infarction.
Important, pleural effusion: Occurs in approximately 25 percent of patients, especially after several months of therapy. Symptoms are dyspnea, cough, chest pain. Treatment with diuretics, steroids, if necessary therapy interruption or dose reduction. In Ph plus ALL and higher doses, the incidence is higher.
Drug Interactions
- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, HIV protease inhibitors): Significantly elevated dasatinib levels, combination preferably avoided or dose reduction
- Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St. John's Wort): Substantially reduced dasatinib levels, combination contraindicated
- Gastric acid modifying agents (PPI, H2 blockers, antacids): Reduced dasatinib absorption; take antacids at least 2 hours apart, preferably avoid PPI or replace with H2 blockers with time interval
- QT prolonging agents: Additive QT prolongation
- Anticoagulants and NSAIDs: Increased bleeding risk with thrombocytopenia
Special Precautions
Pregnancy and lactation: Contraindicated. Effective contraception during and at least 3 months after therapy. Also recommended for men.
Before initiating therapy: Blood count, liver transaminases, electrolytes (magnesium, calcium, potassium), ECG (QT interval), echocardiography to assess pulmonary hypertension predisposition, hepatitis B screening.
Monitoring: Blood count weekly for the first 2 months, then monthly; liver transaminases monthly; molecular diagnostics (BCR ABL PCR) every 3 months to assess response (major molecular response target); ECG in patients with cardiac risk factors or QT prolongation; lung function and echocardiography if dyspnea develops.
Medication adherence: Regular daily intake is critical for therapeutic success. Studies show that even adherence below 90 percent significantly increases the risk of therapy failure.
Therapy discontinuation: With deep molecular response over several years, a treatment free remission trial can be considered, with close BCR ABL monitoring and reinitiation at molecular relapse.
You may also be interested in
- Imatinib, first line TKI in CML
- Nilotinib, another second generation TKI
- Bosutinib, dual SRC ABL inhibitor
- Ponatinib, third generation TKI against T315I mutation
- Asciminib, allosteric BCR ABL inhibitor
Frequently Asked Questions
What is the Philadelphia translocation?
The Philadelphia translocation t(9;22) is a genetic abnormality in which chromosomes 9 and 22 exchange pieces. The result is the BCR ABL fusion gene, which encodes a constitutively activated tyrosine kinase. This activates growth in hematopoietic stem cells and blocks apoptosis, leading to CML and some forms of ALL. Tyrosine kinase inhibitors such as dasatinib directly target this disease causing kinase.
What is a pleural effusion and how is it treated?
A pleural effusion is an accumulation of fluid between the lung and chest wall. Symptoms are dyspnea, cough and chest pain. Pleural effusion is a characteristic adverse effect of dasatinib, especially after several months of therapy. Treatment includes diuretics, glucocorticoids, if necessary drainage of the effusion, therapy interruption or dose reduction. In recurrent effusions, switching to another TKI may be appropriate.
How is therapeutic response assessed?
By quantitative PCR measurement of the BCR ABL transcript in blood, expressed on the international scale. Goals are major molecular response (MMR, BCR ABL below 0.1 percent) and deeper levels. This measurement is performed every 3 months and is a central tool for therapy management.
Can I ever stop taking dasatinib?
After several years of therapy with sustained deep molecular response (BCR ABL below 0.01 percent for at least 2 years), a treatment free remission trial can be considered under close monitoring. Approximately 50 percent of patients remain in sustained molecular remission, others require reinitiation. This strategy is offered in clinical trials and specialized centers.
Sources
- EMA, Sprycel (Dasatinib) EPAR
- DGHO Onkopedia, Chronic Myeloid Leukemia
- Gelbe Liste, Dasatinib Active Ingredient Profile
- BfArM, Federal Institute for Drugs and Medical Devices
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