Dasatinib

Dasatinib is an oral tyrosine kinase inhibitor used primarily in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. It inhibits BCR-ABL, the abnormal tyrosine kinase produced by the BCR-ABL fusion gene associated with the Philadelphia chromosome, thereby reducing signaling that promotes abnormal leukemia-cell growth and survival. Dasatinib also inhibits several other kinases, including SRC-family kinases. It is administered orally, generally once daily, and is available as film-coated tablets. Unlike treatments that require intravenous infusion, dasatinib can be taken at home when prescribed and monitored appropriately. Its clinical importance comes from its activity against BCR-ABL and several BCR-ABL mutations associated with resistance to earlier therapy, although some mutations, including T315I, remain resistant to dasatinib. Dasatinib is used in newly diagnosed adult chronic-phase CML and in CML or Philadelphia chromosome-positive ALL when previous treatment, including imatinib, has been unsuccessful or not tolerated. It is also approved for certain pediatric patients with Philadelphia chromosome-positive CML and newly diagnosed Philadelphia chromosome-positive ALL in combination with chemotherapy.

Dasatinib was developed as a second-generation BCR-ABL tyrosine kinase inhibitor designed to inhibit BCR-ABL and SRC-family kinase activity. The U.S. Food and Drug Administration granted its initial approval on June 28, 2006, for adults with chronic myeloid leukemia resistant or intolerant to prior therapy including imatinib, as well as Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior treatment. The FDA subsequently expanded its use, including approval for newly diagnosed Philadelphia chromosome-positive chronic-phase CML in 2010 and pediatric indications in later years. The European Commission granted marketing authorization for Sprycel on November 20, 2006. Major clinical development programs included studies in imatinib-resistant or intolerant CML and the phase 3 DASISION study, which evaluated dasatinib against imatinib in newly diagnosed chronic-phase CML. Pediatric development included studies evaluating dasatinib in children with Philadelphia chromosome-positive CML and acute lymphoblastic leukemia.

Dasatinib is approved for adults with newly diagnosed Philadelphia chromosome-positive chronic-phase CML and for adults with chronic, accelerated, or myeloid or lymphoid blast-phase Philadelphia chromosome-positive CML who have resistance or intolerance to previous therapy including imatinib. It is also indicated for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. In pediatric patients aged 1 year and older, dasatinib is indicated for Philadelphia chromosome-positive CML in chronic phase and for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia in combination with chemotherapy. In pediatric ALL, dasatinib forms part of a multidrug chemotherapy regimen rather than being used as the sole antileukemic treatment.

Dasatinib is administered orally once daily and may be taken with or without food. For adults with newly diagnosed chronic-phase CML, the recommended starting dose is 100 mg once daily. For adults with accelerated-phase CML, myeloid or lymphoid blast-phase CML, or Philadelphia chromosome-positive ALL, the recommended starting dose is 140 mg once daily. Pediatric dosing for CML and ALL is based on body weight and is recalculated periodically as the child's weight changes. Tablets should be swallowed whole and should not be crushed, cut, or chewed. Treatment in adults and children with chronic-phase CML is generally continued until disease progression or unacceptable toxicity. In pediatric Philadelphia chromosome-positive ALL, treatment is administered with chemotherapy and is generally continued for a maximum of two years under the approved regimen. Dose interruption or reduction may be required for myelosuppression or significant non-hematologic toxicity.

Common side effects of dasatinib include low blood cell counts, fluid retention, diarrhea, headache, skin rash, bleeding, shortness of breath, fatigue, nausea, abdominal discomfort, and musculoskeletal pain. Pleural effusion, in which fluid accumulates around the lungs, is a characteristic adverse effect that can occur during treatment. The frequency and severity of adverse effects vary according to the disease phase, dose, duration of treatment, age, and whether dasatinib is administered with chemotherapy. Many adverse effects can be managed through monitoring, supportive treatment, temporary treatment interruption, or dose adjustment under medical supervision.

Important risks associated with dasatinib include severe myelosuppression, serious bleeding, fluid retention including pleural or pericardial effusion, cardiovascular toxicity, pulmonary arterial hypertension, QT-interval prolongation, severe skin reactions, tumor lysis syndrome, hepatotoxicity, and embryo-fetal toxicity. Patients should be evaluated promptly for new or worsening shortness of breath, chest discomfort, significant swelling, unusual bleeding, or symptoms suggesting cardiac or pulmonary complications. Pulmonary arterial hypertension requires permanent discontinuation if confirmed. Severe mucocutaneous reactions may also require permanent discontinuation when no other cause is identified. Dasatinib can cause fetal harm, so appropriate contraception is recommended during treatment and for the specified period after the final dose. Pediatric patients require monitoring of growth and bone development during long-term therapy.

Before treatment, clinicians should assess the patient's blood counts, liver function, cardiovascular and pulmonary history, concurrent medicines, and disease status. Complete blood counts are monitored regularly, with more frequent testing during initial treatment and in advanced disease or Philadelphia chromosome-positive ALL. Liver function should be assessed before treatment and periodically during therapy. Dasatinib is metabolized primarily through CYP3A4, making strong CYP3A4 inhibitors and inducers clinically important. Strong CYP3A4 inhibitors may increase dasatinib exposure, while strong CYP3A4 inducers may reduce exposure and should generally be avoided when possible. Grapefruit juice should be avoided because it can affect CYP3A4 activity. Antacids should not be taken simultaneously with dasatinib, and H2-receptor antagonists and proton-pump inhibitors are generally avoided because they can reduce dasatinib absorption. Concomitant anticoagulants or medicines that inhibit platelet function may increase bleeding risk.

Prescribers and pharmacists should confirm the Philadelphia chromosome-positive disease setting, previous tyrosine kinase inhibitor exposure, current disease response, baseline blood counts, liver function, cardiovascular status, pulmonary symptoms, and medication history before initiating treatment. Patients should be counselled to take dasatinib consistently once daily and to swallow tablets whole. Regular complete blood counts are important, particularly during the early treatment period, while molecular and hematologic response should be assessed according to the CML or ALL treatment plan. New dyspnea, dry cough, pleuritic chest pain, unexplained edema, abnormal bleeding, palpitations, or reduced exercise tolerance should prompt clinical assessment. Pharmacists should specifically screen for acid-reducing medicines, strong CYP3A4 inhibitors or inducers, grapefruit products, anticoagulants, and antiplatelet medicines. In pediatric patients, coordination with the oncology team is important for weight-based dosing, chemotherapy scheduling, growth monitoring, and management of overlapping toxicities.