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Dasatinib is an inhibitor of multiple tyrosine kinases and is active in vitro against leukemic cell lines representing variants of imatinib-sensitive and -resistant disease.
Kinase inhibitor approved for treating several forms of leukemia
Efficacy. The efficacy of dasatinib in patients with CML or Ph+ ALL resistant to or intolerant of treatment with imatinib was established in 4 ongoing, single-arm, multicenter studies. The chronic phase CML study enrolled 186 patients, the accelerated phase CML study 107 patients, the myeloid blast phase study 74 patients, and the lymphoid blast phase CML/Ph+ ALL study 78 patients. Efficacy analyses were based on a minimum of 6 months follow-up after initiation of dasatinib therapy. The primary efficacy end point in chronic phase CML was major cytogenetic response (McyR), defined as elimination (complete cytogenetic response, CcyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary end point in accelerated phase, myeloid blast phase, and lymphoid blast phase CML, as well as Ph+ ALL, was major hematologic response (MaHR), defined as either a complete hematologic response or no evidence of leukemia. In chronic phase CML patients, the McyR rate was 45% with a complete response (0% Ph+ cells) rate of 33%. The MaHR rate was 59% in accelerated phase patients, 32% in myeloid phase patients, 31% in lymphoid blast phase patients, and 42% in Ph+ ALL patients. Most cytogenetic responses occurred after 12 weeks of treatment, when the first cytogenetic analyses were performed. There are no trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival, for dasatinib.
Safety. Treatment with dasatinib is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced CML or Ph+ ALL than in chronic phase CML. Complete blood counts should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression associated with dasatinib is generally reversible and usually managed by withholding dasatinib temporarily or by dose reduction. Severe central nervous system hemorrhages, including fatalities, as well as severe gastrointestinal hemorrhages, have been associated with dasatinib therapy. Most bleeding events have been associated with severe thrombocytopenia. Accordingly, caution should be exercised when administering dasatinib to patients required to take anticoagulants or other medications that inhibit platelet function. Dasatinib is associated with fluid retention, in some cases severe, including pleural and pericardial effusion, ascites, and pulmonary edema. In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Dasatinib should be administered with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. As dasatinib is a CYP3A4 substrate, concomitant use of the agent and drugs that inhibit CYP3A4 (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin) should be avoided. Conversely, if dasatinib is coadministered with a CYP3A4 inducer, an increase in the dasatinib dose should be considered. Long-term suppression of gastric acid secretion by H2 blockers or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. Caution is recommended when administering dasatinib to patients with hepatic impairment. The most common adverse events reported in association with dasatinib include pleural effusion, diarrhea, nausea, abdominal pain and vomiting, and bleeding events.
Dosing. The recommended dose of dasatinib is 140 mg/d administered orally in 2 divided doses (70 mg twice daily), 1 in the morning and 1 in the evening with or without a meal. Dose increase or reduction in 20-mg increments per dose is recommended based on individual safety and tolerability. If the dasatinib dose is increased, the patient should be monitored carefully for toxicity. In clinical studies of adult CML and Ph+ ALL patients, dose escalation up to 90 mg BID (chronic phase CML) or 100 mg BID (advanced phase CML and Ph+ ALL) was allowed in patients who did not achieve a hematologic or cytogenetic response at the recommended dosage. Myelosuppression taking place in clinical studies was managed by dose interruption, dose reduction, or discontinuation of study therapy. Hematopoietic growth factor has been used in patients with resistant myelosuppression.