Dasatinib is a small-molecule inhibitor of multiple
tyrosine kinases, including BCR-ABL, SRC, c-KIT,
ephrin A receptor and
platelet-derived growth factor-beta receptor kinases, at nanomolar concentrations. In vitro,
dasatinib is 325-fold more potent than
imatinib against cells expressing wild-type BCR-ABL. The efficacy and tolerability of oral
dasatinib has been established in the START phase II trials in adults with
chronic myeloid leukemia (CML) or
Philadelphia chromosome-positive
acute lymphoblastic leukemia (Ph-positive ALL) who were intolerant or resistant to
imatinib, and optimal
dasatinib dosage regimens were identified in phase III randomized trials. In patients with chronic phase CML, the major cytogenetic response rate in the START-C trial (median follow-up 15.2 months) was 59% with
dasatinib, and in the randomized START-R trial (median follow-up 15 months), was greater with
dasatinib than with high-dose
imatinib (52% vs 33%). Major hematologic response rates with
dasatinib were 63% in patients with accelerated phase CML (follow-up > or =9 months; START-A trial), 34% in patients with myeloid
blast phase CML and 35% in those with lymphoid
blast phase CML (follow-up > or =12 months; START-B and START-L trials), and 41% in patients with Ph-positive ALL (follow-up > or =12 months; START-L trial). Based on phase III results, a once-daily
dasatinib regimen is considered optimal in chronic phase CML (starting dosage 100 mg once daily), while a twice-daily regimen continues to be recommended in accelerated phase, myeloid
blast phase or lymphoid
blast phase CML and Ph-positive ALL (starting dosage 70 mg twice daily). Adverse events were frequent in patients treated with
dasatinib, but most were mild to moderate in severity. Grade 3/4 adverse events were uncommon and were clinically manageable.