Dasatinib: a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia.

摘要

BACKGROUND: The Philadelphia chromosome is formed from a translocation of genetic material involving human chromosomes 9 and 22. The resulting gene product, BCR-ABL, encodes for an abnormal tyrosine kinase (TK) that is a factor in the pathology of chronic myelogenous leukemia (CML). Use of targeted therapy that inhibits BCR-ABL kinase activity may lead to hematologic and cytogenetic responses in affected individuals. The oral TK inhibitor dasatinib was approved in 2006 for use in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) who are unable to tolerate or have not responded to other treatments. OBJECTIVE: This paper reviews the available data on dasatinib, including its pharmacokinetic and pharmacodynamic properties, findings of in vitro and in vivo studies, adverse effects, and potential place in therapy. METHODS: Pertinent information was identified through searches of MEDLINE (1966-May 2007), EMBASE (1980-first quarter 2007), and International PharmaceuticalAbstracts (1970-May 2007) using the terms dasatinib, BMS-354825, chronic myelogenous leukemia, Sprycel, Philadelphia chromosome, and acute lymphoblastic leukemia. All clinical studies and case reports published at the time of the search were included in this review. RESULTS: Observed mutations in the amino acid sequence of BCR-ABL cause the failure of treatment with existing TK inhibitors. Dasatinib has shown in vitro and in vivo activity against BCR-ABL, including mutations that are resistant to other available TK inhibitors. Preliminary results are available from several noncomparative studies of dasatinib in patients who were unable to tolerate or were resistant to previous therapies. The 5 phases of START (SRC/ABL Tyrosine kinase inhibition Activity Research Trials of dasatinib) represent the largest and most comprehensive evaluation of dasatinib in the treatment of patients in all stages of CML or Philadelphia chromosome-positive ALL who had undergone previous treatment for leukemia. Dasatanib had the greatest benefit in patients in the chronic phase of CML, with complete hematologic responses in 90% of patients, 52% of whom achieved a major hematologic response. Compared with those in the chronic phase, patients in the accelerated phase or blast crisis of CML, or with Philadelphia chromosome-positive ALL had lower responses. In the START-R trial, which compared the response to dasatinib and high-dose imatinib (800 mg/d), both regimens had comparable ability to induce a complete hematologic response (95% and 93%, respectively), although more patients achieved a major cytogenetic response with dasatinib (32% vs 7%). Adverse effects include significant myelosuppression. Dasatinib may have the potential for use in the management of nonleukemic malignancies. CONCLUSIONS: Dasatinib has a wider spectrum of activity against a broader range of BCR-ABL forms than existing TK inhibitors. It has shown clinical benefit and tolerability in patients in all phases of CML, as well as in those with Philadelphia chromosome-positive ALL. Dasatinib illustrates the potential for targeted drug development based on an understanding of the genetic alterations leading to CML and the development of resistance to treatment.