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

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. 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. Pertinent information was identified through searches of MEDLINE (1966-May 2007), EMBASE (1980-first quarter 2007), and International Pharmaceutical Abstracts (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. 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. 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.

Steinberg M 《CLINICAL THERAPEUTICS》

Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.

The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting. Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233 [ClinicalTrials.gov].).

Talpaz M ，Shah NP ，Kantarjian H ，Donato N ，Nicoll J ，Paquette R ，Cortes J ，O'Brien S ，Nicaise C ，Bleickardt E ，Blackwood-Chirchir MA ，Iyer V ，Chen TT ，Huang F ，Decillis AP ，Sawyers CL ... -  《-》

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate.

Brave M ，Goodman V ，Kaminskas E ，Farrell A ，Timmer W ，Pope S ，Harapanhalli R ，Saber H ，Morse D ，Bullock J ，Men A ，Noory C ，Ramchandani R ，Kenna L ，Booth B ，Gobburu J ，Jiang X ，Sridhara R ，Justice R ，Pazdur R ... -  《-》

Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.

Druker BJ ，Sawyers CL ，Kantarjian H ，Resta DJ ，Reese SF ，Ford JM ，Capdeville R ，Talpaz M ... -  《NEW ENGLAND JOURNAL OF MEDICINE》

Ponatinib: A new tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

Shamroe CL ，Comeau JM 《-》