Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis
Cortes, Jorge E.
Pardanani, Animesh Dev
Thomas, Deborah A.
Kantarjian, Hagop M.
UMass Chan AffiliationsProgram in Molecular Medicine
Department of Biochemistry and Molecular Biology
Graduate School of Biomedical Sciences
KeywordsAdult; Aged; Antineoplastic Agents; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Mastocytosis, Systemic; Middle Aged; Philadelphia Chromosome; Pyrimidines; Remission Induction; Thiazoles; Treatment Outcome
Medicine and Health Sciences
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AbstractPURPOSE: Molecular characterization of Philadelphia chromosome-negative (Ph-) chronic myeloproliferative disorders, such as systemic mastocytosis (SM), has provided a clear rationale for investigating novel targeted therapies. The tyrosine kinase (TK) inhibitor dasatinib is 325-fold more potent against Bcr-Abl TK than imatinib in vitro, significantly inhibiting wild-type KIT and platelet-derived growth factor receptor beta TKs, and is active against cells carrying the mutant KIT-D816V gene. EXPERIMENTAL DESIGN: In this phase 2, open-label study, the efficacy of dasatinib (140 mg/d) was investigated in 67 patients with various Ph- myeloid disorders, including SM (n = 33; 28 KIT-D816V positive). RESULTS: The overall response rate to dasatinib in patients with SM was 33%. Only two patients, one with SM-myelofibrosis and one with SM-chronic eosinophilic leukemia, achieved complete response (elimination of mastocytosis) lasting for 5 and 16 months, respectively. Both patients were negative for KIT-D816V mutation, had low tryptase levels, abnormal WBC counts, and anemia, and had failed prior therapy with erythropoietin. Additional nine SM patients had symptomatic response, lasting 3 to 18+ months. Complete responses were achieved in two other patients (acute myeloid leukemia and hypereosinophilic syndrome). No responses were observed among patients with myelodysplastic syndromes and primary myelofibrosis. The majority of adverse events were grade 1/2. CONCLUSION: These data show that dasatinib therapy may benefit a selected group of SM patients, primarily by improving their symptoms, but it does not eliminate the disease in the patients with KIT-D816V mutation.
SourceClin Cancer Res. 2008 Jun 15;14(12):3906-15. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/32968
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