Phase II study of dasatinib in philadelphia chromosome - Negative acute and chronic myeloid diseases, including systemic mastocytosis

Srdan Verstovsek, Ayalew Tefferi, Jorge Cortes, Susan O'Brien, Guillermo Garcia-Manero, Animesh Pardanani, Cem Akin, Stefan Faderl, Taghi Manshouri, Deborah Thomas, Hagop Kantarjian

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

Purpose: 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 βTKs, 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.

Original languageEnglish (US)
Pages (from-to)3906-3915
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number12
DOIs
StatePublished - Jun 15 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Verstovsek, S., Tefferi, A., Cortes, J., O'Brien, S., Garcia-Manero, G., Pardanani, A., Akin, C., Faderl, S., Manshouri, T., Thomas, D., & Kantarjian, H. (2008). Phase II study of dasatinib in philadelphia chromosome - Negative acute and chronic myeloid diseases, including systemic mastocytosis. Clinical Cancer Research, 14(12), 3906-3915. https://doi.org/10.1158/1078-0432.CCR-08-0366