Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis.

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 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.

• Authors: Srdan Verstovsek, Ayalew Tefferi, Jorge Cortes, Susan O'Brien, Guillermo Garcia-Manero, Animesh Pardanani, Cem Akin, Stefan Faderl, Taghi Manshouri, Deborah Thomas, Hagop Kantarjian
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 12 Pg. 3906-15 (Jun 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18559612 (Publication Type: Clinical Trial, Phase II, Journal Article)

Chemical References

• Antineoplastic Agents
• Pyrimidines
• Thiazoles
• Dasatinib

Topics

• Adult
• Aged
• Antineoplastic Agents (adverse effects, therapeutic use)
• Dasatinib
• Female
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Leukemia, Myeloid, Acute (drug therapy)
• Male
• Mastocytosis, Systemic (drug therapy)
• Middle Aged
• Philadelphia Chromosome
• Pyrimidines (adverse effects, therapeutic use)
• Remission Induction
• Thiazoles (adverse effects, therapeutic use)
• Treatment Outcome