Phase II Study of Dasatinib in Philadelphia Chromosome–Negative Acute and Chronic Myeloid Diseases, Including Systemic Mastocytosis

• Published in: Clinical cancer research Vol. 14; no. 12; pp. 3906 - 3915
• Main Authors: VERSTOVSEK, Srdan, TEFFERI, Ayalew, KANTARJIAN, Hagop, CORTES, Jorge, O'BRIEN, Susan, GARCIA-MANERO, Guillermo, PARDANANI, Animesh, AKIN, Cem, FADERL, Stefan, MANSHOURI, Taghi, THOMAS, Deborah
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.06.2008
• Subjects: acute myeloid leukemia; Adult; Aged; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Dasatinib; Female; Humans; hypereosinophilic syndrome; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myeloid, Acute - drug therapy; Male; Mastocytosis, Systemic - drug therapy; Medical sciences; Middle Aged; myelodysplastic syndrome; Pharmacology. Drug treatments; Philadelphia Chromosome; primary myelofibrosis; Pyrimidines - adverse effects; Pyrimidines - therapeutic use; Remission Induction; systemic mastocytosis; Thiazoles - adverse effects; Thiazoles - therapeutic use; Treatment Outcome; Chromosomal aberration; Antineoplastic agent; Human; Dasatinib; Mastocytosis; Tyrosine kinase inhibitor; Chronic disease; Acute; Philadelphia chromosome; Abnormal chromosome C9; Treatment; Phase II trial; Systemic disease; Abnormal chromosome G22; Abnormal chromosome; Multikinase inhibitor
• DOI: 10.1158/1078-0432.CCR-08-0366
• ISSN: 1078-0432

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 β 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.