Phase II Study of Dasatinib (SPRYCEL™) in Philadelphia Chromosome-Negative Acute and Chronic Myeloid Diseases, Including Systemic Mastocytosis.
Authors: Verstovsek Srdan , Ayalew Tefferi , Jorge Cortes , O’Brien Susan , Garcia-Manero Guillermo , Pardanani Animesh , Akin Cem , Faderl Stefan , Thomas Deborah , Kantarjian Hagop 
Published: April 2020

Abstract
Dasatinib is approved as a second line therapy (Rx) for Philadelphia chromosome (Ph)-positive chronic myeloid leukemia, as it targets Bcr/Abl tyrosine kinase. Due to its activity against other kinases, like KIT and PDGFR, we conducted a Phase II study of dasatinib in patients with Ph-negative acute and chronic myeloid diseases. Sixty-eight patients were treated at the starting dose of 70mg PO BID (9 patients with SM received 140mg as a single dose daily); 4 weeks=1 cycle. All patients were assessed for response and toxicity (no Grade 4 toxicity was observed). The results by disease type are detailed. Systemic mastocytosis: 33 patients were treated (18 indolent, 9 aggressive, 6 with associated hematologic malignancy); median age 57 years (29–74); 14 were males, all PDGFRA−; # prior Rx 1 (0–4), 16 not previously treated; median # cycles 4 (1–20). Two achieved CR: one SM-MF (JAK2 V617F+, complex cytogenetics) and one SM-HES; both c-KIT mutation negative, low tryptase, anemic, failed erythropoietin, and had abnormal WBC differential. SM-MF patient progressed to AML after 8 months on Rx and died, and SM-HES is still in CR after 18+ months. Nine patients had improvement in symptoms related to SM, lasting from 3–18+ months. Nineteen Grade 3 toxicities were observed; dose was reduced to −1 level in 15, and to −2 level in 5 patients. Acute myeloid leukemia: 9 patients were treated; median age 70 years (51–91); 7 were males, 4 had abnormal cytogenetics; # prior Rx 2 (0–3); median # cycles 1 (1–18). CR was observed in an 80y old male with trisomy 8, previously treated with 3+7 chemotherapy with short CR. He relapsed on dasatinib Rx after 60 weeks. Eight patients had no response (4 stopped Rx within first month). Six Grade 3 toxicities were observed. Myelodysplastic syndrome/chronic myelomonocytic leukemia: 6 patients were treated (3+3); median age 68 years (51–75); 4 were males, 1 with abnormal cytogenetics; # prior Rx 1.5 (0–5); median # cycles 1 (1–2). No responses were observed (2 stopped Rx within first month); one Grade 3 toxicity was observed. Hypereosinophilic syndrome/chronic eosinophilic leukemia: 8 patients were treated (5+3); median age 58 years (23–75); 5 were males, 3 had abnormal cytogenetics, all PDGFRA-; # prior Rx 1.5 (0–3); median # cycles 3 (1–17). One female patient with HES achieved CR (previously Rx with gleevec without response). She relapsed after 58 weeks while off Rx due to toxicity. Other patients did not respond (1 stopped Rx within first month); 5 Grade 3 toxicities were observed. Polycythemia vera: one patient was treated; 50yr old female, with no prior Rx, had no response after 3 months of dasatinib Rx. Chronic idiopathic myelofibrosis: 11 patients were treated; median age 63 years (47–77); 10 were males, 2 had abnormal cytogenetics; # prior Rx 2 (0–7); median # cycles 6 (1–9). No responses were observed (1 stopped Rx within first month); 4 Grade 3 toxicities were observed. Conclusion: Dasatinib is active in systemic mastocytosis (overall response rate 33%). Updated clinical and molecular results will be presented.