ASP2215, a novel FLT3/AXL inhibitor: Preclinical evaluation in combination with cytarabine and anthracycline in acute myeloid leukemia (AML).

Abstract

7071 Background: Patients with AML harboring internal tandem duplication (ITD) of FLT3 have a poor prognosis following the current chemotherapeutic treatment of cytarabine (AraC) and anthracycline (daunorubicin, DNR or idarubicin, IDR). ASP2215 is a novel small molecule FLT3/AXL inhibitor in a clinical trial. Methods: Cell cycle distribution and apoptosis induction in MV4-11 AML cells, which harbor FLT3-ITD, treated with ASP2215, AraC, and DNR were evaluated via flow cytometry and Western blot. Antitumor efficacy was evaluated in MV4-11 xenografted mice administered with oral daily ASP2215 starting either a week prior to or concomitantly with, intraperitoneal AraC for 5 days, and intravenous DNR or IDR for 3 days. The pharmacokinetics in xenografted mice were also investigated. Results: ASP2215 treatment resulted in an increase in the proportion of MV4-11 cells in the G1 phase of the cell cycle at 24 h, and then the concentration-dependent induction of apoptosis, as determined by the increase in annexin V-positive cells and intracellular PARP cleavage. ASP2215 enhanced AraC- or DNR-induced apoptosis regardless of the treatment schedule. In mice xenografted with MV4-11 cells, the simultaneous administration of ASP2215, AraC, and DNR induced tumor regression, including complete remission. In contrast, combination chemotherapy (AraC and DNR) only induced tumor growth inhibition. Further, treatment of ASP2215 for a week followed by combination with DNR and AraC also induced tumor regression with a final tumor volume similar to that of simultaneous combination therapy. No obvious influence of toxicities on body weight, behavior, or diarrhea was noted for treatment of ASP2215. Concentrations of ASP2215, AraC, and DNR in plasma and tumor were not influenced by their use in combination therapy. ASP2215 also enhanced the antitumor efficacy of AraC plus IDR in the same model. Conclusions: ASP2215 in combination with AraC and either DNR or IDR induced superior antitumor efficacy compared to combination chemotherapy, regardless of dosing schedule. These findings support the development of ASP2215 in combination with chemotherapy for the potential treatment of AML.