The novel thrombopoietic agent AMG 531 is effective in pre-clinical models of chemo/radiotherapy induced thrombocytopenia

Abstract

1233 AMG 531 is a novel thrombopoietic agent that engages c-mpl and has been demonstrated to elevate platelet counts in normal individuals and in patients with idiopathic thrombocytopenic purpura (ITP)1. Consistent with this clinical data, AMG 531 increases platelet counts in mice in a dose-related fashion. We sought to determine whether AMG 531 would be an effective agent in models of chemo/radiotherapy induced thrombocytopenia. We therefore employed a model combining chemotherapy with radiation (CRT) that results in severe thrombocytopenia2. The effects of a single injection of AMG 531 were examined in this mouse model.Mice were treated with the combination of carboplatin (62.5 mg/kg) and 4 hours later sub-lethal irradiation (5 Gy total body irradiation). Two hours post-irradiation, groups were treated with either placebo (n=20) or AMG531 (n=20). Platelet counts in mice treated with placebo fell to 10% of the initial platelet count by day 10 after CRT and returned to normal by day 21. Animals that received only placebo showed nadir platelet counts of 700X106/mL and the nadir was brought forward to between days 5 and 6. At the dose studied this was then followed by a substantial overshoot in platelets though dose reduction was not investigated. Platelet counts were significantly improved (AMG 531 vs. placebo) between days 7 and 19 (p= 0.001 on day 7) when platelets recovered in the unsupported group to pre-treatment values. We conclude that AMG531 reduces the severity and duration of the thrombocytopenia resulting from CRT when compared to placebo-treated mice. The beneficial effect was similar to that seen historically for mice treated with CRT and that received other mpl ligands. Further work is required to establish the optimal dose and schedule for administration of AMG531 in chemotherapy induced thrombocytopenia. 1 Bussel, et al An Open-Label, Dose-Finding Study Evaluating the Safety and Platelet Response of a Novel Thrombopoietic Protein (AMG 531) in Thrombocytopenic Adult Patients with Immune Thrombocytopenic Purpura (ITP). Blood. 102(11): 86a 2003, November 16 2 Hokom, et al Pegylated Megakaryocyte Growth and Development Factor Abrogates the Lethal Thrombocytopenia Associated With Carboplatin and Irradiation in Mice. Blood. 86(12): 4486-92, 1995 Dec 15