Efficacy of delayed administration of sargramostim up to 120 hours post exposure in a nonhuman primate total body radiation model
Yifei Zhong, Mylène Pouliot, Anne-Marie Downey, Colleen Mockbee, Debasish Roychowdhury, W Wierzbicki, Simon Authier
Abstract
Background High dose ionizing radiation exposure is associated with myelo-depression leading to pancytopenia and the expected clinical manifestations of acute radiation syndrome (ARS). Herein, we evaluated the efficacy of sargramostim (Leukine®, yeast-derived rhu GM-CSF), with regimens delivered at 48, 72, 96, or 120 h after radiation exposure.Methods A randomized and blinded nonhuman primate (NHP) study was conducted to assess the effects of sargramostim treatment on ARS. NHPs were exposed to total body radiation (LD83/60 or lethal dose 83% by Day 60) and were randomized to groups receiving daily subcutaneous dosing of sargramostim starting from either 48, 72, 96, or 120 h post-irradiation. Additionally, separate groups receiving sargramostim treatment at 48 h post-irradiation also received prophylactic treatment with azithromycin. Sargramostim treatment of each animal continued until the preliminary absolute neutrophil count (ANC) returned to ≥1000/μL post-nadir for three consecutive days or the preliminary ANC exceeded 10,000/μL, which amounted to be an average of 15.95 days for all treatment groups. Prophylactic administration of enrofloxacin was included in the supportive care given to all animals in all groups. All animals were monitored for 60 days post-irradiation for mortality, hematological parameters, and sepsis.Results Delayed sargramostim treatment at 48 h post-irradiation significantly reduced mortality (p = .0032) and improved hematological parameters including neutrophil but also lymphocyte and platelet counts. Additional delays in sargramostim administration at 72, 96, and 120 h post-irradiation were also similarly effective at enhancing the recovery of lymphocyte, neutrophil, and platelet counts compared to control. Sargramostim treatment also improved the survival of the animals when administered at up to 96 h post-irradiation. While sargramostim treatment at 48 h significantly reduced mortality associated with sepsis (p ≤ .01), the additional prophylactic treatment with azithromycin did not have clinically significant effects.Conclusion In a NHP ARS model, sargramostim administered starting at 48 h post-radiation was effective to improve survival, while beneficial hematological effects were observed with sargramostim initiated up to 120 h post exposure.