A nonhuman primate model of acute, partial-body, high-dose irradiation with minimal (2.5%) bone marrow sparing was used to assess endogenous gastrointestinal and hematopoietic recovery and the ability of Neulasta® (pegylated granulocyte colony-stimulating factor) or Neupogen® (granulocyte colony-stimulating factor) to enhance recovery from myelosuppression when administered at an increased interval between exposure and initiation of treatment. A secondary objective was to assess the effect of Neulasta or Neupogen on mortality and morbidity due to the hematopoietic acute radiation syndrome and concomitant gastrointestinal acute radiation syndrome. Nonhuman primates were exposed to 10.0 Gy, 6 MV, linear accelerator-derived photons delivered at 0.80 Gy min−1. All nonhuman primates received subject-based medical management. Nonhuman primates were dosed daily with control article (5% dextrose in water), initiated on day 1 postexposure; Neulasta (300 μg kg−1), administered on days 1, 8, and 15 or days 3, 10, and 17 postexposure; or Neupogen (10 μg kg−1), administered daily postexposure following its initiation on day 1 or day 3 until neutrophil recovery (absolute neutrophil count ≥1,000 cells μL−1 for 3 consecutive days). Mortality in the irradiated cohorts suggested that administration of Neulasta or Neupogen on either schedule did not affect mortality due to gastrointestinal acute radiation syndrome or mitigate mortality due to hematopoietic acute radiation syndrome (plus gastrointestinal damage). Following 10.0 Gy partial-body irradiation with 2.5% bone marrow sparing, the mean duration of neutropenia (absolute neutrophil count <500 cells μL−1) was 22.4 d in the control cohort vs. 13.0 and 15.3 d in the Neulasta day 1, 8, 15 and day 3, 10, 17 cohorts, relative to 16.2 and 17.4 d in the Neupogen cohorts initiated on day 1 and day 3, respectively. The absolute neutrophil count nadirs were 48 cells μL−1 in the controls; 117 cells μL−1 and 40 cells μL−1 in the Neulasta days 1, 8, and 15 or days 3, 10, and 17 cohorts, respectively; and 75 cells μL−1 and 37 cells μL−1 in the Neupogen day 1 and day 3 cohorts, respectively. Therefore, the earlier administration of Neulasta or Neupogen was more effective in this model of marginal 2.5% bone marrow sparing. The approximate 2.5% bone marrow sparing may approach the threshold for efficacy of the lineage-specific medical countermeasure. The partial-body irradiation with 2.5% bone marrow sparing model can be used to assess medical countermeasure efficacy in the context of the concomitant gastrointestinal and hematopoietic acute radiation syndrome sequelae.
1University of Maryland School of Medicine, Baltimore, MD;
2University of Maryland Medical System, Department of Radiation Oncology, Baltimore, MD;
3Statistician, Rockville, MD.
The authors declare no conflicts of interest.
For correspondence contact Ann M. Farese, University of Maryland, 10 South Pine St., MSTF 6-04D, Baltimore, MD 21201, or email at email@example.com.
(Manuscript accepted 21 February 2018)