Efficacy of Neulasta or Neupogen on H-ARS and GI-ARS Mortality and Hematopoietic Recovery in Nonhuman Primates After 10-Gy Irradiation With 2.5% Bone Marrow Sparing

Abstract

A nonhuman primate (NHP) model of acute, partial-body, high dose, irradiation with minimal (2.5%) bone marrow sparing (PBI/BM2.5) was used to assess the endogenous gastrointestinal and hematopoietic recovery and the ability of Neulasta ® (pegylated granulocyte colony stimulating factor [G-CSF]) or Neupogen ® (G-CSF) 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 the mortality and morbidity due to the hematopoietic acute radiation syndrome (H-ARS) and concomitant acute gastrointestinal (GI)-ARS. NHP were exposed to 10.0 Gy 6 megavolt (MV) linear accelerator (LINAC)-derived photons delivered at 0.80 Gy min −1 . All NHP received subject-based medical management. NHP were dosed daily with control article (5% dextrose in water) initiated on day 1 post-exposure, or Neulasta ® (300 μg kg −1 ) administered on days 1 and 8 or days 3 and 10 post-exposure, or Neupogen ® (10 μg kg −1 ) administered daily post-exposure following its initiation on day 1 or day 3 until neutrophil recovery (absolute neutrophil count [ANC] ≥ 1,000 cells μL −1 for 3 consecutive days). Mortality in the irradiated-cohorts suggested that administration of Neulasta ® or Neupogen ® at either schedule did not affect mortality due to acute GI-ARS or mitigate mortality due to H-ARS (plus GI damage). Following 10.0 Gy PBI/BM2.5, the mean duration of neutropenia (absolute neutrophil count < 500 cells μL −1 ) was 22.4 days in the control cohort, versus 13.0 and 15.3 days in the Neulasta ® day 1-8 and day 3-10 cohorts relative to 16.2 and 17.4 days 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 days 3, 10 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% BM sparing. The approximate 2.5% BM-sparing may approximate the threshold for efficacy of the lineage-specifc

Mitigating Effects of 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on Hematopoietic Acute Radiation Syndrome after Total-Body Ionizing Irradiation in Mice

“…Many government agencies involved in national security and public health, including the U.S. FDA, have been searching for suitable radiation countermeasures for the treatment of H-ARS and GI-ARS for several decades (5-7). However, to date, only a limited number of medical options are available, including G-CSF and PEGylated G-CSF, as mitigators of H-ARS (8)(9)(10)(11). Therefore, the development of safe and effective radiation countermeasures is a priority project for the government.…”

“…Over several decades, the U.S. Department of Health and Human Services (specifically, National Institutes of Health and the Biomedical Advanced Research and Development Authority) has sought to investigate potential radiation countermeasures that are safe, easily administered and effective at reducing adverse health effects that occur after radiation exposure (5)(6)(7). Despite these ongoing efforts, as of 2015, only Neupogent (granulocyte colony-stimulating factor; G-CSF) and Neulastat (pegylated G-CSF) have been approved by the U.S. Food and Drug Administration (FDA) as radiation countermeasures for the treatment of H-ARS (8)(9)(10)(11). Recently, Leukinet (granulocyte-macrophage colony-stimulating factor; GM-CSF) was approved by the FDA as a radiomitigator to increase survival and to facilitate the recovery of white blood cells in adults and pediatric patients acutely exposed to a sub-lethal dose of radiation (12).…”

Emergency response to radiological and nuclear accidents and incidents

“…In emergency exposure scenarios it is unlikely there will be uniform acute whole‐body exposure. Shielding of as little as 2·5–5% of the bone marrow is needed for molecularly‐cloned haematopoietic growth factors to be effective and obviates the possible need for haematopoietic cell transplant in most instances (Waselenko et al , 2004; Farese et al , 2019; MacVittie et al , 2019).…”

Use of Growth Factors and Cytokines to Treat Injuries Resulting from a Radiation Public Health Emergency

“…Likewise, if given too early after exposure the transient increase in neutrophils that follows irradiation can lead to faster drug clearance and a shorter halflife. Meanwhile, the presence of spared bone marrow resulting from the heterogenous, non-uniform radiation exposures and the shelter-in-place guidance expected after an incident may allow for lower doses or delayed administration of GFs (29,30). Preclinical studies suggest that one half of the recommended 10 lg/kg dose of G-CSF could be used, while GM-CSF might represent a treatment option if early growth factor administration is not possible, since it was shown to be efficacious 48 h postirradiation in published NHP studies (31).…”