title: The Effect of Radiation Dose and Variation in Neupogen® Initiation Schedule on the Mitigation of Myelosuppression during the Concomitant GI-ARS and H-ARS in a Nonhuman Primate Model of High-dose Exposure with Marrow Sparing.
abstract: A nonhuman primate (NHP) model of acute high-dose, partial-body irradiation with 5% bone marrow (PBI/BM5) sparing was used to assess the effect of Neupogen® [granulocyte colony stimulating factor (G-CSF)] to mitigate the associated myelosuppression when administered at an increasing interval between exposure and initiation of treatment. A secondary objective was to assess the effect of Neupogen® on the mortality or morbidity of the hematopoietic (H)- acute radiation syndrome (ARS) and concurrent acute gastrointestinal radiation syndrome (GI-ARS). NHP were exposed to 10.0 or 11.0 Gy with 6 MV LINAC-derived photons at approximately 0.80 Gy min. All NHP received medical management. NHP were dosed daily with control article (5% dextrose in water) initiated on day 1 post-exposure or Neupogen® (10 μg kg) initiated on day 1, day 3, or day 5 until recovery [absolute neutrophil count (ANC) ≥ 1,000 cells μL for three consecutive days]. Mortality in both the 10.0 Gy and 11.0 Gy cohorts suggested that early administration of Neupogen® at day 1 post exposure may affect acute GI-ARS mortality, while Neupogen® appeared to mitigate mortality due to the H-ARS. However, the study was not powered to detect statistically significant differences in survival. The ability of Neupogen® to stimulate granulopoiesis was assessed by evaluating key parameters for ANC recovery: the depth of nadir, duration of neutropenia (ANC < 500 cells μL) and recovery time to ANC ≥ 1,000 cells μL. Following 10.0 Gy PBI/BM5, the mean duration of neutropenia was 11.6 d in the control cohort vs. 3.5 d and 4.6 d in the day 1 and day 3 Neupogen® cohorts, respectively. The respective ANC nadirs were 94 cells μL, 220 cells μL, and 243 cells μL for the control and day 1 and day 3 Neupogen® cohorts. Following 11.0 Gy PBI/BM5, the duration of neutropenia was 10.9 d in the control cohort vs. 2.8 d, 3.8 d, and 4.5 d in the day 1, day 3, and day 5 Neupogen® cohorts, respectively. The respective ANC nadirs for the control and day 1, day 3, and day 5 Neupogen® cohorts were 131 cells μL, 292 cells μL, 236 cells μL, and 217 cells μL, respectively. Therefore, the acceleration of granulopoiesis by Neupogen® in this model is independent of the time interval between radiation exposure and treatment initiation up to 5 d post-exposure. The PBI/BM5 model can be used to assess medical countermeasure efficacy in the context of the concurrent GI- and H-ARS.
authors.affiliation: *University of Maryland, School of Medicine, Department of Radiation Oncology, Baltimore, MD; †University of Maryland Medical Center, Department of Radiation Oncology, Baltimore, MD; ‡Statistician, Rockville, MD.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: MacVittie
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Bennett
authors.forename: Ann M
authors.initials: AM
authors.lastname: Farese
authors.forename: Cheryl
authors.initials: C
authors.lastname: Taylor-Howell
authors.forename: Cassandra P
authors.initials: CP
authors.lastname: Smith
authors.forename: Allison M
authors.initials: AM
authors.lastname: Gibbs
authors.forename: Karl
authors.initials: K
authors.lastname: Prado
authors.forename: William
authors.initials: W
authors.lastname: Jackson
mesh_terms: D054508:Acute Radiation Syndrome / Q000175:diagnosis / Q000503:physiopathology* / Q000517:prevention & control*; D000818:Animals; D001853:Bone Marrow / Q000528:radiation effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D000069585:Filgrastim / Q000008:administration & dosage*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D059351:Organ Sparing Treatments / Q000379:methods; D011829:Radiation Dosage; D011837:Radiation-Protective Agents / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D011837:Radiation-Protective Agents; D000069585:Filgrastim