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.

Figure 1.. TBI vs. PBI/BM5 GI- and H-ARS survival curves.

Rhesus macaques were exposed to TBI or PBI/BM5 utilizing 6 MV LINAC-derived photons. Animals were euthanized according to a set of IACUC-approved clinical criteria. Probit curves of 15- and 60-day survival are plotted.

Figure 2.. ANC kinetics post-PBI/BM5 or TBI with Neupogen^® treatment.

Rhesus macaques were exposed to 10.0 Gy or 11.0 Gy PBI/BM5 or TBI, or 7.5 Gy TBI utilizing 6 MV LINAC-derived photons. Animals were administered control article (5% dextrose in water) or Neupogen^® beginning at the indicated times post-irradiation, through the third consecutive day an ANC ≥ 1,000 μL⁻¹ was observed post-nadir. Peripheral blood was drawn daily, and the ANC was calculated using values obtained from an automated CBC and manual WBC differential. The plotted values are means. A comparison between irradiation models and doses is shown in (a), while comparisons between control and Neupogen^®-treated cohorts exposed to 10.0 Gy or 11.0 Gy are shown in (b) and (c), respectively.

Figure 2.. ANC kinetics post-PBI/BM5 or TBI with Neupogen^® treatment.

Rhesus macaques were exposed to 10.0 Gy or 11.0 Gy PBI/BM5 or TBI, or 7.5 Gy TBI utilizing 6 MV LINAC-derived photons. Animals were administered control article (5% dextrose in water) or Neupogen^® beginning at the indicated times post-irradiation, through the third consecutive day an ANC ≥ 1,000 μL⁻¹ was observed post-nadir. Peripheral blood was drawn daily, and the ANC was calculated using values obtained from an automated CBC and manual WBC differential. The plotted values are means. A comparison between irradiation models and doses is shown in (a), while comparisons between control and Neupogen^®-treated cohorts exposed to 10.0 Gy or 11.0 Gy are shown in (b) and (c), respectively.

Figure 2.. ANC kinetics post-PBI/BM5 or TBI with Neupogen^® treatment.

Rhesus macaques were exposed to 10.0 Gy or 11.0 Gy PBI/BM5 or TBI, or 7.5 Gy TBI utilizing 6 MV LINAC-derived photons. Animals were administered control article (5% dextrose in water) or Neupogen^® beginning at the indicated times post-irradiation, through the third consecutive day an ANC ≥ 1,000 μL⁻¹ was observed post-nadir. Peripheral blood was drawn daily, and the ANC was calculated using values obtained from an automated CBC and manual WBC differential. The plotted values are means. A comparison between irradiation models and doses is shown in (a), while comparisons between control and Neupogen^®-treated cohorts exposed to 10.0 Gy or 11.0 Gy are shown in (b) and (c), respectively.

Figure 3.. Platelet kinetics post-PBI/BM5 with Neupogen^® treatment.

Rhesus macaques were exposed to 10.0 Gy or 11.0 Gy PBI/BM5 or TBI utilizing 6 MV LINAC-derived photons. Animals were administered control article (5% dextrose in water) or Neupogen^® beginning at the indicated times post-irradiation, through the third consecutive day an ANC ≥ 1,000 μL⁻¹ was observed post-nadir. Peripheral blood was drawn daily, and the platelet counts were obtained from an automated CBC. The plotted values are means. A comparison between irradiation models and doses is shown in (a), while comparisons between control and Neupogen^®-treated cohorts exposed to 10.0 Gy or 11.0 Gy are shown in (b) and (c), respectively.

Figure 3.. Platelet kinetics post-PBI/BM5 with Neupogen^® treatment.

Rhesus macaques were exposed to 10.0 Gy or 11.0 Gy PBI/BM5 or TBI utilizing 6 MV LINAC-derived photons. Animals were administered control article (5% dextrose in water) or Neupogen^® beginning at the indicated times post-irradiation, through the third consecutive day an ANC ≥ 1,000 μL⁻¹ was observed post-nadir. Peripheral blood was drawn daily, and the platelet counts were obtained from an automated CBC. The plotted values are means. A comparison between irradiation models and doses is shown in (a), while comparisons between control and Neupogen^®-treated cohorts exposed to 10.0 Gy or 11.0 Gy are shown in (b) and (c), respectively.

Figure 3.. Platelet kinetics post-PBI/BM5 with Neupogen^® treatment.

Rhesus macaques were exposed to 10.0 Gy or 11.0 Gy PBI/BM5 or TBI utilizing 6 MV LINAC-derived photons. Animals were administered control article (5% dextrose in water) or Neupogen^® beginning at the indicated times post-irradiation, through the third consecutive day an ANC ≥ 1,000 μL⁻¹ was observed post-nadir. Peripheral blood was drawn daily, and the platelet counts were obtained from an automated CBC. The plotted values are means. A comparison between irradiation models and doses is shown in (a), while comparisons between control and Neupogen^®-treated cohorts exposed to 10.0 Gy or 11.0 Gy are shown in (b) and (c), respectively.