Sargramostim (rhu GM-CSF) Improves Survival of Non-Human Primates with Severe Bone Marrow Suppression after Acute, High-Dose, Whole-Body Irradiation

Abstract

Exposure to acute, high-dose, whole-body ionizing radiation results in bone marrow failure (hematopoietic acute radiation syndrome with resultant infection, bleeding, anemia, and increased risk of death). Sargramostim (yeastderived rhu GM-CSF), a yeast-derived, molecularly cloned, hematopoietic growth factor and pleiotropic cytokine supports proliferation, differentiation, maturation and survival of cells of several myeloid lineages. We evaluated the efficacy of sargramostim in non-human primates (rhesus macaques) exposed to whole-body ionizing radiation at a 50-60% lethal dose. The primary end point was day 60 survival. Non-human primates received daily subcutaneous sargramostim (7 mcg/ kg/day) or control. To reflect the anticipated setting of a nuclear or radiologic event, treatment began 48 h postirradiation, and non-human primates received only moderate supportive care (no whole blood transfusions or individualized antibiotics). Sargramostim significantly increased day 60 survival to 78% (95% confidence interval, 61-90%) vs. 42% (26-59%; P ¼ 0.0018) in controls. Neutrophil, platelet and lymphocyte recovery rates were accelerated and infection rates decreased. Improved survival when sargramostim was started 48 h postirradiation, without use of intensive supportive care, suggests sargramostim may be effective in treating humans exposed to acute, high-dose whole-body, ionizing radiation in a scenario such as a mass casualty event.

Histopathological Analysis of Adrenal Glands after Simian Varicella Virus Infection

“…In the irradiated animal, SVV antigen was present in the cortex and corticomedullary junctions but absent in the medulla; more hemorrhage and necrosis were seen throughout. The increased cell death and hemorrhage, as well as an absence of CD45-positive cells in the adrenal gland of the irradiated animal, is not surprising as radiation therapy is known to cause necrosis, thrombocytopenia, and leukopenia [ 23 ].…”

Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?

“…Sargramostim given to older adults with de novo acute myeloid leukemia (AML) during intensive induction and consolidation chemotherapy decreased treatment-related morbidity and mortality primarily related to fewer infections (104,105). Lastly, sargramostim use improved survival of nonhuman primates following exposure to high doses of acute whole body ionizing radiations not receiving blood transfusions (106)(107)(108). Based on these data sargramostim is approved in several settings including: 1. shortening interval to neutrophil recovery and reducing incidence of severe and life-threatening infection following induction chemotherapy in AML; 2. accelerating myeloid reconstitution after autologous transplantation; 3. accelerating myeloid recovery following allogeneic hematopoietic cell transplantation; 4. therapy for posttransplant delayed neutrophil recovery or graft-failure; and 5. increasing survival after exposure to acute, high-dose ionizing radiations.…”

Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond

“…Recombinant GM-CSF improves the recovery of white cells in various strains of mice (Tanikawa et al 1989;Atkinson et al 1991;Waddick et al 1991;Patchen et al 1993), canines (MacVittie et al 1991Selig et al 1991;Nothdurft et al 1992), and NHPs (Monroy et al 1988;Farese et al 1993;Neelis et al 1997;Clayton et al 2021). Results consistently demonstrate that treatment with GM-CSF following acute irradiation exposure serves to enhance the recovery process from severe neutropenia and supports the concept that the medical use of the recombinant provides a significant therapeutic advantage in cases of H-ARS.…”