Comparing High and Low Total Body Irradiation Dose Rates for Minimum-Intensity Conditioning of Dogs for Dog Leukocyte Antigen–Identical Bone Marrow Grafts

Abstract

We tested the hypothesis that total body irradiation (TBI) given at a high dose rate would be more immunosuppressive and lead to a higher incidence of stable hematopoietic cell engraftment following suboptimal levels of conditioning irradiation than irradiation given at a low dose rate. We assessed engraftment success of dog leukocyte antigen identical marrow transplantation into recipients given 100, 150, and 200 cGy TBI, administered at 7 or 70 cGy/min. Dogs received donor marrow the same day as TBI and were subsequently treated with postgrafting immunosuppression consisting of mycophenolate mofetil (28 days) and cyclosporine (37 days). Donor chimerism was tested until the end of study, which was characterized by either graft rejection or stable engraftment. Increasing the radiation dose rate from the traditional 7 cGy/min to 70 cGy/min did not lead to increased engraftment success at any of the irradiation doses tested. The dose rate of 70 cGy/minute was no more hematotoxic than 7 cGy/minute. TBI delivered at a high dose rate was well tolerated but did not lead to a better rate of allogeneic hematopoietic cell engraftment than TBI delivered at a lower rate.

Low Radiation Dose and Low Cell Dose Increase the Risk of Graft Rejection in a Canine Hematopoietic Stem Cell Transplantation Model

“…In the present study, radiation dose was identified as the most influential risk factor in graft rejection. In agreement with our data, previous preclinical studies have shown a significant association between nonmyeloablative radiation dose and the stability of engraftment [22][23][24]. Furthermore, some clinical studies in humans have described an increased risk of graft rejection in patients receiving nonmyeloablative conditioning compared with patients treated with a RIC regimen [25]; however, another clinical investigation failed to demonstrate an association between conditioning intensity and rejection rate in the nonmyeloablative/RIC HSCT setting [26].…”

Toward Immunotherapy With Redirected T Cells in a Large Animal Model

“…6,7 In addition, naturally occurring cancers in dogs often closely mimic human disease and offer a novel platform to study immunotherapies. Among canine malignancies, osteosarcoma (OS) has a high incidence, affecting roughly 8,000 dogs per year in the US.…”

Implementation of total body photon irradiation as part of an institutional bone marrow transplant program for the treatment of canine lymphoma and leukemias

“…For larger patients, an approximately 20 cm distance from the body wall to the beam spoiler was estimated, and it reached approximately 30 cm for smaller patients. Since normal dog TBI studies have been performed on awake dogs with no bolus material or beam spoiler and dosimetry data for these patients has not been published, we felt that the use of the beam spoiler was a reasonable choice to attempt to improve skin and buildup region dose homogeneity and decrease setup time. In this study, skin dose ranged from 94% to 104% and 87% to 118% of the planned dose in cadaver and patient dogs, respectively.…”

“…Administration of high‐dose TBI is replete with challenges. It is common to deliver treatment in multiple fractions and at low dose rates, in order to minimize risk of severe normal tissue injury . This can be accomplished with use of a special low dose rate package that is available on some linear accelerators.…”