Total body irradiation across conditioning intensities: historical context, dose-fractionation strategy, and the role of the chemotherapy backbone.

Total body irradiation (TBI) is a form of radiotherapy that provides a uniform dose of ionizing radiation to the entire body. It has been a mainstay of the conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) for many decades. The clinical usefulness of TBI is based on the balance of its cytotoxic and immunosuppressive effects, which allow for the eradication of remaining malignant cells, including sanctuary sites, as well as the establishment of a successful transplant. Early "supra-lethal" single-dose schedules of TBI were highly effective but also came with a substantial treatment-related toxicity burden. As a result, fractionated doses of TBI were developed to improve the tolerability of the regimen. Currently, TBI is used as a component of the conditioning regimen for all three types of allo-HSCT conditioning: myeloablative conditioning (MAC, typically TBI ≥ 12 Gy or equivalent), nonmyeloablative conditioning (NMA, typically TBI ≤ 2 Gy), and reduced-intensity conditioning (RIC, intermediate doses). The dose of TBI is intended to balance the efficacy of the regimen against non-relapse mortality (NRM). High doses of TBI are more effective in reducing the risk of relapse but also increase the risk of NRM, particularly in the elderly. The lowest doses of NMA, typically 2 Gy, have expanded the scope of allo-HSCT but may be insufficient for durable disease control in high-risk disease because relapse remains a major cause of failure. intermediate TBI doses (4-8 Gy) are used in reduced or intermediate-intensity platforms to enhance antileukemic activity while limiting toxicity relative to fully myeloablative regimens. It is important to note that the outcomes of the regimen are not determined by TBI dose only, but by the interaction among dose/fractionation, the chemotherapy backbone, disease status, and transplant platform. The available data suggests a need for a platform-specific dose-adapted regimen of TBI rather than a standard dose.