Assessment on the Precision of Total Marrow Irradiation: From Clinical to Preclinical Implementation

Abstract

Total Body irradiation (TBI) has been used for many years as the preconditioning regime before bone marrow transplant. Dose escalation of TBI produced decreased relapse rates in patients with leukemia; however, treatment-related deaths increased because of organ toxicity from TBI negating any potential therapeutic gain. In 2005 a new technique called Total Marrow radiation (TMI) was founded as an alternative to TBI. TMI is a highly conformal treatment of the human skeleton structure requiring a high degree of precision and accuracy for treatment delivery. However, there are several challenges to establish and advance TMI treatment; specifically, 1) the existence of differences in treatment setup between centers which may cause differences in dose delivery and treatment accuracy. 2) the lack of a preclinical model to better understand the biological differences between TMI and TBI. Lack of preclinical TMI model, limits us for in depth understanding of how TMI dose escalation and bone marrow microenvironment plays role in leukemia relapse and whether new therapeutics (e.g. TMI and immune modulation) could be developed to improve treatment outcomes. In this thesis, I assessed the state of current clinical TMI pre-treatment setup and its effect on dose delivery. Patient setup techniques differed between centers, creating variations in dose delivery. Image fusion accuracy varied by anatomical regions and by imaging technique. This effort allowed us to standardize treatment setup which can be used as reference for all centers. After creating a multi-center reference for TMI dose distribution, we developed and validated image guided preclinical TMI treatment technique in mice. Dose reduction in preclinical TMI mirrored that in clinical TMI.TMI treated mice showed full long-term donor engraftment after primary bone marrow transplant (BMT) and second serial BMT. Engraftment was similar to TBI. TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI. MVCT imaging and whole-body patient immobilization was essential for assessing treatment setup, allowing for the complete analysis of 3D dose distribution in the PTV and lungs. The development of a new 3D targeted preclinical system paves the way for new exploratory studies in the field of bone marrow transplant and radiobiology.