Advances in conventional total body irradiation (TBI) used for bone marrow transplant regimens have been stalled for five decades due to the inherent conflict between the efficacy of high dose irradiation (i.e., reduced relapse) and radiation induced toxicity. More specifically, studies show that higher doses of radiation reduce relapse, but increase toxicity to organs at risk (OAR) including the lungs, heart, eyes, liver, and kidneys. We propose to study the feasibility of a novel technique called """"""""adaptive total body and marrow irradiation"""""""" (adaptive TBMI). This new approach has three clear advantages: 1) Incorporation of image guided tomotherapy that allows """"""""focused radiation"""""""" to be delivered to the target (bone marrow and other disease sites), thereby differentially delivering doses of radiation to various organs;2) Monitoring of radiation dose delivered to the patients and adjustment of subsequent treatments (as needed) to achieve the prescribed dose, also known as the adaptive process;and, 3) Allowance for higher radiation doses (dose escalation) without increasing toxicity by using an enhanced therapeutic ratio of dose to disease sites versus dose to OARs and soft tissues. These advantages will make it possible to conduct clinical trials to determine a safe and efficacious maximum tolerated dose (MTD) of TBMI in the setting bone marrow transplant. We will conduct a feasibility trial, using adaptive TBMI techniques to: (i) provide an understanding of body motion and the accuracy of dose delivery;(ii) individualize treatment through the adaptive processes;and, (iii) improving radiobiological precision of dose escalation. The dose escalation available through the enhanced therapeutic ratio of adaptive TBMI is expected to increase efficacy (i.e. leukemia kill) without increased toxicity to healthy organs. The central hypothesis of this work is that the dose escalation of adaptive TBMI is safe and efficacious, and provides a treatment option to patients with high risk hematological malignancies. We will test this hypothesis through two aims: 1) To Determine the maximum radiation dose of TBMI by performing a phase I dose escalation study and to estimate the efficacy of this approach in a phase II study, and 2) To optimize TBMI delivery by measuring the accuracy of 3D whole body localization within the scanner, measuring the accuracy of the TBMI dose delivery, and establishing an adaptive TBMI therapy process. Subjects (0-45 years of age) with advanced, chemotherapy refractory leukemia (those who fail to achieve complete remission) will be eligible. These patients have very poor survival, with most dying from their disease within weeks to months. If successful, TBMI may offer significant benefits over TBI through better leukemia control and thus, is expected to have a significant impact on patients with advanced leukemia and other hematologic diseases. Adaptive TBMI has the potential for better disease control, reduced disease recurrence and increased patient survival, consistent with the well-established NIH scientific mission.

Public Health Relevance

Relapse is the major cause of death for patients with acute leukemia and other hematological malignancies, yet conventional total body irradiation (TBI) cannot provide enough radiation to prevent relapse without inducing fatal toxicities. We propose to assess a novel total body and marrow irradiation (TBMI) technique that allows for targeted and elevated radiation doses to disease sites while sparing healthy organs and minimizing toxicities. Our goal is to use TBMI for better disease control, decreased disease recurrence and improved patient survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Vikram, Bhadrasain
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University of Minnesota Twin Cities
Schools of Medicine
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Hui, Susanta; Brunstein, Claudio; Takahashi, Yutaka et al. (2017) Dose Escalation of Total Marrow Irradiation in High-Risk Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 23:1110-1116
Magome, Taiki; Froelich, Jerry; Holtan, Shernan G et al. (2017) Whole-Body Distribution of Leukemia and Functional Total Marrow Irradiation Based on FLT-PET and Dual-Energy CT. Mol Imaging 16:1536012117732203
Hui, Susanta; Takahashi, Yutaka; Holtan, Shernan G et al. (2017) Early assessment of dosimetric and biological differences of total marrow irradiation versus total body irradiation in rodents. Radiother Oncol 124:468-474
Arentsen, Luke; Hansen, Karen E; Yagi, Masashi et al. (2017) Use of dual-energy computed tomography to measure skeletal-wide marrow composition and cancellous bone mineral density. J Bone Miner Metab 35:428-436
Kaveh, Kamran; Takahashi, Yutaka; Farrar, Michael A et al. (2017) Combination therapeutics of Nilotinib and radiation in acute lymphoblastic leukemia as an effective method against drug-resistance. PLoS Comput Biol 13:e1005482
Varadhan, Raj; Magome, Taiki; Hui, Susanta (2016) Characterization of deformation and physical force in uniform low contrast anatomy and its impact on accuracy of deformable image registration. Med Phys 43:52
Magome, Taiki; Froelich, Jerry; Takahashi, Yutaka et al. (2016) Evaluation of Functional Marrow Irradiation Based on Skeletal Marrow Composition Obtained Using Dual-Energy Computed Tomography. Int J Radiat Oncol Biol Phys 96:679-87
Magome, Taiki; Haga, Akihiro; Takahashi, Yutaka et al. (2016) Fast Megavoltage Computed Tomography: A Rapid Imaging Method for Total Body or Marrow Irradiation in Helical Tomotherapy. Int J Radiat Oncol Biol Phys 96:688-95
Wilke, Christopher; Holtan, Shernan G; Sharkey, Leslie et al. (2016) Marrow damage and hematopoietic recovery following allogeneic bone marrow transplantation for acute leukemias: Effect of radiation dose and conditioning regimen. Radiother Oncol 118:65-71
Hui, Susanta K; Arentsen, Luke; Sueblinvong, Thanasak et al. (2015) A phase I feasibility study of multi-modality imaging assessing rapid expansion of marrow fat and decreased bone mineral density in cancer patients. Bone 73:90-7

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