Relapse is the major cause of death in patients with poor-risk leukemia. Increasing the dose of conventional total body irradiation (TBI) as preconditioning for hematopoietic cell transplantation (HCT) potentially reduces relapse but results in increased toxicity to vital organs and no survival benefit. Therefore, in the last several years, total marrow and lymphoid irradiation (TMLI) preparative HCT regimens have been developed to safely target increased doses to sites of disease. This continuation application expands on previous successful dose escalation strategies using TMLI to enhance the therapeutic gain (dose ratio of bone marrow to vital organs) in refractory and relapsed leukemia patients, compared to conventional TBI. Phase I TMLI trials demonstrate that dose escalation is feasible with acceptable toxicities. Initial results are encouraging in patients with refractory or relapsed leukemia not eligible for standard of care transplant regimens, as exemplified in one study showing a two-year progression-free survival rate of 27%. However, the disease relapse rate is still high (~65%). To address this problem, the investigators have developed a state-of-the-art non-invasive hybrid imaging technology, a multi- modal imaging methodology, that detects a heterogeneous spatial association between acute myeloid leukemia (AML) and the bone marrow environment (BME) to identify areas of FLT-avid high disease burden and potential sites for disease relapse and to uncover skeletal-wide spatial variations in BME damage or destabilization (BMED) that may adversely affect bone marrow (BM) engraftment. Thus, based on the knowledge gained in the last funding period, the objective is to maximize the benefit of tumor cell killing without increasing BME damage that is reflected by reduced cellularity/hematopoietic stem cell (HSC) self- renewal capacity and increased differentiation of mesenchymal stem cells (MSCs) towards adipogenesis. Initial study reveals that escalated TMLI radiation doses lead to tolerable BMED. This work will be expanded in Aim 1 to assess spatial and temporal effects of TMLI on BMED in an ongoing clinical trial using patient-derived biological samples and non-invasive imaging, namely, whole body, dual energy CT (DECT) and water fat MRI (wfMRI) for longitudinal assessment of BMED.
In Aim 2, a hybrid 3?-deoxy-3?[(18)F] -fluorothymidine positron emission tomography (FLT PET)-DECT- wfMRI imaging system to assess skeletal-wide spatial distribution of disease and its association with treatment response (relapse/remission) will be utilized. The feasibility of this functional TMLI (fTMLI) to allow augmented doses (or dose painting) to areas of FLT-avid high disease burden for targeted specific dose escalation will also be characterized.
In Aim 3, the investigators will use a newly developed mouse model of clinical TMLI to study how TMLI doses impact BMED and engraftment. Identifying an optimal dose to minimize BMED and maximize leukemia cell killing will complement the goals of Aims 1 and 2. This strategy has the potential to significantly improve the safety and efficacy of TMLI as HCT conditioning for AML patients by reducing disease relapse without significantly increasing toxicity.

Public Health Relevance

Relapse is the major cause of death in patients with acute leukemia. We have developed the total marrow and lymphoid irradiation (TMLI) regimen to precisely direct radiation to areas of disease while sparing healthy organs; however, relapses are still common. This project is designed to provide improved tumor control and safe outcomes by discovering optimal dose escalation strategies and by developing methods to limit damage and destabilization to surrounding tissues.

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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Beckman Research Institute/City of Hope
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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
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
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
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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