Project Details
Description
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.
Status | Active |
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Effective start/end date | 9/13/11 → 12/31/24 |
Funding
- National Cancer Institute: $313,325.00
- National Cancer Institute: $708,512.00
- National Cancer Institute: $103,363.00
- National Cancer Institute: $294,526.00
- National Cancer Institute: $2,916,769.00
- National Cancer Institute: $313,325.00
- National Cancer Institute: $303,925.00
- National Cancer Institute: $209,962.00
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