Conformal Total Body and Marrow Irradiation for Leukemia

白血病的适形全身和骨髓照射

• 批准号: 9888218
• 负责人: Susanta K Hui
• 金额: $ 70.85万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-13 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888218
• 关键词: 3-Dimensional; Acute Myelocytic Leukemia; Acute leukemia; Address; Adipocytes; Affect; Aftercare; Allogenic; Area; Biological; Bioluminescence; Biophysics; Biopsy; Blood; Bone Marrow; Bone marrow biopsy; Cause of Death; Cells; Cellularity; Clinical; Clinical Trials; Complement; Cues; Detection; Disease; Disease remission; Dose; Engraftment; Environment; Evaluation; Exposure to; Extramedullary; Fatty acid glycerol esters; Funding; Generations; Global Change; Goals; Grant; Hematopoietic stem cells; Hybrids; Image; Imaging technology; Immunocompetent; Individual; Kinetics; Knowledge; Lead; Leukemic Cell; Location; Luciferases; MLL-AF9; Magnetic Resonance Imaging; Marrow; Measurement; Measures; Mesenchymal Differentiation; Mesenchymal Stem Cells; Methodology; Methods; Modality; Monitor; Multimodal Imaging; Mus; Organ; Outcome; Pathologic; Pathology; Patients; Phase; Positron-Emission Tomography; Preparation; Process; Progression-Free Survivals; Publications; Publishing; Radiation; Radiation Dose Unit; Recurrence; Recurrent disease; Red Marrow; Refractory; Regimen; Relapse; Reporting; Research Personnel; Residual state; Risk; Rodent Model; Role; Safety; Sampling; Site; Skeletal bone; Skeletal system; Spatial Distribution; Survival Rate; Therapeutic; Tissues; Toxic effect; Transplantation; Transplantation Conditioning; Validation; Variant; Water; Whole-Body Irradiation; Work; Yellow Marrow; base; bone; bone preservation; burden of illness; cell killing; chemoradiation; conditioning; design; disorder control; experience; hematopoietic cell transplantation; hematopoietic stem cell self-renewal; imaging modality; imaging system; improved; insight; irradiation; leukemia; lipid biosynthesis; lymphoid irradiation; mouse model; multidisciplinary; neoplastic cell; non-invasive imaging; preconditioning; preservation; prospective; response; self-renewal; simulation; skeletal; spatiotemporal; standard of care; treatment planning; treatment response; tumor

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.

复发是风险较差的白血病患者死亡的主要原因。增加常规总剂量 人体照射（TBI）作为造血细胞移植（HCT）的预处理 但是导致对重要器官的毒性增加，并且没有生存益处。因此，在过去的几年中，总计 已经开发了制备的HCT方案的骨髓和淋巴照射（TMLI）以安全靶向靶向 增加了疾病部位的剂量。此继续应用程序扩展了以前的成功剂量 使用TMLI提高治疗性增益（骨髓与重要器官的剂量比）的升级策略 与常规TBI相比，难治性和传递性白血病患者。 I期TMLI试验表明 剂量升级是可行的，具有可接受的毒性。难治性患者或 复发性白血病不符合护理标准移植方案的资格，这在一项研究中举例说明了 两年的无进展生存率为27％。但是，疾病中继率仍然很高（约65％）。解决 这个问题，调查人员开发了一种最先进的非侵入性混合成像技术 模态成像方法，检测急性髓样白血病之间的异质空间关联 （AML）和骨髓环境（BME），以识别Flt-avid高疾病伯恩的区域 疾病缓解的部位并发现BME损伤或不稳定的骨骼范围的空间变化 （BMed）可能会对骨髓（BM）植入产生不利影响。这是根据在 最后的融资期，目的是最大化肿瘤细胞杀死的好处而不会增加BME损害 细胞/造血干细胞（HSC）自我更新能力的降低反映了这一点 间充质干细胞（MSC）朝着脂肪形成的分化。最初的研究表明，升级 TMLI辐射剂量导致可耐受的BMED。这项工作将在AIM 1中扩展，以评估空间和临时性 在正在进行的临床试验中，使用患者衍生的生物样品和非侵入性的TMLI对BMED的影响 成像，即全身，双能CT（DECT）和水脂MRI（WFMRI），用于纵向评估 BMed。在AIM 2中，混合3'-脱氧3'[（18）F] - 氟氨酰胺极性发射断层扫描（FLT PET）-DECT- WFMRI成像系统评估疾病的骨骼整个空间分布及其与治疗的关联 响应（复发/缓解）将被使用。该功能性TMLI（FTMLI）的可行性允许增强 针对特定剂量升级的Flt-Avid高疾病伯恩的剂量（或剂量绘画）也将 被描述。在AIM 3中，研究人员将使用新开发的临床TMLI小鼠模型来研究 TMLI剂量如何影响BMed和植入。识别最佳剂量以最大程度地减少BMED并最大化 白血病细胞杀戮将完成目标1和2的目标。该策略有可能显着 通过减少疾病的缓解，提高TMLI作为HCT调节的安全性和易度性 没有显着增加毒性。