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.

复发是低危白血病患者死亡的主要原因。增加常规总剂量 全身照射（TBI）作为造血细胞移植（HCT）的预处理可能减少复发 但导致对重要器官的毒性增加且没有存活益处。因此，在过去的几年里， 已经开发了骨髓和淋巴照射（TMLI）制备HCT方案，以安全地靶向 增加对患病部位的剂量。此继续应用扩展了先前成功的剂量 使用TMLI增强治疗增益（骨髓与重要器官的剂量比）的递增策略 难治性和复发性白血病患者相比，传统的TBI。I期TMLI试验证明， 剂量递增是可行的，毒性可接受。对于难治性或复发性乳腺癌患者来说，初步结果令人鼓舞 复发性白血病不符合标准护理移植方案，如一项研究所示， 两年无进展生存率为27%。然而，疾病复发率仍然很高（~65%）。解决 这个问题，研究人员已经开发出一种最先进的非侵入性混合成像技术，一种多功能， 模态成像方法，检测急性髓系白血病之间的异质性空间关联 (AML)和骨髓环境（BME），以确定FLT-avid高疾病负担和潜在的区域 疾病复发的部位，并揭示BME损伤或不稳定的空间变化 （BMED），其可能不利地影响骨髓（BM）植入。因此，根据在研究中获得的知识， 在最后一个资助期，目标是在不增加BME损害的情况下最大限度地提高肿瘤细胞杀伤的益处 这反映在细胞性/造血干细胞（HSC）自我更新能力降低和造血干细胞（HSC）自我更新能力增加。 间充质干细胞（MSC）向脂肪形成的分化。初步研究显示， TMLI辐射剂量导致可耐受的BMED。这项工作将在目标1中扩大， 在一项正在进行的临床试验中，TMLI对BMED的影响，该试验使用患者来源的生物样本和非侵入性 成像，即全身、双能量CT（DECT）和水脂肪MRI（wfMRI），用于纵向评估 BMED。在Aim 2中，使用混合3 '-脱氧-3'[（18）F] -氟胸苷正电子发射断层扫描（FLT PET）-DECT- wfMRI成像系统，用于评估疾病的全脑空间分布及其与治疗的相关性 将使用缓解（复发/缓解）。该功能性TMLI（fTMLI）允许增强的可行性 针对特定靶向剂量递增的FLT-avid高疾病负担区域的剂量（或剂量绘制）也将 被描述。在目标3中，研究人员将使用新开发的临床TMLI小鼠模型进行研究 TMLI剂量如何影响BMED和植入。确定最佳剂量以最小化BMED并最大化 杀死白血病细胞将补充目标1和2的目标。这一战略有可能大大 通过减少疾病复发，提高TMLI作为AML患者HCT预处理的安全性和有效性 而不显著增加毒性。