Conformal Total Body and Marrow Irradiation for Leukemia

白血病的适形全身和骨髓照射

基本信息

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
项目类别：
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

项目摘要

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。身体照射（TBI）作为造血细胞移植（HCT）的预处理可能会减少复发但会导致重要器官的毒性增加，并且没有生存益处，因此，在过去几年中，总体而言。骨髓和淋巴照射 (TMLI) 准备性 HCT 方案已开发用于安全靶向增加了疾病部位的剂量，该延续应用扩展了先前成功的剂量。使用 TMLI 的升级策略来提高治疗增益（骨髓与重要器官的剂量比）与传统的 TBI 相比，难治性和复发性白血病患者的 I 期 TMLI 试验证明了这一点。对于难治性或难治性患者，剂量递增是可行的且毒性可接受。复发性白血病不符合标准护理移植方案，一项研究表明两年无进展生存率为 27%，但疾病复发率仍然很高（约 65%）。针对这个问题，研究人员开发了一种最先进的非侵入性混合成像技术，一种多模态成像方法，检测急性髓系白血病之间的异质空间关联 (AML) 和骨髓环境 (BME)，以确定 FLT 热衷的高疾病负担和潜力领域疾病复发的位点并揭示 BME 损伤或不稳定的骨骼范围空间变化 (BMED) 可能会对骨髓 (BM) 植入产生不利影响。最后一个资助期的目标是在不增加 BME 损伤的情况下最大限度地发挥肿瘤细胞杀伤作用这反映在细胞结构/造血干细胞 (HSC) 自我更新能力的降低和增强初步研究表明间充质干细胞（MSC）向脂肪生成的分化不断升级。 TMLI 辐射剂量导致可耐受的 BMED。这项工作将在目标 1 中扩展，以评估空间和时间。 TMLI 在一项正在进行的临床试验中对 BMED 的影响，该试验使用患者来源的生物样本和非侵入性方法成像，即全身、双能 CT (DECT) 和水脂肪 MRI (wfMRI)，用于纵向评估在目标 2 中，混合 3'-脱氧-3'[(18)F]-氟胸苷正电子发射断层扫描 (FLT PET)-DECT- wfMRI 成像系统可评估疾病的骨骼范围空间分布及其与治疗的关系将利用该功能性 TMLI (fTMLI) 的可行性来允许增强。向 FLT 热衷的高疾病负担区域进行剂量（或剂量涂抹）以进行有针对性的特定剂量升级也将在目标 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。白血病细胞杀伤将补充目标 1 和 2 的目标。该策略有可能显着通过减少疾病复发，提高 TMLI 作为 AML 患者 HCT 调理的安全性和有效性且不会显着增加毒性。