Conformal Total Body and Marrow Irradiation for Leukemia

复发是低风险白血病患者的主要死亡原因。增加常规总量的剂量 全身照射(TBI)作为造血细胞移植(HCT)的预适应有可能减少复发 但会导致对重要器官的毒性增加，对生存没有好处。因此，在过去的几年里，总共 已开发出骨髓和淋巴照射(TMLI)制备性HCT方案以安全靶向 增加了对疾病部位的剂量。此延续应用程序在以前成功剂量的基础上进行扩展 使用TMLI提高治疗增益(骨髓与重要器官的剂量比)的升级策略 难治性和复发性白血病患者，与传统的TBI相比。第一阶段TMLI试验证明 剂量递增是可行的，毒性可以接受。难治性或慢性阻塞性肺疾病患者的初步结果令人鼓舞。 复发性白血病不符合标准治疗移植方案的条件，一项研究表明 两年无进展生存率为27%。然而，该病的复发率仍然很高(~65%)。致信地址 针对这一问题，研究人员开发了一种最先进的非侵入性混合成像技术，一种多用途的 模式成像方法，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)，以确定高疾病负担和潜在疾病的地区 疾病复发的部位，并发现BME损害或不稳定的骨骼范围的空间差异 (BMed)，这可能对骨髓(BM)植入产生不利影响。因此，根据在调查中获得的知识 在上一个资助期，目标是在不增加BME损害的情况下最大化杀灭肿瘤细胞的好处 这反映在细胞性/造血干细胞(HSC)自我更新能力的降低和增加 间充质干细胞向成脂方向的分化。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，以评估空间和时间 使用患者来源的生物样本和非侵入性的正在进行的临床试验中TMLI对BMED的影响 成像，即全身、双能CT(DECT)和水脂肪MRI(WfMRI)，用于纵向评估 BMed。在目标2中，3‘-脱氧-3’[(18)F]-氟代胸腺嘧啶核素正电子发射断层扫描(Flt PET)-DECT- WfMRI成像系统评估疾病的骨骼范围空间分布及其与治疗的关系 将利用反应(复发/缓解)。这种功能性TMLI(FTMLI)允许扩展的可行性 对疾病负担高的地区进行有针对性的特定剂量升级的剂量(或剂量涂抹)也将 被刻画出来。在目标3中，研究人员将使用一种新开发的临床TMLI小鼠模型来研究 TMLI剂量如何影响BMED和植入。确定使BMED最小化和最大化的最佳剂量 杀死白血病细胞将补充目标1和2的目标。这一战略有可能显著 通过减少疾病复发提高TMLI作为急性髓系白血病患者HCT预适应的安全性和有效性 而不会显著增加毒性。

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.