Blood and Marrow Transplant Clinical Trials Network

描述（申请人提供）：在过去的二十年中，异基因造血细胞移植（HCT）实践的进展导致了移植相关死亡率（TRM）的降低，扩大了对老年和/或医学高危人群的可及性，并为没有适当HLA匹配供体的患者开发了替代方法。（不相关的脐带血[UCB]和单倍相合移植物），此外，潜在有益的新型细胞治疗方法的诱人暗示正在单中心或有限中心研究中出现。然而，仍然存在重大问题。复发是失败的最大原因，预防复发和/或复发的挽救治疗必须是BMT CTN向前发展的关键目标。移植物抗宿主病（GVHD）继续导致不可接受的发病率，特别是在接受强度降低的PBSC方法的老年患者数量不断增加的情况下。替代供体方法受到高排斥率和TRM的困扰。最后，使用非相关供体（URD）来源的非恶性疾病HCT的成功受到过度GVHD，TRM和排斥反应的限制，并可能受益于疾病特异性移植方法的优化。儿科血液和骨髓移植联盟（PBMTC），一个由北美和澳大利亚75个最好的儿科HCT中心组成的组织，是唯一有资格解决这些重要问题的组织。在过去的两个资助期内，PBMTC在患者增加、数据质量、实验室合规性和领导力方面一直是顶级核心中心之一。PBMTC与儿童肿瘤学小组（COG）和国际血液和骨髓移植研究中心（CIBMTR）的临床试验部门达成了合作协议，使其能够在儿科重点试验的开发中成为强有力的声音，并为儿童/成人BMT CTN试验提供发展援助和招募。该BMT CTN核心中心更新补助金的PBMTC提案旨在优化用于治疗噬血细胞性疾病的高度免疫清除性降低强度的制备方案。来自PBMTC中心的初步数据显示，使用所提出的方案，移植相关死亡率有望从35%降至10%。该提案包含重要的生物学问题，重点是减少GVHD，改善植入，定义最佳Alemtuzumab给药和给药时间，以及关键遗传和免疫学指标与结局的相关性。这项试验的成功将改变这些疾病的治疗标准，并为其他复杂的非恶性疾病的类似方法的适应奠定基础。相关性（参见说明）：血液和骨髓移植临床试验网络（BMT CTN）应该研究新的方法来预防复发，减少移植物抗宿主病，开发更好的替代供体方法，并改善非恶性疾病患者的预后。儿科血液和骨髓移植联盟（PBMTC）为BMT CTN带来了重要的儿科专业知识和良好的记录。PBMTC核心中心的提案旨在使用一种新的方法来治疗噬血细胞疾病，以提高生存率。

DESCRIPTION (provided by applicant): Over the past two decades, advances in the practice of allogeneic hematopoietic cell transplantation (HCT) have resulted in decreased transplant related mortality (TRM), expanded access to older and/or medically at- risk populations, and the development of alternative approaches for patients without appropriately HLA- matched donors (unrelated cord blood [UCB] and haploidentical grafts), in addition, tantalizing hints of potentially beneficial novel cellular therapy approaches are appearing in single or limited center studies. Significant problems remain, however. Relapse is the largest cause for failure, and prevention of relapse and/or salvage therapies for relapse must be key goals of the BMT CTN moving forward. Graft-vs-host disease (GVHD) continues to cause unacceptable morbidity, especially In the expanding number of older patients receiving reduced intensity PBSC approaches. Alternative donor approaches are plagued with high rates of rejection and TRM. Finally, the success of HCT for non-malignant disorders using unrelated donor (URD) sources is limited by excessive GVHD, TRM, and rejection, and could benefit from disease-specific optimization of transplant approaches. The Pediatric Blood and Marrow Transplant Consortium (PBMTC), a group consisting 75 ofthe finest pediatric HCT centers in North America and Australia, Is uniquely qualified to address these important issues. The PBMTC has been one of the top Core Centers over the last two grant periods in patient accrual, data quality, laboratory compliance, and leadership. The PBMTC has collaborative agreements with the Children's Oncology Group (COG) and with the clinical trials arm of the Center for International Blood and Marrow Transplant Research (CIBMTR) that allow it to be a strong voice In the development of pediatric-focused trials and In providing developmental assistance and enrollment for combined pediatric/adult BMT CTN trials. The PBMTC proposal for this BMT CTN Core Center renewal grant seeks to optimize a highly immunoablative reduced Intensity preparative regimen for the treatment of hemophagocytic disorders. Preliminary data from PBMTC centers show promise of decreasing transplant related mortality from 35% to as little as 10% using the proposed regimen. The proposal contains significant biology questions focused upon decreasing GVHD, improving engraftment, defining optimal alemtuzumab dosing and dose timing, and correlating key genetic and immunologic measures with outcome. Success with this trial will change the standard of care for treatment of these diseases and lay the foundation for adaptation of similar approaches to other complex non-malignant conditions. RELEVANCE (See instructions): The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) should study novel approaches to prevent relapse, reduce graft vs. host disease, develop better alternative donor methods, and improve outcomes for patients with non-malignant diseases. The Pediatric Blood and Marrow Transplant Consortium (PBMTC) brings significant pediatric expertise and a proven track record to the BMT CTN. The PBMTC Core Center proposal alms to improve survival using a novel approach to treat hemophagocytic disorders.