Blood and Marrow Transplant Clinical Trials Network

描述（由申请人提供）：此外，在过去的二十年中，同种异体造血细胞移植（HCT）实践的进步导致了移植相关死亡率（TRM）的降低，扩大了老年人和/或医学上有风险人群的可及性，并为没有适当HLA匹配供体（非亲属脐带血[UCB]和单倍相同移植）的患者开发了替代方法。在单个或有限的中心研究中，潜在有益的新型细胞治疗方法的诱人暗示正在出现。然而，重大问题依然存在。复发是失败的最大原因，预防复发和/或挽救治疗复发必须是BMT CTN向前发展的关键目标。移植物抗宿主病（GVHD）继续引起不可接受的发病率，特别是在越来越多的老年患者接受低强度PBSC方法。替代的供体方式受到高排异率和TRM的困扰。最后，使用非亲属供体（URD）来源的HCT治疗非恶性疾病的成功受到过度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）由北美和澳大利亚75家最好的儿科HCT中心组成，是唯一有资格解决这些重要问题的组织。在过去的两个拨款期内，PBMTC在患者累积、数据质量、实验室依从性和领导力方面一直是顶级核心中心之一。PBMTC与儿童肿瘤组（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，使其能够在以儿科为重点的试验的发展中发挥强大的作用，并为儿科/成人BMT CTN联合试验提供发展援助和登记。PBMTC对BMT CTN核心中心续期拨款的建议旨在优化用于治疗噬血细胞疾病的高度免疫消融降低强度准备方案。来自PBMTC中心的初步数据显示，使用该方案有望将移植相关死亡率从35%降低到10%。该提案包含重要的生物学问题，重点是降低GVHD，改善植入，确定最佳阿仑单抗剂量和给药时间，以及将关键的遗传和免疫措施与结果相关联。这项试验的成功将改变治疗这些疾病的护理标准，并为采用类似方法治疗其他复杂的非恶性疾病奠定基础。相关性（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，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可靠的跟踪记录。PBMTC核心中心的提案旨在通过一种治疗噬血细胞疾病的新方法来提高生存率。

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.