1/2A Phase III Randomized Trial Comparing Unrelated Donor Bone Marrow Transplantation with Immune Suppressive Therapy for Newly Diagnosed Pediatric and Young Adult Patients with Severe Aplastic Anemia

摘要 获得性重型再生障碍性贫血(SAA)是一种罕见的骨髓衰竭疾病，年发病率为3-4 在北美每百万人(美国每年有300-500例，年龄在25岁)。绝大多数案件都是 由自身免疫破坏造血干细胞(HSCs)引起；因此，这种疾病可能是 通常通过免疫抑制疗法(IST)或骨髓移植(BMT)来治疗和治愈。 20世纪90年代开发的ATG/环孢素(CsA)联合疗法是新生的IST的首选方法 诊断为SAA患者，有效率为60%-80%，5年生存率超过90%。来自AN的BMT 人类白细胞抗原相合同胞捐献者(MSD)是新诊断的年轻患者的初始治疗标准。 然而，由于长期存活率超过95%，只有20%的患者有合适的兄弟姐妹捐赠者， 因此，绝大多数患者接受IST作为初步治疗。匹配不相关的结果 在过去的十年中，SAA的供者(MUD)骨髓移植有了显著的改善，有类似的研究报告 使用MUD和MSD进行骨髓移植的结果比较。尽管这些数据具有挑衅性，但MUD BMT携带 存在重大风险，两种方法之间存在一种平衡状态。为了应对这一挑战， 北美儿童再生障碍性贫血联盟(NAPAAC)，与儿科协会合作 移植和细胞治疗联盟(PTCTC)进行了一项由NHLBI资助的试点试验，该试验已经 显示了在IST和MUD骨髓移植之间随机选择患者的可行性和安全性。在此群集中 应用，临床研究资源在骨髓移植(RCI BMT)，预期的临床试验分支 国际血液和骨髓移植研究中心(CIBMTR)将作为数据 协调中心(DCC)管理最终的第三阶段随机对照试验(RCT) 与NAPAAC和PTCTC的临床协调中心(CCC)合作。我们的特定 目的是：1)比较无免疫抑制存活的SAA患者和适当存活的SAA患者的比例 对于被随机分为IST和BMT的患者，包括了解两者之一的影响，计算时间为两年 关于生育、生活质量和生物因素的治疗，2)支持和管理有效的实施， 治理和完成此RCT，以及3)利用现有系统和专业知识来确保 坚持高质量的数据收集。拟议的DCC提供了一个高效和经验丰富的 利用现有关系的基础设施和已成功交付临床应用的框架 超过15年的试验，包括经验丰富的统计团队。这些资产将确保这项试验的设计， 以最完整和最有效的方式进行分析和实施，并将实现其推进的目标 有关儿童和青少年SAA最佳治疗方法的知识。

ABSTRACT Acquired severe aplastic anemia (SAA) is a rare bone marrow failure disorder with an annual incidence of 3-4 per million in North America (300-500 cases < age 25 in the US yearly). The large majority of cases are caused by autoimmune destruction of hematopoietic stem cells (HSCs); accordingly the disease can be treated and often cured by either immune suppression therapy (IST) or bone marrow transplantation (BMT). The ATG/ cyclosporine (CsA) combination developed in the 1990s is the preferred IST approach for newly diagnosed SAA patients and has response rates of 60-80%, with 5-year survival exceeding 90%. BMT from an HLA matched sibling donor (MSD) is the standard for initial therapy for younger, newly diagnosed patients with long-term survival rates of over 95% however, only 20% of patients have a suitable sibling donor, consequently, the large majority of patients receive IST for initial therapy. Outcomes of matched unrelated donor (MUD) BMT for SAA have improved significantly over the past decade, with studies reporting similar outcomes for BMT using MUD compared to MSD. Although these data are provocative, MUD BMT carries significant risks, and a state of equipoise exists between the two approaches. To address this challenge, the North American Pediatric Aplastic Anemia Consortium (NAPAAC), in collaboration with the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) conducted an NHLBI funded pilot trial, which has shown the feasibility and safety of randomizing patients between IST and MUD BMT. In this cluster application, the Resource for Clinical Investigation in BMT (RCI BMT), the prospective clinical trial arm of the Center for International Blood and Marrow Transplant Research (CIBMTR), will serve as the Data Coordinating Center (DCC) to manage the definitive Phase III Randomized Controlled Trial (RCT) in collaboration with the Clinical Coordinating Center (CCC) partnership of NAPAAC and PTCTC. Our specific aims are to: 1) compare the proportion of SAA patients with immune suppression free survival with adequate counts at two years for patients randomized to IST versus BMT, including to understand the impact of either therapy on fertility, quality of life and biological factors, 2) support and manage the efficient implementation, governance and completion of this RCT, and 3) leverage existing systems and expertise to ensure adherence to high quality data collection. The proposed DCC provides an efficient and experienced infrastructure that leverages existing relationships and a framework which has successfully delivered clinical trials over 15 years, including a seasoned statistical team. These assets will ensure that this trial is designed, analyzed and conducted with the utmost integrity and efficiency and that it will meet its goal of advancing knowledge regarding the best therapy for children and young adults with SAA.