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

1/2A III 期随机试验，比较无关供体骨髓移植与免疫抑制治疗对新诊断患有严重再生障碍性贫血的儿童和年轻成人患者的影响

• 批准号: 10600143
• 负责人: Bronwen Shaw
• 金额: $ 137.69万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2029-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600143
• 关键词: Address; Adherence; Age; American; Aplastic Anemia; Area; Biological Factors; Biology; Biometry; Blood; Bone Marrow Transplantation; Bone marrow failure; Boston; Canada; Cell Therapy; Child; Child Care; Childhood; Clinical; Clinical Trials; Clinical Trials Network; Collaborations; Communication; Complement; Cyclosporine; Data; Data Collection; Data Coordinating Center; Dedications; Development; Disease; Enrollment; Ensure; Equipoise; Fertility; Funding; Goals; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human Resources; Immune; Immunosuppression; Incidence; Infrastructure; Knowledge; Lead; Leadership; Marrow; Medidata; Monitor; National Heart, Lung, and Blood Institute; Newly Diagnosed; North America; Outcome; Participant; Patients; Pediatric Hospitals; Phase; Pilot Projects; Quality of life; Randomized; Randomized, Controlled Trials; Reporting; Research; Research Personnel; Resources; Risk; Role; Running; Seasons; Siblings; Survival Rate; System; Transplantation; Wisconsin; arm; autoimmune pathogenesis; clinical application; clinical investigation; clinical research site; clinical trial enrollment; design; electronic data; electronic patient reported outcomes; experience; improved; international center; medical schools; member; novel therapeutic intervention; pilot trial; programs; prospective; randomized trial; recruit; research study; response; safety and feasibility; transplantation therapy; trial comparing; young adult

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.

抽象的 获得性严重再生障碍性贫血 (SAA) 是一种罕见的骨髓衰竭疾病，年发病率为 3-4 北美每百万人（美国每年 300-500 例 < 25 岁病例）。绝大多数情况是 由造血干细胞（HSC）的自身免疫性破坏引起；因此，该疾病可以是 通过免疫抑制疗法 (IST) 或骨髓移植 (BMT) 进行治疗并通常治愈。 20 世纪 90 年代开发的 ATG/环孢素 (CsA) 组合是新近治疗的首选 IST 方法。 诊断出SAA患者，有效率达60-80%，5年生存率超过90%。 BMT 来自 HLA 匹配的兄弟姐妹捐赠者 (MSD) 是年轻新诊断患者初始治疗的标准 长期存活率超过 95%，然而，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 作为初始治疗。匹配不相关的结果 过去十年中，SAA 的捐赠者 (MUD) BMT 有了显着改善，研究报告了类似的结果 与 MSD 相比，使用 MUD 进行 BMT 的结果。尽管这些数据具有挑衅性，但 MUD BMT 携带 存在重大风险，并且两种方法之间存在平衡状态。为了应对这一挑战， 北美儿科再生障碍性贫血协会 (NAPAAC) 与儿科合作 移植和细胞治疗联盟 (PTCTC) 进行了 NHLBI 资助的试点试验，该试验已 显示了在 IST 和 MUD BMT 之间随机分配患者的可行性和安全性。在这个集群中 应用程序，BMT 临床研究资源 (RCI BMT)，该组织的前瞻性临床试验部门 国际血液和骨髓移植研究中心（CIBMTR）将作为数据 协调中心 (DCC) 负责管理最终的 III 期随机对照试验 (RCT) 与 NAPAAC 和 PTCTC 的临床协调中心 (CCC) 合作。我们的具体 目的是： 1) 比较无免疫抑制生存期的 SAA 患者与充分生存期的比例 对随机接受 IST 与 BMT 的患者进行两年计数，包括了解两者的影响 对生育力、生活质量和生物因素的治疗，2) 支持和管理有效实施， 该 RCT 的治理和完成，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 提供了一个高效且经验丰富的团队 利用现有关系的基础设施和已成功交付临床的框架 超过 15 年的试验，包括经验丰富的统计团队。这些资产将确保该试验的设计， 以最大程度的完整性和效率进行分析和实施，并将实现其推进的目标 有关 SAA 儿童和年轻人最佳治疗的知识。