A 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

一项针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进行非亲缘供体骨髓移植与免疫抑制治疗比较的 III 期随机试验

• 批准号: 10722602
• 负责人: Michael A Pulsipher
• 金额: $ 70.48万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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/10722602
• 关键词: Phase; III; Randomized; Trial; Comparing

Project Summary/Abstract Acquired severe aplastic anemia (SAA) is a rare bone marrow failure disorder with an annual incidence of 3 per million in North America (>300 cases < age 25 in the US yearly). The disease can be treated and often cured by either immune suppression therapy (IST) or hematopoietic stem cell transplantation (HSCT), with the recommended approach in SAA being early matched sibling donor bone marrow transplantation (BMT). However, only 20% of patients have sibling donors, consequently, the large majority of patients receive IST for initial therapy. From initiation of IST it takes 2-6 months to see hematologic improvement, with responses occurring 70-80% of the time in children. Unfortunately, 20-30% of patients eventually relapse, requiring additional immune suppression, and some become cyclosporin-dependent. The results of matched unrelated donor (URD) BMT for SAA has improved significantly over the past decade, with studies reporting similar outcomes for BMT using URD compared to MSD. Although these data are provocative, URD BMT carries significant risks, and most consensus opinions still conclude that IST should be considered standard of care when a matched sibling donor is not available, until a definitive study shows otherwise. 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 R34-funded pilot trial to determine feasibility and safety of randomizing between IST and URD BMT. Our recently published results of the first 23 patients showed high rates of acceptance of randomization, receipt of randomized therapy without significant adverse events, and rapid institution of definitive therapy (IST or BMT) (Pulsipher et al., Pediatric Blood and Cancer, 2020). Having demonstrated feasibility, we submit this application to support a paradigm-changing randomized trial in partnership with the Center for International Blood and Marrow Transplant Research (CIBMTR). The study proposes a multi-center phase III trial to compare the percentage of newly diagnosed SAA patients with immune suppression-free survival with adequate counts (ISFS-AC) at 2-years between those randomized to IST vs 9-10/10 HLA matched URD BMT. The study will also address patient-reported outcomes and fertility preservation in each arm and explore critical biological correlates including assessing germline genetic mutations associated with pediatric SAA that may affect response to BMT or IST and the development of clonal hematopoiesis following IST vs BMT in pediatric SAA. The study proposed would represent the largest randomized study in pediatric SAA ever attempted with the goal of providing practice-altering conclusions to the field.

项目概要/摘要 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 北美每百万人（美国每年 < 25 岁的病例> 300 例）。这种疾病是可以治疗的，并且经常 通过免疫抑制疗法（IST）或造血干细胞移植（HSCT）治愈 SAA 的推荐方法是早期匹配的同胞供体骨髓移植 (BMT)。 然而，只有 20% 的患者有兄弟姐妹捐赠者，因此，绝大多数患者接受 IST 是为了 初始治疗。从开始 IST 起，需要 2-6 个月才能看到血液学改善并产生反应 70-80%的时间发生在儿童身上。不幸的是，20-30% 的患者最终会复发，需要 额外的免疫抑制，有些变得依赖环孢菌素。匹配不相关的结果 过去十年中，SAA 的捐赠者 (URD)​​ BMT 有了显着改善，研究报告了类似的结果 与 MSD 相比，使用 URD 进行 BMT 的结果。尽管这些数据具有挑战性，但 URD BMT 携带 重大风险，大多数共识意见仍然认为 IST 应被视为护理标准 当没有匹配的兄弟姐妹捐赠者时，直到明确的研究表明情况并非如此。为了解决这个问题 北美小儿再生障碍性贫血联盟 (NAPAAC) 与 儿科移植和细胞治疗联盟 (PTCTC) 进行了 NHLBI R34 资助的试点 确定 IST 和 URD BMT 之间随机化的可行性和安全性的试验。我们最近发布的 前 23 名患者的结果显示随机化接受率很高，接受随机化 无明显不良事件的治疗，并快速建立明确治疗（IST 或 BMT）（Pulsipher 等人，儿科血液和癌症，2020）。经证明可行性后，我们将此申请提交给 与国际血液和血液中心合作支持一项改变范式的随机试验 骨髓移植研究（CIBMTR）。该研究提出了一项多中心 III 期试验来比较 新诊断的 SAA 患者中无免疫抑制生存且计数充足的百分比 (ISFS-AC) 在随机接受 IST 与 9-10/10 HLA 匹配 URD BMT 的患者之间进行 2 年观察。该研究将 还解决患者报告的结果和每只手臂的生育力保存，并探索关键的生物学 相关性包括评估与儿科 SAA 相关的种系基因突变，这可能会影响 儿科 SAA 对 BMT 或 IST 的反应以及 IST 与 BMT 后克隆造血的发展。 拟议的研究将代表儿科 SAA 有史以来最大的随机研究 为该领域提供改变实践的结论的目标。