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: 10368246
• 负责人: Michael A Pulsipher
• 金额: $ 69.23万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368246
• 关键词: Address; Adult; Adverse event; Affect; Age; American; Aplastic Anemia; Biological; Blood; Bone Marrow Transplantation; Bone marrow failure; Cell Therapy; Child; Childhood; Childhood Hematopoietic Neoplasm; Clinical; Collaborations; Consensus; Cyclophosphamide; Cyclosporine; Cyclosporins; DNA Sequence Alteration; Data; Disease; Disease-Free Survival; Donor Selection; Dose; Equus caballus; Failure; Fertility; Funding; Genetic; Goals; HLA Antigens; Hematology; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immune; Immunosuppression; In complete remission; Incidence; Institution; Marrow; Mind; Molecular; Movement; National Heart, Lung, and Blood Institute; Newly Diagnosed; North America; Oryctolagus cuniculus; Outcome; Patient Outcomes Assessments; Patients; Pediatric cohort; Phase; Publishing; Quality of life; Randomized; Relapse; Reporting; Research; Risk; Siblings; Survival Rate; Time; United States National Institutes of Health; Whole-Body Irradiation; arm; autoimmune pathogenesis; cohort; cytopenia; fertility preservation; fludarabine; graft failure; graft vs host disease; health related quality of life; human leukocyte antigen testing; improved; international center; mortality; pediatric patients; phase III trial; phase change; pilot trial; randomized trial; response; safety and feasibility; standard of care; therapy development; transplantation therapy; trial comparing; young adult

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.

项目摘要/摘要 获得的严重性性贫血（SAA）是一种罕见的骨髓衰竭障碍，年发病率为3 北美的百万（> 300例<美国年龄25岁）。该疾病可以治疗，并且经常 通过免疫抑制疗法（IST）或造血干细胞移植（HSCT）固化 SAA中推荐的方法是早期匹配的同胞供体骨髓移植（BMT）。 但是，只有20％的患者有同胞供体，因此，绝大多数患者接受了IST 初始疗法。从IST的启动开始需要2到6个月才能看到血液学改善，并有反应 在儿童中发生70-80％的时间。不幸的是，20-30％的患者最终需要复发，需要 额外的免疫抑制作用，有些成为环孢素依赖性。匹配无关的结果 在过去的十年中 与MSD相比，使用URD的BMT结果。尽管这些数据是挑衅的，但乌尔德BMT携带 重大风险，大多数共识的意见仍然得出结论，IST应视为护理标准 当匹配的兄弟姐妹捐赠者不可用时，直到确定的研究表明。解决这个问题 挑战，北美儿科性贫血联盟（NAPAAC）与 小儿移植和细胞治疗联盟（PTCTC）进行了NHLBI R34资助的飞行员 试验以确定IST和URD BMT之间随机化的可行性和安全性。我们最近出版的 前23名患者的结果表明，随机分配的接受率很高，接收到随机的率 没有重大不良事件的治疗，以及确定治疗的快速制度（IST或BMT）（Pulsipher） 等，儿科血液和癌症，2020年）。证明可行性后，我们将此申请提交给 与国际血液中心合作，支持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，以比较 有足够计数的新诊断为免疫抑制生存的新诊断的SAA患者的百分比 （ISFS-AC）在随机分为IST与9-10/10 HLA匹配的URD BMT的2年之间。研究将 还解决了每个手臂中患者报告的结果和生育能力，并探索关键的生物学 相关性，包括评估可能影响儿科SAA相关的种系基因突变 对BMT或IST的反应以及小儿SAA IST与BMT后克隆造血的发展。 提出的研究将代表有史以来最大的儿科SAA随机研究 为该领域提供改变实践的结论的目标。