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

项目总结/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性疾病， 在北美每百万人（在美国每年>300例<25岁）。这种疾病是可以治疗的， 通过免疫抑制疗法（IST）或造血干细胞移植（HSCT）治愈， SAA中推荐的方法是早期匹配的同胞供体骨髓移植（BMT）。 然而，只有20%的患者有兄弟姐妹供体，因此，绝大多数患者接受IST的时间为 初始治疗从IST开始，需要2-6个月才能看到血液学改善， 70-80%发生在儿童身上。不幸的是，20-30%的患者最终复发，需要 额外的免疫抑制，有些变得依赖环孢霉素。结果匹配无关 在过去的十年中，SAA的供体（URD）BMT有了显著改善，研究报告类似 与MSD相比，使用URD的BMT结果。虽然这些数据是挑衅性的，URD BMT进行 重大风险，大多数共识意见仍然认为IST应被视为标准治疗 当没有匹配的同胞捐赠者时，直到确定的研究表明不是这样。为了解决这个 挑战，北美儿科再生障碍性贫血联盟（NAPAAC），与 儿科移植和细胞治疗联盟（PTCTC），进行了一项由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。我们最近出版的 前23名患者的结果显示，接受随机化的比例很高， 无显著不良事件的治疗，以及快速确定性治疗（IST或BMT）（Pulsipher 例如，儿科血液和癌症，2020）。经论证可行性后，我们将此申请提交给 与国际血液中心合作，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， 新诊断SAA患者的无免疫抑制生存率（计数充足）百分比 随机分配至IST组与9-10/10 HLA匹配的URD BMT组患者之间的2年（ISFS-AC）。这项研究将 还讨论了每组患者报告的结局和生育力保存，并探讨了关键的生物学 相关性，包括评估与儿童SAA相关的生殖系基因突变， 儿童SAA患者对BMT或IST的反应以及IST与BMT后克隆性造血的发展。 这项研究将代表有史以来最大的儿童SAA随机研究， 目标是为该领域提供改变实践的结论。

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.