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

项目摘要/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 北美为每百万人(美国每年为300例，年龄25岁)。这种疾病是可以治疗的，而且经常 通过免疫抑制疗法(IST)或造血干细胞移植(HSCT)治愈， SAA的推荐方法是早期相合同胞供者骨髓移植(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治疗 初步治疗。从开始IST开始，需要2-6个月的时间才能看到血液学的改善，并有反应 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，有些会变得依赖环孢素。匹配无关的结果 在过去的十年中，SAA的供者(URD)骨髓移植有了显著的改善，研究报告了类似的 使用URD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URD BMT携带 重大风险，大多数共识意见仍然认为，IST应该被视为护理的标准 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。要解决这个问题 挑战，北美儿童再生障碍性贫血联合会(NAPAAC)与 儿童移植和细胞治疗联盟(PTCTC)，进行了一项由NHLBI R34资助的试点 试验确定在IST和URD骨髓移植之间随机分组的可行性和安全性。我们最近出版的 前23名患者的结果显示，接受随机分组的比率很高，接受随机分组 没有重大不良事件的治疗，以及快速建立最终治疗(IST或BMT)(Pulsipher 等人，《儿科血液与癌症》，2020年)。在论证了可行性后，我们将此申请提交给 与国际血液和营养中心合作，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，以比较 新诊断的SAA患者无免疫抑制存活且计数充足的百分比 (ISFS-AC)在随机分为IST组和9-10/10组的URD骨髓移植患者之间的2年。这项研究将 还解决了患者报告的结果和每条手臂的生育能力保留问题，并探索关键的生物学 相关因素包括评估与可能影响儿童SAA的种系基因突变 儿童SAA患者骨髓移植与骨髓移植后对骨髓移植的反应和克隆性造血的发展。 这项拟议的研究将是有史以来在儿科SAA中尝试的最大规模的随机研究 目标是向实地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.