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

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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.