Project Summary Acquired severe aplastic anemia (SAA) is a rare bone marrow failure disorder with an estimated annual incidence of 2 per million in North America (just over 600 new diagnoses in the United States each year). The large majority of cases may be caused by autoimmune destruction of hematopoietic stem cells (HSCs); accordingly SAA can be treated and often cured by either immune suppression therapy (IST) or marrow replacement through hematopoietic cell transplantation (HCT). HCT from a human leukocyte antigen (HLA) matched sibling donor (MSD) is considered the standard for initial therapy of younger, newly diagnosed patients with long-term survival rates of up to 95-100% in patients under 20. However, only 18-20% of patients will have matched sibling donors, consequently, the large majority of patients receive IST for initial therapy. We propose a phase II trial comparing up front matched unrelated donor (URD) HCT with IST for children and very young adults with SAA. The primary endpointwould be proportion of patients alive at 2 years and immune suppression free with adequate counts. We have an open and accruing pilot study that is assessing key feasibility issues with the clinical design including acceptance of randomization, timely acquisition of donors, and safety of HCT. In addition, the pilot is testing the feasibility of acquiring, shipping and processing key biological specimens obtained from patients located at institutions across the country that will allow us in the future to elucidate the immunologic phenotype and genomic landscape of the marrow, and to understand the mechanisms of response and toxicity. Success of this pilot study and the phase III trial proposed in this BMT CTN renewal application is strengthened by a joint effort between two strong, established consortia: the North American Pediatric Aplastic Anemia Consortium (NAPAAC) and the Pediatric Blood and Marrow Transplant Consortium (PBMTC). If successful, this phase III trial will improve short-term immune suppression free and long- term overall survival and quality of life in young patients with SAA.