1/2A 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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ABSTRACT Acquired severe aplastic anemia (SAA) is a rare bone marrow failure disorder with an annual incidence of 3-4 per million in North America (300-500 cases < age 25 in the US yearly). The large majority of cases are caused by autoimmune destruction of hematopoietic stem cells (HSCs); accordingly the disease can be treated and often cured by either immune suppression therapy (IST) or bone marrow transplantation (BMT). The ATG/ cyclosporine (CsA) combination developed in the 1990s is the preferred IST approach for newly diagnosed SAA patients and has response rates of 60-80%, with 5-year survival exceeding 90%. BMT from an HLA matched sibling donor (MSD) is the standard for initial therapy for younger, newly diagnosed patients with long-term survival rates of over 95% however, only 20% of patients have a suitable sibling donor, consequently, the large majority of patients receive IST for initial therapy. Outcomes of matched unrelated donor (MUD) BMT for SAA have improved significantly over the past decade, with studies reporting similar outcomes for BMT using MUD compared to MSD. Although these data are provocative, MUD BMT carries significant risks, and a state of equipoise exists between the two approaches. 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 funded pilot trial, which has shown the feasibility and safety of randomizing patients between IST and MUD BMT. In this cluster application, the Resource for Clinical Investigation in BMT (RCI BMT), the prospective clinical trial arm of the Center for International Blood and Marrow Transplant Research (CIBMTR), will serve as the Data Coordinating Center (DCC) to manage the definitive Phase III Randomized Controlled Trial (RCT) in collaboration with the Clinical Coordinating Center (CCC) partnership of NAPAAC and PTCTC. Our specific aims are to: 1) compare the proportion of SAA patients with immune suppression free survival with adequate counts at two years for patients randomized to IST versus BMT, including to understand the impact of either therapy on fertility, quality of life and biological factors, 2) support and manage the efficient implementation, governance and completion of this RCT, and 3) leverage existing systems and expertise to ensure adherence to high quality data collection. The proposed DCC provides an efficient and experienced infrastructure that leverages existing relationships and a framework which has successfully delivered clinical trials over 15 years, including a seasoned statistical team. These assets will ensure that this trial is designed, analyzed and conducted with the utmost integrity and efficiency and that it will meet its goal of advancing knowledge regarding the best therapy for children and young adults with SAA.