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.
