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.