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 stem cell transplantation (HSCT). HSCT 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 20% of patients will have matched family donors, consequently, the large majority of patients receive IST for initial therapy. We propose a pilot study at eight pediatric centers comparing up front matched unrelated donor (MUD) HSCT with IST for children and very young adults with SAA. The pilot study will assess key feasibility issues with the clinical design including acceptance of randomization, timely acquisition of donors, and safety of HSCT. In addition, we will test 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. This pilot study will lead to a paradigm shifting phase III trial to be carried out in 27 institutions nationwide where we will test our hypotheses that initial therapy with MUD HSCT will lead to improved immune suppression-free survival with superior hematopoietic recovery by 2 years from diagnosis, and will also result in a decrease in the high risk of late progression to MDS/AML. Success of this pilot study and the subsequent phase III trial is strengthened by the joint effort between two strong, established consortia: the North American Pediatric Aplastic Anemia Consortium (NAPAAC) and the Pediatric Blood and Marrow Transplant Consortium (PBMTC).
We propose a pilot study to determine the feasibility of randomizing children with acquired aplastic anemia for either immunosuppression therapy (current standard of care) with highly matched unrelated donor hematopoietic stem cell transplant. If the pilot is successful, the planned subsequent phase III study of 27 institutions will lead to a change in standard of care for children with acquired aplastic anemia in North America and worldwide.
