Historical overview of pediatric HSCT

With a better understanding of transplantation biology and immunology derived from animal models, hematopoietic stem cell transplantation (HSCT) in humans has become possible. Attempts at HSCT in humans were first reported as early as the 1930s. However, with the detonation of two atomic bombs at the end of World War II and advent of the “Atomic Age,” interest in HSCT as a treatment modality for the effects of exposure to sublethal and lethal doses of irradiation on bone marrow function was reignited. Before the mid-1970s, the majority of HSCTs in humans were performed for nonmalignant conditions with 40% for severe aplastic anemia and 15% for primary immunodeficiencies. While attempts were made to treat advanced, refractory acute leukemia patients with HSCT, they were generally unsuccessful and used identical twin sibling as the donor initially. The first reports of successful sustained engraftment occurred in the early 1960s, but these patients died from complications associated with what is now known as graft versus host disease. It was not until 1968 that there were reports of three infants with primary immunodeficiency conditions that were long-term survivors after matched sibling donor bone marrow transplantation. Of note, all three patients are still alive today. In the late 1970s, Thomas and his colleagues reported their findings that of 100 patients with refractory acute leukemia, 13 were alive and leukemia-free 1-4.5 years after undergoing HLA-identical sibling donor bone marrow transplantation. These results showed that some patients with advanced acute leukemia could be cured of their disease with HSCT and that HSCT should be undertaken in the first or second remission (i.e., not with active disease) if the patient has an HLA-matched sibling donor because outcomes would be predictably better. Thus, by the mid-1980s, approximately 75% of all allogeneic HSCTs were performed to treat leukemia, and the vast majority were with HLA-identical sibling donors. As supportive care improved, drugs (such as calcineurin inhibitors) became available for graft versus host disease (GvHD) prophylaxis, and the use of alternative donor HSCTs (including matched unrelated donors, mismatched related and unrelated donors, familial haploidentical donors, and umbilical cord blood) was investigated, HSCT became a viable option for many more patients. Furthermore, the development of less intensive conditioning regimens and use of alternative hematopoietic stem cell sources made HSCT a feasible treatment modality for those who would otherwise be ineligible for HSCT. Nowadays, HSCT is a very important treatment modality for both pediatric and adult patients for a wide range of malignant and nonmalignant disorders. This chapter is divided into two major sections with the first part focusing on the seminal discoveries in transplantation biology and immunology using animal models (scientific and preclinical perspective) and with the second part highlighting key human clinical reports related to HSCT (clinical perspective).