Hematopoietic cell transplantation for correction of primary immunodeficiencies

The first hematopoietic cell transplants in humans with durable success were reported in 1968, in three patients with primary immunodeficiencies who received grafts from HLA-matched siblings (two with SCID and one with Wiskott-Aldrich syndrome). Significant progress has been made in correcting lethal primary immunodeficiencies (PIDs) with hematopoietic transplantation in the ensuing 40 years due to several factors: (1) ability to phenotype and quantitate (CD34+) hematopoietic stem cells, (2) advent of high-resolution tissue typing, (3) availability of closely matched unrelated donor bone marrow, peripheral blood stem cells, and cord blood, and (4) the application of reduced intensity conditioning regimens pre-transplant. Furthermore, the genetic basis of the majority of lethal PIDs has been defined, allowing more accurate studies of the natural history of the disorders without HCT intervention, and providing a compelling rationale for early transplantation in disorders with median survivals of 15-20 years. In the current era, we can identify several factors, which influence the ultimate success of HCT for PID. These include the age at transplant and general health of the patient. Young age is associated with fewer comorbidities and less frequent pre-transplant exposure to herpes family and enteric viruses, thus lowering the risks of related post-transplant complications. The careful selection of pre-transplant conditioning can significantly reduce early TRM in patients with certain immunodeficiencies, and increase the probability of durable engraftment in others. Because of the specific needs of children with PIDs, HCT from unrelated donors should, ideally, be performed in centers with extensive expertise and experience in the treatment of such disorders. In such centers, donor selection based on high-resolution tissue typing, younger age and specific viral immunity has led to survival rates following matched unrelated donor HCT for PIDs, which are very similar to those obtained with HCT from matched sibling donors. While ultimate success rates are similar, transplant-related management of children receiving unrelated grafts is considerably more complicated and prolonged than following matched sibling HCT.