• Attain phenotypic correction of the disease.
  

• Obtain engraftment without development of graft vs host disease, establish stable mixed chimerism, improve radity of immune reconstitution, determine days to neutrophil recovery, measure incidence of CMV reactivation, measure transfusion requirements.
  

Drug: Busulfan
N/A
Drug: Campath-1 H
N/A
Drug: Sirolimus
N/A
Procedure: BMT
N/A
Procedure: Apheresis
N/A
Procedure: Total Body Irradiation
N/A
Procedure: GCSF Injections
N/A

Congenital immunodeficiencies - including chronic granulomatous disease, leukocyte adhesion deficiency and others - comprise a group of disorders in which the immune system fails to develop normally due to a genetic defect. As a result, affected patients suffer from recurrent infections and have a significantly shortened life expectancy. The current management of these patients is limited to close surveillance for infections, administration of prophylactic antimicrobials, and rapid and aggressive treatment of suspected and documented infections with broad-spectrum antibiotics. Although often effective, these treatments can require long hospitalizations, impacting on the overall quality of life significantly, and lead to significant morbidity, such as renal failure and deafness.

Currently, the only available cure for these disorders is bone marrow transplantation, which most commonly uses an HLA-matched related sibling as the donor (Allogeneic Stem Cell Transplantation). However, as only 30% of patients in the general population have an HLA- matched related sibling, allogeneic related transplantation is often not an option, resulting in the need for matched unrelated donor transplantation. The National Marrow Donor Program serves as both a national registry of volunteers who are willing to donate progenitor cells to eligible recipients as well as a repository of cord blood products. Despite continued improvement in the use of transplantation schemas - including the development of nonmyeloablative regimens - there remain significant morbidity and mortality associated with transplantation, in particular, graft versus host disease (GvHD).

GvHD is a result of the graft recognizing host antigens as foreign, typically in the presence of inflammation, and results in a type of iatrogenic autoimmune disease. For patients with non-malignant diseases, the aim of the transplant is solely to replace the defective or deficient cell population. Furthermore, as a graft versus tumor effect is not required, regimens designed to establish tolerance induction and/or stable mixed chimerism may be preferable for cure in this patient population; therefore, alternate transplant strategies can and should be used to further suppress the development of any GvHD effects. To reduce the morbidity and mortality associated with transplantation, we propose to use a combination of uniquely designed conditioning regimens to achieve adequate engraftment in congenitally immunodeficient patients, using either alloPBSC transplantation for patients with an HLA-matched related sibling donor, or MUD transplantation for those without an appropriate HLA-matched related sibling donor. For the alloPBSC transplantation (Group 1), we propose using a novel busulfan-based, nonmyeloablative conditioning regimen combined with Campath-1-H or h-ATG, an immunosuppressive monoclonal antibody, and sirolimus, a tolerance inducing immunosuppressant used for GvHD prophylaxis. For the MUD transplantation (Group 2), we will also use a similar conditioning regimen, with a few modifications (due to the increased risk of graft rejection with HLA-matched but unrelated cells) to perform matched unrelated and cord blood transplantation in patients with immunodeficiencies. Given its novelty, this combination will be tested in a pilot trial and will be compared to historical controls.