Matched Related and Unrelated Donor Stem Cell Transplantation for Severe Combined Immune Deficiency (SCID): Busulfan-based Conditioning With h-ATG, Radiation, and Sirolimus

This is an open-label pilot study of human leukocyte antigen (HLA)-matched related and unrelated donor hematopoietic stem cell (HSC) transplant (also referred to as peripheral blood stem cell [PBSC] transplant or bone marrow transplant [BMT]) for up to 20 patients with severe combined immune deficiency (SCID). SCID is most commonly caused by mutations in the IL2RG gene encoding the interleukin (IL) receptor signaling gamma chain (gamma c); however, patients with JAK-3 mutations have the same phenotypes and are similarly affected. The study population is older children (greater than or equal to 3 years of age) and adults (less than or equal to 40 years of age) who are experiencing deteriorating and/or dysfunctional immunity and/or any of a constellation of severe or chronic medical problems warranting transplantation. The study is designed to evaluate whether the use of uniquely designed transplant conditioning either containing total body irradiation (TBI) or not, along with a graft-versus-host disease (GvHD) prevention regimen achieves sufficient engraftment of donor HSCs to facilitate robust restoration of cellular immunity (T cell/natural killer [NK] cell number and function) including thymic function, and humoral immunity (B cell number and function), while at the same time enhancing tolerance of the donor graft in a fashion that reduces the occurrence of GvHD but not significantly enhancing the risk of post-transplant viral infection. One target population is SCID patients who received matched sibling or haploidentical lymphocyte-depleted transplants as infants with little or no myeloid conditioning, resulting in variable restoration of T cell immunity, but little or no restoration of NK or B cell immunity. Another target population is SCID patients with partial production or function of gamma c or JAK3 or SCID patients with clonal somatic reversion of the mutation in the IL2RG or JAK-3 gene, who have less severe immune deficiency in childhood. A subset of patients from all of these target SCID populations may experience progressive deterioration of immune function leading to acute and chronic medical problems that warrant consideration of allogeneic transplant to restore immunity.

The conditioning and GvHD prevention regimens for this HSC transplant protocol are designed to use mobilized PBSCs or bone marrow (if mobilization is not possible) from either an HLA-matched related donor (MRD) as first choice or from an HLA-matched unrelated donor (MUD) for those without an appropriate HLA-MRD. If there is no appropriate MRD nor MUD adult donor available, then an appropriate cord blood from the cord blood registries may be used for small children SCID recipients. We propose using a busulfan-based, nonmyeloablative conditioning regimen plus or minus TBI combined with horse anti-thymocyte globulin (h-ATG) immune suppression conditioning plus post-transplant sirolimus as a tolerance-inducing immunosuppressant to prevent GvHD.