Inherited Immune Deficiencies Clinical Trial
Official title:
Allogeneic and Matched Unrelated Donor Stem Cell Transplantation for Congenital Immunodeficiencies or Patients With Autoinflammatory/Immunodysregulatory Conditions: Busulfan-Based Conditioning With Campath- 1H or h-ATG, Radiation, and Sirolimus
This study uses transplantation to treat patients with problems in their immune system. The immune system cells come from the bone marrow where they grow from special cells called stem cells. Giving patients stem cells from someone else may help to cure many patients with certain immune diseases. This is called 'bone marrow transplantation'. This procedure can have side effects that are life-threatening. To try to make transplantation safer we are using lower doses of the medications used in preparing the patient for the transplant. 'Conditioning' treatments are given to patients to create space in their bone marrow. This lets the cells of the donor go into the bone marrow and produce normal immune cells. This study will use lower doses of a drug called busulfan and lower doses of radiation than what are currently being used in other kinds of bone marrow transplantation for other diseases. Another problem that can occur with bone marrow transplantation is 'graft-versus-host disease'. This happens when the cells of the donor attacks different parts of the patient s body. This study will use a medicine called sirolimus instead of the usual medicine, cyclosporine, to prevent graft-versus-host disease. To go onto this study, you must have: 1. A severe immune deficiency, such as chronic granulomatous disease or leukocyte adhesion deficiency. 2. Have problems from the disease that call for stem cell transplantation. 3. You must also be between the ages of 2 and 40 years. Two groups of patients are included in this study: 1. Patients who have a brother or sister that have stem cells that match the patient. This is known as an allogeneic matched sibling transplant. 2. Patients who do not have a matched sibling donor but have a donor that matches in the National Marrow Donor Program. This is know as matched unrelated donor transplantation. Patients will have the following procedures: - To create space in the bone marrow, patients are given two drugs, Campath-1H and busulfan. To prevent the body from getting rid of the donated cells, patients are given sirolimus. On the day before the BMT, patients in the matched unrelated donor group also receive a low-dose of whole-body radiation. This will further improve the chances that the patients body will accept the donor cells. - Patients will get the donor stem cells through an intravenous (IV) line that goes into a vein in their body. The cells make their way to the bone marrow space and slowly refill the marrow over the next several weeks. Patients will usually stay in the hospital for 30 days after the transplant. - For the first 3 months after the transplant, patients are watched closely. The patients will have frequent visits to the clinic. During these visits the patient will have a physical examination and blood tests. The doctor and nurse will also check any symptoms the patient may have. At day 100 after the transplant a sample of bone marrow is taken. - Patients will continue to be followed periodically for at least 5 years after the transplant.
This is an open-label pilot study of HLA-matched allogenic and matched unrelated donor (MUD) hematopoietic stem cell (HSC) transplant (also referred to as peripheral blood stem cell (PBSC) or bone marrow transplant (BMT)) for patients with X-linked severe combined immune deficiency (XSCID). XSCID is caused by mutations in the IL2RG gene encoding the interleukin receptor signaling gamma chain [gamma c]). The study population are older children (greater than or equal to 2 years of age) and adults (less than or equal to 40 years of age) who are experiencing deteriorating and/or dysfunctional immunity and 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 and graft-versus-host disease (GvHD) prevention regimens achieve sufficient engraftment of donor hematopoietic stem cells (HSCs) to facilitate robust restoration of cellular immunity (T cell/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 at significantly enhancing the risk of post-transplant virus infection. One target population are XSCID 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 are XSCID patients with partial production or function of gamma c or XSCID patients with clonal somatic reversion of the mutation in the IL2RG gene, who have less severe immune deficiency in childhood. A subset of patients from all of these target XSCID populations may experience progressive deterioration of immune function leading to acute and chronic medical problems that warrant consideration of allogeneic or MUD transplant to restore immunity. The conditioning and GvHD prevention regimens for this HSC transplant protocol are designed to use mobilized peripheral blood stem cells (PBSC) or bone marrow (BM) (if mobilization is not possible) from either an HLA-matched related sibling donor (alloPBSC) as first choice or from an HLA matched unrelated donor (MUD) for those without an appropriate HLA-matched related sibling donor. If there is no appropriately matched sibling donor nor MUD adult donor available, then an appropriately matched cord blood from the cord blood registries may be used for small children XSCID recipients. For the alloPBSC (or alloBM) transplantation (referred to as Group 1), we propose using a busulfan-based, nonmyeloablative conditioning regimen combined with horse Anti-human Thymocyte Globulin (h-ATG) immune suppression conditioning plus post-transplant sirolimus for tolerance inducing immunosuppressant to prevent GvHD. For the MUD or unrelated cord blood transplantation (referred to as Group 2), we will use a similar conditioning regimen, with a few modifications that include addition of total body irradiation with shielding and reduction in busulfan dosing, changes designed to address the increased risk of graft rejection with HLA-matched but unrelated donor HSC. ;