Donor Stem Cell Transplantation for Congenital Immunodeficiencies
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:
- A severe immune deficiency, such as chronic granulomatous disease or leukocyte adhesion deficiency.
- Have problems from the disease that call for stem cell transplantation.
- You must also be between the ages of 3 and 65 years.
Two groups of patients are included in this study:
- Patients who have a brother or sister that have stem cells that match the patient. This is known as an allogeneic matched sibling transplant.
- 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.
HLA Matched Transplant
Drug: Campath-1 H
Procedure: Total Body Irradiation
Procedure: GCSF Injections
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- 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 require...
|Study Start Date:||January 2007|
|Estimated Study Completion Date:||August 2015|
|Estimated Primary Completion Date:||August 2015 (Final data collection date for primary outcome measure)|
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 and subset of patients with autoinflammatory/immunodysregulatory conditions, 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.
|Contact: Nana Kwatemaa, R.N.||(301) firstname.lastname@example.org|
|Contact: Elizabeth M Kang, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL) 800-411-1222 ext TTY8664111010 firstname.lastname@example.org|
|Principal Investigator:||Elizabeth M Kang, M.D.||National Institute of Allergy and Infectious Diseases (NIAID)|