Chronic Granulomatous Disease
Conditions
Keywords
Haplo-identical, Allogeneic Stem Cell Transplant, Peripheral Blood Stem Cell Transplant, Graft Versus Host Disease, Non-Myeloablative Conditioning Regimen
Brief summary
Background: CGD causes infections and inflammation. The only cure currently is a bone marrow transplant. Most often a perfectly matched bone marrow donor is used. Researchers want to see if they can lower the risks of using a mismatched donor. Objectives: To see if it is safe to use a related bone marrow donor who is only a partial match to a person with CGD. To see how well drugs given to a person before and after transplant help the body accept the transplant. Eligibility: People ages 4-65 with CGD for whom stem cell transplant may be a cure and who do not have a perfectly matched donor, related or unrelated. Design: Participants will be screened with: Medical history Physical exam Blood tests Participants will be admitted to the hospital about 2 weeks before the transplant. They will have blood, urine, breathing, and heart tests. They may have CT and/or MRI scans. They will have a needle inserted into their hipbone to remove marrow. They will have dental, neurologic, and psychologic tests. They will have a central catheter placed: A line will be placed into a vein in their upper chest. They will get drugs, chemotherapy, and radiation to prepare for the transplant. Participants will receive the donated cells through their catheter. The cells will be from one of their relatives. Participants will stay in the hospital about 6 weeks after the transplant. After they leave the hospital, participants will have to stay in the area with visits about 2 times a week for approximately 100 days post transplant. Then visits will be every 3 to 6 months for 2 years. Then visits will be once a year.
Detailed description
Allogeneic transplant using human leukocyte antigen (HLA) matched donors, both related and unrelated, has proven curative for patients with various immunodeficiencies, including those with ongoing infections. However, donor availability remains a limiting factor in the application of this treatment modality. For this protocol, a haploidentical donor is a related donor with more than 1 HLA antigen mismatch. The use of haploidentical related donors has in the past been fraught with a greater rate of complications related to both higher rates of graft versus host disease (GvHD) and delayed immunorecovery. Newer transplant regimens appear to have diminished these risks and improved outcomes. We propose using a reduced intensity novel conditioning regimen using alemtuzumab, targeted busulfan, and low dose total body irradiation (see schema below) followed by post-transplant cyclophosphamide for patients with chronic granulomatous disease (CGD) who do not have an HLA matched donor but whose circumstances necessitate the use of a potentially curative, albeit high-risk treatment modality. However, patients with CGD have high rates of Crohn s Disease-like inflammatory bowel disease, predominantly colitis, where uncontrolled severe IBD may increase risk of GvHD. For this reason, the first 10 patients enrolled will exclude those deemed to have intestinal inflammation in the severe category. As part of the study design, the protocol will enroll patients sequentially.
Interventions
DRUGBusulfan
3 days of IV Busulfan. An alkylating chemotherapeutic agent determined to have broad myelosuppressive effects. On this study is being used as part of conditioning regimen for myelosuppressive properties as per package insert and standard of care.
DRUGAlemtuzumab
5 days of IV Alemtuzumab. A humanized monoclonal antibody directed against CD52 (which is abundantly expressed on all human lymphocytes), and causes T cell activation in vitro as well as complement-mediated lysis and antibody-dependent cellular toxicity. For this study, being used as part of the conditioning regimen per package insert and standard of practice.
DRUGCyclophosphamide
2 days of IV Cyclophosphamide. This is an antineoplastic, and for this study is bine used for its immunosuppressive mechanism of action per package insert and standard of care
DRUGSirolimus
Post Peripheral blood stem cell infusion. It is used for its immunosuppressive mechanism of action.
RADIATIONTotal Body Irradiation
2 fractionated doses on -2 day. It is used for its immunosuppressive mechanism of action. It is SOP for conditioning for transplant.
BIOLOGICALAllogeneic peripheral blood stem cell
IV infused donor peripheral blood stem cell. Stem cells are cells that give rise to the blood cells - red blood cells that carry oxygen, white blood cells that help the body to fight infections, and platelets that help make the blood clot. Collected and infused per the standard of operating procedures established by the Department of Transfusion Medicine.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: * Must have sufficient complications from underlying disease to warrant undergoing transplantation. (History of one or more life threatening infections and/or an ongoing infection not responsive to current medical therapy and/or ongoing inflammation along with an oxidase level within quartile 1 or 2. * Patients will be reviewed at a multidisciplinary meeting for assessment of the risk/benefit ratio of transplant for the patient to determine suitability for this high risk treatment. This multidisciplinary meeting is a combined NCI/NIAID bimonthly meeting comprised of investigators from multiple branches of the NC and NIAID to review patients with immunodeficiencies being considered for various transplant protocols. * Patients who are deemed to have colitis in the severe category (severe colitis) as defined below in the Subject
Exclusion criteria
, who are at high risk for GvHD, will be included in enrollment to the protocol after 10 patients have completed the protocol regimen successfully. Patients among the first 10 may have colitis that is not deemed in the severe category. The success of the regimen will be determined as engraftment with a maximum GvHD of grade 2 (See the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment - Chimerism | Day 30, 100, 6mo, 12 mo | Myeloid chimerism \>50% without incurring grade 3 steroid refractory or any grade 4 acute graft versus host disease or severe extensive chronic graft versus host disease post transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Viral immune titrels | 6 mo, 1 year, 2 year, and 3 years post transplant. | Viral Immune Reconstitution using viral reactivation as a marker. |
| Overall Survival/Event-Free survival | continuous observation/Day +14, 30, 60, 100, 6 mo, 12 mo, 18 mo, 2,3,4,5 years | 3\) Assessment of rates of Overall Survival and Event Free Survival (event being late graft loss or recurrence of CGD phenotype). |
| DHR as a marker of normal neutrophil function | Day 30, 100, 6 month and 1 year | 1\) Myeloid immune reconstitution levels with DHR as a marker of normal neutrophil function by 1-year post transplant. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORElizabeth M Kang, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Outcome results
None listed