Matched Unrelated or Non-Genotype Identical Related Donor Transplantation For Chronic Granulomatous Disease

Study Overview
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Brief Summary
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This study is for patients with chronic granulomatous disease (CGD), which is a disorder of the immune system that puts them at risk for severe infections. CGD is caused by a genetic defect that stops or prevents the white blood cells from killing certain bacteria and fungi. This condition cannot presently be cured by standard treatment with drugs or surgery. Medicine including antibiotics, antifungals, and interferon gamma, may help some patients with CGD; however even with continuous treatment, most patients with CGD will have chronic and recurrent infections. Transfusion of white blood cells may help overcome infection, but white cell transfusions lead to allergic reactions and fever and the benefit of transfusion lasts only a matter of hours. Ultimately, chronic infections can damage or injure the body organs. Injury to the lung or liver can lead to lung or liver failure and death. Medicines used to treat infection can damage body organs too. Infections may become resistant to antibiotic or antifungal treatment, and infections not responding to treatment can be deadly. It is now known that under specific conditions and with special treatment, blood stem cells (the cells that make blood) can be transplanted from one person to another. Stem cell transplantation has been done for patients with CGD who have a healthy sibling and who share the same immune type (HLA type) as the patient. Stem cell transplantation allows healthy or normal white cells from the stem cell donor to grow or develop in the patient's bone marrow. These healthy white cells can fight infection and prevent future infections for a patient with CGD. Patients on this study will receive stem cells from a related or unrelated donor. The donor will be closely matched to the patient's immune type but the donor is not a sibling. The reason this treatment is investigational is that we do not know the likelihood of benefit that the patient will receive. It is possible that they will have great benefit, like some of the patients who have been transplanted from a brother or sister. It is possible that the side-effects of treatment may be too severe so that the transplant won't work. The purpose of this research study is to evaluate whether or not patients with CGD treated with a stem cell transplant from a non-matched and/or non-related donor can have a good outcome from the procedure with an acceptable number of side-effects.

Detailed Description
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In order to transplant stem cells we will need to give the patient drugs or high-dose chemotherapy to kill or destroy most of the blood forming and immune cells in the bone marrow. This is necessary to allow the donor stem cells to live and grow (engraft) in the bone marrow space. After the drug treatment is completed, the patient will be given the stem cells from the donor. The drug treatment is as follows: Day -9 Busulfan Day -8 Busulfan Day -7 Busulfan Day -6 Busulfan Day -5 Alemtuzumab, Fludarabine, Cyclophosphamide Day -4 Alemtuzumab, Fludarabine, Cyclophosphamide Day -3 Alemtuzumab, Fludarabine, Cyclophosphamide Day -2 Alemtuzumab, Fludarabine, Cyclosporine, Cyclophosphamide Day -1 REST Day 0 Stem cell infusion The day after the chemotherapy treatment is completed, the patient will receive the healthy stem cells by vein, like a blood transfusion. Once in the bloodstream, the marrow cells will go to the bone marrow and grow. It is also possible that if the marrow takes, it will cause a disease known as graft-versus-host disease (GVHD). To prevent GVHD, we will give the patient cyclosporine and Methotrexate. Methotrexate will be administered on Days 1, 3, 6 and 11 after the transplant. The cyclosporine therapy will continue for a longer period of time, however if the patient does not develop GVHD, it will be discontinued by 6 months after the stem cell transplant.

Official Title
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HLA Matched Unrelated or Non-Genotype Identical Related Donor Transplantation For Chronic Granulomatous Disease

Conditions
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Chronic Granulomatous Disease

Intervention / Treatment
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* Drug: Busulfan
* Biological: Alemtuzumab
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Cyclosporine
* Procedure: Stem Cell Infusion


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: CGD patients as documented by an abnormal NBT assay in a male patient and/or abnormal NADPH enzyme mutation confirmed by genetic analysis with abnormal NBT. Patients must not have an HLA genotype identical donor. Patients must have a 5/6 or 6/6 HLA-matched unrelated donor or a 5/6 or 6/6 HLA phenotype-matched related donor. Patients must have had at least one serious infection characteristic of those manifested in patients with CGD. Patients must not have active infection. An active infection may include the following: 1) clinical findings consistent with an infection such as fever, cavitary organ lesions, osteomyelitis; 2) progression of presumed infection based upon findings of diagnostic imaging (two or more studies at least 1 month a part). No cumulative organ dysfunction that, in the estimation of the treating physicians, will diminish the patient's likelihood to survive this procedure. Negative pregnancy test for post-pubertal female patients. Echocardiogram shortening fraction >/= 28%. DLCO 50% or greater predicted or FEV1 >/= 50% predicted. EXCLUSION CRITERIA: Active or uncontrolled infection (e.g. lung infection, cavitary organ lesions, osteomyelitis). Markedly elevated C reactive protein or sedimentation rate relative to patient's baseline. Invasive bone or bone marrow disease. Lack of potential hematologic blood product donors in the past (related to McLeod phenotype).
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allogeneic unrelated transplant<br>Conditioning from Day -9 to Day -1. Stem cells given on Day 0. Busulfan, alemtuzumab, cyclophosphamide, fludarabine, cyclosporine, stem cell infusion. | Drug: Busulfan<br>* Days -9 through -6 1 mg/kg initially (based on weight)<br>* Other names: Busulfex;Biological: Alemtuzumab<br>* Day -5 through Day -2 Dose is based on weight: Less than 15 kg: 3 mg More than 15 kg to 30 kg: 5 mg More than 30 kg: 15 mg<br>* Other names: Campath;Drug: Cyclophosphamide<br>* Days -5 through -2 50 mg/kg<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Day -5 through Day -2 30 mg/m^2<br>* Other names: Fludara;Drug: Cyclosporine<br>* Cyclosporine will be administered beginning Day -2. Initial dose will 5 mg/kg infused over 24 hours.<br>* Other names: Sandimmune;Procedure: Stem Cell Infusion<br>* Stem Cell: Either bone marrow, cord blood, or peripheral blood stem cells may be used for stem cell transplantation. It is desired to infuse: for bone marrow, nucleated cells ≥ 4 X 10^8/kg recipient weight; for cord blood ≥ 3 X 10^7/kg nucleated cells; for peripheral blood stem cells ≥ 1 X 10^/kg CD34+ cells.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Engraftment | To estimate the engraftment rate for patients with CGD using busulfan, cyclophosphamide, fludarabine and alemtuzumab (Campath 1H) as conditioning therapy for SCT from 5/6 or 6/6 HLA-matched unrelated or 5/6 or 6/6 HLA phenotype-matched related donors. | 28 days post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients That Have Complete Donor Chimerism After Transplant. | To estimate the likelihood of complete donor chimerism for patients with CGD using busulfan, cyclophosphamide, fludarabine and alemtuzumab (Campath 1H) as conditioning therapy for SCT from 5/6 or 6/6 HLA-matched unrelated or 5/6 or 6/6 HLA phenotype-matched related donors. | 120 days post transplant | 
| Number of Patients That Have Acute GVHD and Regimen Related Morbidity/Mortality Post Transplant. | To estimate the risk for acute GVHD and regimen related morbidity/mortality for patients with CGD following stem cell transplant from 5/6 or 6/6 HLA matched unrelated or 5/6 or 6/6 HLA phenotype matched related donors. | Assessed between day 0 and day 100 post transplant | 
| Number of Patients That Have Chronic GVHD and Regimen Related Morbidity/Mortality Post Transplant. | To estimate the risk for chronic GVHD and regimen related morbidity/mortality for patients with CGD following stem cell transplant from 5/6 or 6/6 HLA matched unrelated or 5/6 or 6/6 HLA phenotype matched related donors. | Assessed between day 100 and day 365 post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stem Cell Transplant, Chronic Granulomatous Disease, Fludarabine, Busulfan, Cyclophosphamide