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

• Treat patients with Chronic Granulomatous Disease refractory to conventional therapy and without a HLA matched sibling donor by performing stem cell transplantation from 5/6 or 6/6 HLA matched unrelated or 5/6 or 6/6 HLA phenotype matched related donors. [ Time Frame: 120 days ] [ Designated as safety issue: Yes ]
• Estimate engraftment rate [ Time Frame: 120 days ] [ Designated as safety issue: Yes ]
• To estimate the risk for acute and chronic GVHD and regimen related morbidity/mortality for patients with CGD following SCT from 5/6 or 6/6 HLA matched unrelated or 5/6 or 6/6 HLA phenotype matched related donors. [ Time Frame: 120 days ] [ Designated as safety issue: Yes ]
• To examine the potential for reversal of organ toxicity (e.g. lung, liver, intestine) following engraftment and stable normal neutrophil function. [ Time Frame: 120 days ] [ Designated as safety issue: No ]

• Estimating the risk for acute and chronic GVHD and regimen related morbidity/mortality for patients with CGD following SCT from 5/6 or 6/6 HLA matched unrelated or 5/6 or 6/6 HLA phenotype matched related donors. [ Time Frame: 120 days ] [ Designated as safety issue: Yes ]
• Examining the potential for reversal of organ toxicity (e.g. lung, liver, intestine) following engraftment and stable normal neutrophil function [ Time Frame: 120 days ] [ Designated as safety issue: No ]

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. The course over time of CGD may differ in severity among patients, but those children who develop severe infection at a young age are most likely to have a more severe clinical course. Medicine including antibiotics, antifungals, and interferon gamma, may help some patients with CGD; however even with continuous treatment with these medications, most patients with CGD will have chronic and recurrent infections. Transfusion of healthy or normal 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 such as the lung, liver, or bone. Injury to the lung or liver can lead to lung or liver failure and death. Medicines used to treat infection can damage body organs such as the kidney. 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 transferred or transplanted from one person to another. Stem cell transplantation has been done for patients with CGD who have a healthy brother or sister 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 making the donor's white cells. 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 an unrelated donor. The donor will be closely matched to the patients immune type but the donor is not a brother or sister. This type of transplantation has been done only a few times for patients with CGD, although this type of transplant is commonly done for other reasons, e.g. leukemia. 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.

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. The Methotrexate will be administered on day 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.

• Drug: Busulfan

  days -9 through -6

  1 mg/kg initially (based on weight)

  Other Name: Busulfex
• Biological: alemtuzumab

  day -5 through day -2

  Dose is based on weight:

  Less than 15kg: 3mg

  More than 15kg to 30kg: 5 mg

  More than 30kg: 15mg

  Other Name: campath
• Drug: Cyclophosphamide

  days -5 through -2

  50 mg/kg

  Other Name: cytoxan
• Drug: Fludarabine

  day -5 through day -2

  30 mg/m^2

  Other Name: Fludara
• Drug: cyclosporine
  Cyclosporine will be administered beginning day -2. Initial dose will 5 mg/kg infused over 24 hours.
  Other Name: Sandimmune
• Procedure: stem cell infusion
  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.

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 should have an unsatisfactory response to g-interferon defined as severe invasive infection while on therapy or intolerance to interferon necessitating withdrawal from treatment.

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)