Protocol Number: 01-I-0013

Title:

HLA-Matched, Peripheral Blood Stem Cell Transplantation Using Low Intensity Conditioning to Treat Patients with Chronic Granulomatous Disease Who Are Actively Infected

Number:

01-I-0013

Summary:

This study will investigate the safety and effectiveness of a new stem cell transplant procedure for treating chronic granulomatous disease (CGD) in patients with active infection. CGD is an inherited disorder of neutrophils-a type of infection-fighting white blood cell-that leaves patients vulnerable to life-threatening infections. Standard treatment with antibiotics, and sometimes surgery, is not always successful, and patients with persisting infections have a poor long-term prognosis.

Transplantation of donated stem cells (cells produced by the bone marrow that mature into the different blood components-white cells, red cells and platelets) can cure CGD. However, this procedure carries a significant risk of death, particularly in patients with active infection, because it requires completely suppressing the immune system with high-dose chemotherapy and radiation. In addition, lymphocytes-another type of infection-fighting white blood cell-from the donor may cause what is called graft vs. host disease (GvHD), in which the donor cells "see" patient's cells as "foreign" and mount an immune response to reject them. To try to reduce these risks, patients in this study will be given low-dose chemotherapy and no radiation, a regimen that is easier for the body to tolerate and involves a shorter period of complete immune suppression. Also, the donor's lymphocytes will be removed from the rest of the stem cells to be transplanted, reducing the risk of GvHD.

Patients with CGD between the ages of age 1 and 55 years old who have an active non-viral infection may be eligible for this study. They will have a medical history, physical examination and blood tests (including testing for adequacy of the genetic match with the donor). A bone marrow sample will be taken to evaluate disease status. This test, done under a local anesthetic, uses a special needle to draw out bone marrow from the hipbone. A central venous catheter (flexible plastic tube placed in a vein) will be put in place before treatment begins. It will be used to draw and transfuse blood, give medications, and infuse the donated stem cells.

Several days before the transplant procedure, patients will start low-dose chemotherapy with cyclophosphamide and fludarabine, two commonly used anti-cancer drugs. They will also be given anti-thymocyte globulin to prevent rejection of the donated cells. When this conditioning therapy is completed, the stem cells will be infused through the central line. Patients will be given cyclosporine 4 days before and 3 months after the stem cell transplant to help prevent rejection.

About 3 weeks after the transplant, patients will be discharged from the hospital. They will return for follow-up clinic visits weekly and then twice weekly for 3 months. These visits will include a symptom check, physical examination, and blood tests. Blood transfusions will be given if needed. Subsequent visits will be scheduled at 4, 6, 12, 18, 24, 30 and 36 months after the transplant, or more often if required, and then yearly.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

PATIENT:

Ages 1-55 years.

DHR proven CGD: Includes gp91phox, p47phox, p22phox, and p67phox deficiency.

Must have an active, life threatening non-viral infection that persists despite adequate and appropriate medical or surgical therapy (continued presence of pathogens on histology, culture positivity or continued radiographic evidence of infection). Patients with a progressive infectious process despite appropriate medical or surgical intervention may be considered for expedited enrollment into the study.

HIV negative.

No major organ dysfunction precluding transplantation.

HLA identical sibling or parent compatible at all 6 of the HLA A, B and DR antigens by molecular typing techniques.

Left ventricular ejection fraction greater than 35% predicted.

ECOG performance status of 0-3.

DONOR:

HLA identical sibling or parent donor.

Fit to receive G-CSF and give peripheral blood stem cells (weight over 18kg, normal blood count, normotensive, no history of stroke, no history of severe heart disease).

Female carriers of X-linked must have greater than 30% normal neutrophils.

If donor is a sibling who is a minor, he/she is the oldest eligible sibling and no adults are eligible donors.

EXCLUSION CRITERIA:

Pregnant patients or donors.

Age greater than 55 years.

ECOG performance status of 4 or more. Psychiatric disorder or mental deficiency of the patient or the donor sufficiently severe as to make compliance with PBSC transplantation treatment unlikely, and making informed consent impossible.

Evidence of rapid deterioration due to progressive infection and/or organ damage.

Left ventricular ejection fraction: less than 35% predicted.

Creatinine Clearance less than 50. A maximum age adjusted serum creatinine will be used for patients who are unable to provide an accurate 24 hour urine collection.

Serum bilirubin greater 4 mg/dl, Transaminases greater than 4 times the upper limit of normal.

HIV positive (donor or recipient). Donors who are positive for HBV, HCV or HTLV will be used at the discretion of the investigator.

Malignant diseases liable to relapse or progress within 5 years.

Donor who is unfit to receive G-CSF and undergo apheresis. (Uncontrolled hypertension, history of stroke, history of heart disease, thrombocytopenia, massive splenomegaly).

Special Instructions: Currently Not Provided

Keywords:

Fludarabine

Non-Myeloablative BMT

Immunodeficiency

Neutrophils

Oxidase

Engraftment

Graft-versus-host Disease

Cyclophosphamide

Donor Apheresis

Peripheral Blood Stem Cells

Therapy

Recruitment Keywords:

None

Conditions:

Chronic Granulomatous Disease

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Marrow transplantation in chronic granulomatous disease: an update, with 6-year follow-up

Allogeneic bone marrow transplantation for chronic granulomatous disease

Bone marrow transplantation in chronic granulomatous disease

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
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