This study will investigate the safety and effectiveness of a modified 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. 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
recognize the patient's cells as foreign and mount an immune response to destroy 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 do not have an active
infection and who have a family member that is a well matched donor may be eligible for this
study. Candidates will have a medical history, physical examination and blood tests, lung
and heart function tests, X-rays of the chest and sinuses, and dental and eye examinations.
A bone marrow sample may be taken to evaluate disease status. This test, done under a local
anesthetic, uses a special needle to draw bone marrow from the hipbone.
Stem cells will be collected from both the patient and donor. To do this, the hormone G-CSF
will be injected under the skin for several days to increase stem cell production. Then, the
stem cells will be collected by apheresis. In this procedure the blood is drawn through a
needle placed in one arm, pumped into a machine where the desired cells are separated out
and removed, and then the rest of the blood is returned through a needle in the other arm.
A large plastic tube (central venous line) is placed into a major vein. It can stay in the
body and be used the entire treatment period to deliver the donated stem cells, give
chemotherapy or other medications, including antibiotics and blood transfusions, if needed,
and withdraw blood samples. 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 by mouth or by vein
from 4 days before until 3 months after the stem cell transplant to help prevent rejection.
The average hospital stay for stem cell transplant is 30 days. After discharge, patients
will return for follow-up clinic visits weekly or twice weekly for 4 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.
Chronic Granulomatous Disease (CGD) is an inherited disorder of neutrophil function.
Patients are profoundly immunocompromised, and are plagued early in life with recurrent, and
life threatening infections. Allogeneic stem cell transplantation is the only cure for CGD.
The goal of this phase I/II study is to investigate the safety and efficacy of a novel
approach to allogeneic stem cell transplantation aimed at decreasing transplant related
morbidity and mortality. We will treat patients with CGD with an allogeneic, G-CSF
mobilized peripheral blood stem cell transplant from an HLA identical family member. The
graft will be T-cell depleted which will decrease the incidence of acute graft vs. host
disease. Donor T-cells will be infused post-transplant if engraftment of donor stem cells
is unsatisfactory. The preparative regimen utilized will provide intense immunosuppression
without myeloablation. It is designed to allow donor stem cell engraftment while minimizing
serious transplant related toxicity.
The end points of this study are engraftment, degree of donor-host chimerism, incidence of
acute and chronic GVHD, transplant related morbidity and mortality as well as overall
Ages 1 to 55 years
DHR proven Chronic Granulomatous Disease: Includes gp91phox, p47phox, p22phox and p67phox
Free of active infection.
Patient has experienced 2 or more prior infections requiring treatment with intravenous
anti-bacterial or anti-fungal therapy.
No major organ dysfunction precluding transplantation.
HLA identical sibling or parent compatible at all 6 of the HLA A, B, and DR antigens by
serotyping or DNA typing techniques.
Left ventricular ejection fraction: greater than 40% predicted.
ECOG performance status of 0 or 1.
HLA identical sibling donor or parent donor.
Fit to receive G-CSF and give peripheral blood stem cells (normal blood count,
normotensive, no history of stroke, no history of severe heart disease).
Female x-linked CGD carriers must have greater than 30% normal neutrophils.
Patient or donor pregnant.
Age greater than 55 years.
ECOG performance status of 2 or more.
Evidence of rapid deterioration due to progressive infection and/or organ damage.
Left ventricular ejection fraction: greater than or equal to 35 percent predicted.
Creatinine Clearance greater than or equal to 50.
Serum bilirubin greater than or equal to 4 mg/dl, transaminases greater than or equal to
3x upper limit or normal.
HIV negative. 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.
Donors unfit to receive G-CSF and undergo apheresis. (Uncontrolled hypertension, history
of stroke, history of heart disease, thrombocytopenia.)