This study will compare the health and well being of children treated with a modified stem
cell transplantation procedure for chronic granulomatous disease (CGD) with that of children
receiving standard of care treatment. 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
white and red blood cells and platelets) can improve immune function in patients with CGD
and possibly cure the disease. However, this procedure carries a significant risk of death,
because it requires complete suppression of the immune system with high-dose chemotherapy.
In addition, lymphocytes-another type of infection-fighting white blood cell-from the donor
may cause what is called graft versus 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 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 2 and 17 years of age who 1) are currently free of active
infection, and 2) have a history of at least one life-threatening infection or a family
member with CGD and a history of at least one life-threatening infection, and 3) a family
member that is a suitable 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
or CT scans of the body, and dental and eye examinations. They will fill out questionnaires
that measure emotional well being, quality of life, and intelligence (ability to learn and
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 move stem cells from the bone marrow to
the bloodstream. Then, the stem cells will be collected by apheresis. In this procedure the
blood is drawn through a needle placed in one arm and pumped into a machine where the
required cells are separated out and removed. Then, the rest of the blood is returned
through a needle in the other arm.
Several days before the transplant procedure, patients will start a 'conditioning regimen'
of chemotherapy with cyclophosphamide, fludarabine and Campath 1H. When the conditioning
therapy is completed, the donor's stem cells will be infused. To help prevent rejection of
donor cells, cyclosporine will be given by mouth or by vein starting 1 month after the
The average hospital stay for stem cell transplantation is 21 days. After discharge,
patients will return to the NIH clinic for follow-up clinic visits weekly or twice weekly
for 2 to 3 months. These visits will include a symptom check, physical examination and blood
tests. Subsequent clinic visits will be scheduled 1 to 3 times a year for at least 5 years.
Chronic Granulomatous Disease (CGD) is one of several inherited disorders of leukocyte
function. Patients are profoundly immunocompromised and plagued early in life with
recurrent and often life threatening infections. Allogeneic stem cell transplantation
significantly improves immune function in patients with CGD. The primary objective of this
study is to investigate efficacy of a novel approach to allogeneic stem cell
transplantation, which is designed to promote partial or complete donor stem cell
engraftment (hematopoietic chimerism) with reduced transplant related morbidity and
mortality. In an attempt to reduce toxicity from pre-transplant bone marrow conditioning,
a highly immunosuppressive, low intensity bone marrow conditioning regimen will be used.
Patients will be transplanted with peripheral blood stem cells from an HLA identical family
member. The graft will be enriched for hematopoietic stem cells in an attempt to decrease
the risk of graft versus host disease. Donor T-cells will be infused at various time points
following the transplant to augment donor hematopoietic chimerism and aid in immune
reconstitution. Patients treated with this approach will be compared to patients who are
considered transplant-eligible but lack an HLA identical family member. These patients
will be treated using the current standard of care. The primary end points of this study
are to demonstrate reduced incidence of CGD-like infections in the transplanted patients
compared to the controls (efficacy) with acceptable incidence of acute and chronic graft
versus host disease and transplant related mortality (safety). Long term follow up data
from transplanted patients and concurrent controls will be analyzed to confirm the
association between establishment of hematopoietic chimerism and clinical benefit.
The following conditions must be met before a patient may be enrolled in the study:
Patients ages 2 to 17 years; minimum weight of 12 kg.
DHR proven chronic granulomatous disease with gp91 phox or p22 phox deficiency.
History of at least one life-threatening infection (defined as any infection requiring
treatment with intravenous antibiotic therapy) or a family member with CGD and a history
of life-threatening infection.
Free of active infection.
Patients with consenting HLA-matched related donors that meet donor selection criteria
(test patients), or patients without an eligible HLA-matched related donor (control
patients). Patients with eligible donors who choose not to undergo stem cell
transplantation or patients with eligible but non-consenting donors may be enrolled in the
control arm of the study. Patients enrolled in the control arm who complete a 24 month
follow-up period may enroll in the transplant arm should an eligible, consenting donor
Patients with adequate organ function as measured by:
Cardiac: Asymptomatic or, if symptomatic, then left ventricular ejection fraction at rest
must be greater than 35%.
Hepatic: SGOT within 4 times normal range and total bilirubin less than 2mg/dL.
Renal: Creatinine clearance greater than or equal to 50 mL/min/ 1.73m(2). A maximum age
adjusted serum creatinine will be used for patients who are unable to provide an accurate
24 hour urine collection. For children less than or equal to 5 years of age, the maximum
serum creatinine (mg/dl) is 0.8; for children whose age is greater than 5 to less than or
equal to 10, the maximum serum creatinine (mg/dl) is 1.0; for children whose age is
greater than 10 to less than or equal to age 15, the maximum serum creatinine (mg/dl) is
1.2; and for children whose age is greater than 15, the maximum serum creatinine (mg/dl)
Pulmonary: DLCO (diffusion capacity) and FEV1 greater than 45 percent of predicted
(corrected for hemoglobin). Minors in whom pulmonary function tests are not possible will
be evaluated for significant pulmonary dysfunction by a pulmonary consultant.
Written informed consent/assent conforming to institutional guidelines obtained from
patient and parent.
Absence of co-existing medical problems that would significantly increase the risk of a
transplant procedure in the judgment of the principal investigator.
Any one of the following conditions eliminates a patient from participating in this
Female patients who are pregnant or lactating.
ECOG performance status of 2 or more or less than 50 percent on the Lansky scale for ages
Seropositivity for HIV due to excessive risk of infection and neurotoxicity of
Evidence of rapid deterioration due to progressive infection and/or organ damage.
Malignant diseases liable to relapse or progress within 5 years.
Donors must be 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, greater
Related to the patient and HLA-phenotypically identical with the patient for HLA-A, B and
DRB1 alleles. Matching assessed minimally by serology for Class I and DNA typing for
Class II antigens.
Female x-linked CGD carriers must have greater than 30 percent normal neutrophils.
If donor is a sibling who is a minor, he/ she is the oldest eligible sibling and no adult
siblings are eligible donors.
Written informed consent from donor. Donors who are minors will be evaluated by a social
worker, psychologist or psychiatrist prior to the assent process to determine willingness
to participate. If willingness to participate has been confirmed, informed consent will
be obtained from adult parent or legal guardian. Informed assent will be obtained from
minor donor in the presence of a third party who will assess comprehension and voluntary