CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation

Graft-versus-host disease (GVHD) is a condition that results from a reaction of transplanted
donor T-lymphocytes against the body and organs of the patient receiving the transplanted
cells. There are two forms: acute (early) and chronic (late). Acute GVHD may produce skin
rashes, liver disease, diarrhea, and an increased risk of infection. Chronic GVHD can appear
in patients without prior acute GVHD. Chronic GVHD may also produce skin rashes, liver
disease, diarrhea and an increased risk of infection. GVHD can make patients very sick, and
have GVHD can make it more likely that patients will not survive their transplant. In this
study, the investigators are offering to treat the donor peripheral blood stem cells in the
hope that it will make it less likely for the patient who receives them from having GVHD.

Patients on this study are being offered an experimental treatment involving the use of the
CliniMACS® Reagent System (Miltenyi Biotec, Germany), a CD34+ selection device to remove
T-cells from the peripheral blood stem cell transplant in order to decrease the risk of acute
and chronic GVHD. CD34+ stem cells are selected from the donor's peripheral blood stem cells.
In doing this, T-cells are also removed. T-cells are the cells which are responsible for
graft versus host disease (GVHD). This study is a clinical trial for patients diagnosed with
a non-malignant disease who will receive a peripheral blood stem cell transplant. Patients
with the following types of non-malignant diseases can participate in this study: Bone marrow
failure syndromes (including Severe Aplastic Anemia, Severe Congenital Neutropenia,
Amegakaryocytic Thrombocytopenia (Kostmann's Syndrome), Diamond-Blackfan Anemia, Schwachman
Diamond Syndrome, Primary Immunodeficiency Syndromes, Acquired Immunodeficiency Syndromes,
and Histiocytic Disorders) and Hemoglobinopathies (including Sickle Cell Anemia and
Sickle/Beta Thalassemia). Patients on this study will be given standard transplant therapy
with either high doses of chemotherapy drugs or lower doses of chemotherapy drugs, depending
on their disease. Diseases within each disease group will receive chemotherapy that is
standard for that condition.

Some patients on this study will receive an allogeneic stem cell transplant (AlloSCT) from a
matched related donor. If a patient does not have a matched related donor, a bone marrow
search will be done at all of the bone marrow banks in the world. The patient will then go on
to receive an AlloSCT from either a partially matched family member or an unrelated adult
stem cell transplant donor. The transplanted cells will allow all the normal parts of the
patient's blood system to recover. The experimental portion of this treatment involves the
use of a Miltenyi CliniMACS CD34+ selection device to remove T-cells from the peripheral
blood stem cell transplant in order to decrease the risk of acute and chronic GVHD. CD34+
stem cell selection AlloSCT has been studied in adults with the malignant and non-malignant
disease with successful engraftment and has shown some improvement in GVHD. It is unknown if
CD34+ stem cell selection will work to prevent severe GVHD in children and adolescents.

Inclusion Criteria:

- General Eligibility (All Patients)

- Patient must be < or = 40 years of age. Patients with sickle cell anemia must be
at least 2 years of age.

- Patient or the patient's legally authorized guardian must be fully informed about
their illness and the investigational nature of the study protocol (including
foreseeable risks and possible side effects) and must sign an informed consent in
accordance with the institutional policies approved by the U.S. Department of
Health and Human Services.

- Approval for the use of this treatment protocol by the individual institution's
Human Rights Committee must be obtained, in accordance with the institutional
assurance policies of the U. S. Department of Health and Human Services.

- Human leukocyte antigen (HLA) typing will be performed by high-resolution
molecular DNA typing for HLA Class I A, B, and C and HLA Class II DRB1 and DQB1
alleles.

- Unrelated donor: An 8/10, 9/10 or 10/10 matched unrelated adult donor (MUD)
will be required for study entry.

- Related Donor: A 5/10, 6/10, 7/10, 8/10, 9/10 or 10/10 matched (or partially
matched) family donor will be required for study entry.

- Non-malignant Disorders per protocol.

- Hemoglobinopathies per protocol.

- Requirement for CD34+ stem cell selection for a second infusion of stem cells
following an allogeneic stem cell transplant from a related or unrelated adult
donor.

- Additional eligibility for patients with non-malignant disorders receiving
myeloablative conditioning

- Adequate renal function as determined by the institutional normal range.

- Adequate liver function per protocol.

- Adequate cardiac function defined by radionucleotide angiogram or echocardiogram.

- Adequate pulmonary function by pulmonary function test. For children who are
uncooperative, no evidence of dyspnea at rest, no exercise intolerance, and a
pulse oximetry >94% on room air.

- Additional eligibility for patients with non-malignant disorders receiving reduced
intensity conditioning

- Adequate renal function as determined by the institutional normal range.

- Adequate liver function per protocol.

- Adequate cardiac function per protocol.

- Adequate pulmonary function per protocol.

Exclusion Criteria:

- Patients with documented uncontrolled infection at the time of study entry are not
eligible.

- Pregnancy/Breast-Feeding Females who are pregnant or breast feeding at the time of
study entry are not eligible.

-- The following additional exclusion criteria for patients with sickle cell anemia
the following exclusion criteria also apply

- Patients with bridging fibrosis or cirrhosis of the liver.

- Uncontrolled bacterial, viral or fungal infection in the past month.

- Seropositivity for HIV.

- Patients who have received prior hematocrit (HCT) within three months of enrollment
for reduced intensity regimen and within six months for myeloablative regimen/reduced
toxicity regimens.