T-cell Depleted Alternative Donor Transplantation

A major issue in alternative donor (mismatched related and unrelated donor transplantation is
the development of graft-versus-host disease (GVHD). Several clinical trials have shown that
the use of T-cell depleted peripheral blood stem cells (PBSC) reduces GVHD in alternative
donor transplants. The purpose of this study is to determine the ability of CD34 positive
selection and T cell depletion using the CliniMACS® Device as the only GVHD prophylaxis to
prevent severe acute GVHD in recipients of an alternative donor PBSC transplant. Mismatched
related donors will match at least 3 of 6 Human leukocyte antigens(HLA)(haplocompatible) and
unrelated donors will match at least 6 out of 8 HLA antigens with the transplant recipient.
The conditioning therapy including chemotherapy, anti-thymocyte globulin (ATG), +/- total
body irradiation (TBI) will be based on the patient's diagnosis. The transplant recipient
will be followed for 5 years after transplant for GVHD, engraftment, post-transplant
infections, disease relapse, and overall survival. In addition, this study will serve as a
platform for a companion study of therapy to accelerate immune recovery after transplant.

Inclusion Criteria:

- Age < 30 years

- Patient must have a malignant or non-malignant disease that can benefit from
alternative stem cell transplantation. Examples include acute and chronic leukemias,
myelodysplastic syndrome, lymphoma, severe acquired and congenital cytopenias, white
and red blood cell abnormalities, and immunodeficiencies.

- Patients with acute lymphoblastic leukemia must be in morphological remission (< 5%
blasts) at the time of transplant. Patients with acute non-lymphocytic leukemia will
preferably be in morphologic remission but may be enrolled when aplastic after
chemotherapy or with < 20% blasts. Patients with lymphoma must be in complete or close
to complete remission (if residual adenopathy, PET scan must be negative or only have
slight uptake, eg. SUV < 2).

- Patients must lack a healthy HLA-identical related donor of at least one year of age.

- Patient must have a mismatched related or an unrelated donor who is:

1. Able to receive G-CSF and undergo apheresis either through placement of catheters
in antecubital veins or a temporary central venous catheter,

2. Healthy,

3. Willing,

4. For recipients of an unrelated donor transplant, recipient eligibility will be
restricted as follows if in the judgment of the recipients' transplant physician,
the recipient cannot receive a transplant with combined positive and negative
fractions as described in Section 6.1.3.2 or an unmanipulated PBSC product.

5. Meets eligibility criteria for donors.

- If only one mismatched related relative is available, an acceptable unrelated donor
must be identified as a backup.

- Patient or authorized guardian must sign informed consent for this study.

Exclusion Criteria:

- Patient with an anticipated life expectancy of < 1 month

- Active infectious hepatitis or CMV infection

- HIV or HTLV-I/II infection

- Serious infection (bacterial, fungal, viral) within the last 4 weeks

- Cardiac ejection fraction < 45%; can be lower if patient is not in clinical cardiac
failure and a reduced intensity conditioning regimen is used.

- Creatinine clearance <60 ml/min/1.72 m2; can be lower if a reduced intensity
conditioning regimen is used.

- Pulmonary diffusion capacity (adjusted for Hgb), FEV1, or FVC <60% of predicted or O2
sat < 94% if unable to perform PFTs; can be lower if a reduced intensity conditioning
regimen is used.

- Serum ALT > 3 x upper limit of normal (can be up to 5 x upper limit of normal if a
reduced intensity conditioning regimen is used) or bilirubin > 2. The bilirubin
criteria for sickle cell disease patients is direct bilirubin >2x upper limit of
normal.

- Performance score (Lansky/Karnofsky) < 50

- Any condition that compromises compliance with the procedures of this protocol, as
judged by the principal investigator.