Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT

For some non-malignant diseases (NMD; i.e., thalassemia, sickle cell disease, most immune
deficiencies) a hematopoietic stem cell transplant may be curative by healthy donor stem cell
engraftment alone. HSCT in patients with NMD differs from that in malignant disorders for two
important reasons: 1) these patients are typically naïve to chemotherapy and
immunosuppression. This may potentially lead to difficulties with engraftment. And 2) RIC
with subsequent bone marrow chimerism may be beneficial even in mixed chimerism and result in
decreased transplant-related mortality (TRM). Nevertheless, any previous organ damage, as a
result of the underlying disease, may remain present after the HSCT.

For other diseases (metabolic disorders, some immunodeficiencies, etc.), a transplant is not
curative. For these diseases, the main intent of the transplant is to slow down, or stop, the
progress of the disease. In select few cases/diseases, the presence of healthy bone marrow
derived cells may even prevent progression and prevent neurological decline.

In this research study, instead of using the standard myeloablative conditioning, the study
doctor is using RIC, in which significantly lower doses of chemotherapy will be used. The
lower doses may not eradicate every stem cell in the patient's bone marrow, however, in the
presented combination, the intention is to eliminate already formed immune cells and provide
maximum growth advantage to healthy donor stem cells. This paves the way to successful
engraftment of donor stem cells. Engrafting donor stem cells can outcompete, and donor
lymphocytes could suppress, the patients' surviving stem cells. With RIC, the side effects on
the brain, heart, lung, liver, and other organ functions are less severe and late toxic
effects should also be reduced.

The purpose of this study is to collect data from the patients undergoing reduced-intensity
conditioning before HSCT, and compare it to the standard myeloablative conditioning. It is
expected there will be therapeutic benefits, paired with better survival rate, less organ
toxicity and improved quality of life, following the RIC compared to the myeloablative
regimen.

Inclusion:

1. A 4/6, 5/6 or 6/6 HLA matched related or unrelated UCB unit available that will
deliver a pre-cryopreservation total nucleated cell dose of ≥ 3 x 10e7 cells/kg, or
double unit grafts, each cord blood unit delivering at least 2 x 10e7 cells/kg OR an 8
of 8 or 7 of 8 HLA allele level matched unrelated donor bone marrow or peripheral
blood progenitor graft.

2. Adequate organ function as measured by:

1. Creatinine ≤ 2.0 mg/dL and creatinine clearance ≥ 50 mL/min/1.73 m2.

2. Hepatic transaminases (ALT/AST) ≤ 4 x upper limit of normal (ULN).

3. Adequate cardiac function by echocardiogram or radionuclide scan (shortening
fraction > 26% or ejection fraction > 40% or > 80% of normal value for age).

4. Pulmonary evaluation testing demonstrating CVC or FEV1/FVC of ≥ 50% of predicted
for age and/or resting pulse oximeter ≥ 92% on room air or clearance by the
pediatric or adult pulmonologist. For adult patients DLCO (corrected for
hemoglobin) should be ≥ 50% of predicted if the DLCO can be obtained.

3. Written informed consent and/or assent according to FDA guidelines.

4. Negative pregnancy test if pubertal and/or menstruating.

5. HIV negative.

6. A non-malignant disorder amenable to treatment by stem cell transplantation, including
but not limited to:

1. Primary Immunodeficiency syndromes including but not limited to:

- Severe Combined Immune Deficiency (SCID) with NK cell activity

- Omenn Syndrome

- Bare Lymphocyte Syndrome (BLS)

- Combined Immune Deficiency (CID) syndromes

- Combined Variable Immune Deficiency (CVID) syndrome

- Wiskott-Aldrich Syndrome

- Leukocyte adhesion deficiency

- Chronic granulomatous disease (CGD)

- X-linked Hyper IgM (XHIM) syndrome

- IPEX syndrome

- Chediak - Higashi Syndrome

- Autoimmune Lymphoproliferative Syndrome (ALPS)

- Hemophagocytic Lymphohistiocytosis (HLH) syndromes

- Lymphocyte Signaling defects

- Other primary immune defects where hematopoietic stem cell transplantation
may be beneficial

2. Congenital bone marrow failure syndromes including but not limited to:

- Dyskeratosis Congenita (DC)

- Congenital Amegakaryocytic Thrombocytopenia (CAMT)

- Osteopetrosis

3. Inherited Metabolic Disorders (IMD) including but not limited to:

- Mucopolysaccharidoses

- Hurler syndrome (MPS I)

- Hunter syndrome (MPS II)

- Sanfilippo syndrome (MPS II)

- Leukodystrophies

- Krabbe Disease, also known as globoid cell leukodystrophy

- Metachromatic leukodystrophy (MLD)

- X-linked adrenoleukodystrophy (ALD)

- Other inherited metabolic disorders

- alpha mannosidosis

- Gaucher Disease

- Other inheritable metabolic diseases where hematopoietic stem cell
transplantation may be beneficial.

4. Hereditary anemias

- Thalassemia major

- Sickle cell disease (SCD) - patients with sickle disease must have one or
more of the following:

- Overt or silent stroke

- Pain crises ≥ 2 episodes per year for past year

- One or more episodes of acute chest syndrome

- Osteonecrosis involving ≥ 1 joints

- Priapism

- Diamond Blackfan Anemia (DBA)

- Other congenital transfusion dependent anemias

5. Inflammatory Conditions

- Crohn's Disease/Inflammatory Bowel Disease

Exclusion:

1. Allogeneic hematopoietic stem cell transplant within the previous 6 months.

2. Any active malignancy or MDS.

3. Severe acquired aplastic anemia.

4. Uncontrolled bacterial, viral or fungal infection (currently taking medication and
with progression of clinical symptoms).

5. Pregnancy or nursing mother.

6. Poorly controlled pulmonary hypertension.

7. Any condition that precludes serial follow-up.