A Reduced Toxicity Allogeneic Unrelated Donor Stem Cell Transplantation (SCT) for Severe Sickle Cell Disease

The primary goal of this pilot study is to determine the safety and feasibility of the
preparative regimen for HSCT using a novel reduced toxicity regimen for stem cell transplant
with unrelated donors. Analysis will be geared to confirm if the study regimen, followed by
an appropriately HLA-matched unrelated donor (MUD)or unrelated cord blood HSCT, can lead to
durable donor engraftment with reasonable toxicity, inhibiting sickle erythropoiesis and
limiting disease related organ toxicity in patients who are at high risk for morbidity and
mortality associated with sickle cell disease (SCD).

Inclusion Criteria:

Patients must have sickle cell disease (genotype Hb SS or Sß° thalassemia), AND must have 1
or more of the following clinical complications related to Sickle cell disease:

1. A clinically significant neurologic event (stroke) or any neurologic defect lasting
>24 hours, that is accompanied by an infarct on cerebral MRI.

2. Minimum of two episodes of acute chest syndrome (defined as new pulmonary alveolar
consolidation involving at least 1 complete lung segment associated with acute
symptoms including fever, chest pain, tachypnea, wheezing or cough) despite adequate
supportive care measures (example: asthma therapy, hydroxyurea).

3. History of severe pain episodes defined as 3 or more severe pain events per year in
the 2 years prior to enrollment despite adequate supportive care measures and
hydroxyurea trial (i.e. Hydroxyurea non-responders). Pain may occur in typical sites
associated with vaso-occlusive painful events and cannot be explained by causes other
than vaso-occlusion mediated by sickle cell disease.

4. Recurrent priapism.

5. Osteo-necrosis of multiple joints

6. Evidence of Pulmonary Hypertension as evidenced by Tricuspid Regurgitation jet
velocity (TRV) > 2.5 m/s on Echocardiogram.

7. Red cell allo-immunization (≥ 2 antibodies) during long term transfusion therapy.

Exclusion Criteria:

1. Invasive bacterial, viral or fungal infections within 1 month prior to starting
conditioning therapy.

2. Female patients who are Pregnant (Beta HCG +) or breastfeeding.

3. HIV positive patients.

4. Patients with HLA-matched related family donors are not eligible for this study.

5. Prior myeloablative allogeneic HCT.

6. Patients on chronic transfusion therapy for ≥ 1 year with evidence of cirrhosis of
liver on biopsy

7. Any significant concurrent disease, illness, severe cognitive delay or psychiatric
disorder that would compromise patient safety or compliance, interfere with consent,
study participation, follow up, or interpretation of study results.