Ph I/II Study of Allogeneic SCT for Clinically Aggressive Sickle Cell Disease (SCD)

Sickle cell disease is an inherited defect caused by a mutation in the Beta globin gene
affecting red blood cells. Symptoms begin at 6 months of life and often lead to debilitating
vaso-occlusive pain crises, acute insults to vital organ systems,chronic organ injury, and
decreased survival with median survival estimated at 42 years for men and 48 years for
women. Several cohort studies have identified clinical and laboratory predictors for
decreased survival which include acute complications, and chronic complications of sickle
cell disease.

Hydroxyurea is the only FDA approved drug to help ameliorate symptoms associated with sickle
cell disease. Two nonrandomized studies have suggested a reduction in mortality after 17
years of long term hydroxyurea treatment. However, the mortality rate is still high in the
hydroxyurea cohort at 43.1% and only 38.1% of patients have a rise in fetal hemoglobin
indicating that a significant percentage of patients still have aggressive disease despite
hydroxyurea treatment. Hydroxyurea therapy also does not seem to prevent the development of
pulmonary hypertension.

In the pediatric population, patients that have not clinically improved despite optimized
hydroxyurea management are offered allogeneic stem cell transplantation. Until recently, the
options were more limited in adults with sickle cell disease that had aggressive disease
despite hydroxyurea therapy. Most rely on chronic red blood cell transfusions which carry
significant risks of infection, iron overload, and alloimmunization. Up to 50% of patients
with sickle cell disease who are on chronic transfusion therapy will develop allo-antibodies
making further transfusions difficult with a high potential for hemolytic transfusion
reactions.

Patients with sickle cell disease often have chronic underlying organ disease and so the
effects of chemotherapy may be unpredictable and potentially more harmful, making low dose
TBI more attractive as a safer modality for conditioning.

The investigators propose to determine the engraftment and transplant related morbidity and
mortality after a non-myeloablative allogeneic hematopoietic stem cell transplant protocol
using immune- suppressive agents and low-dose total body irradiation (TBI) without standard
chemotherapy in patients with aggressive sickle cell disease who are not candidates for or
experienced complications from hydroxyurea therapy.

Fully HLA matched siblings will be used as donors for hematopoietic stem cells to reduce the
risk of morbidity and mortality in this cohort of patients.

An optional correlative trial will be conducted to compare ocular findings after stem cell
transplantation with those findings before stem cell transplantation. Anterior and posterior
ocular examination as well as objective tests will be performed on subjects.

Inclusion Criteria:

- Patients with sickle cell disease, subtype Hgb SS, SC, or SB disease who are on
chronic transfusion therapy for a prior stroke or those patients who were intolerant
of hydroxyurea therapy or were being treated with hydroxyurea therapy and were
complicated by at least one of the following:

- Stroke or central nervous system event lasting longer than 24 hours

- Frequent vaso-occlusive pain episodes, defined as ≥ 3 per year severe enough to
interfere with the patient's normal daily function or require medical attention
in the clinic, emergency room, acute care center, or hospital

- Recurrent episodes of priapism, defined as ≥ 2 per year requiring emergency room
visits

- Acute chest syndrome with recurrent hospitalizations, defined as ≥ 2 lifetime
events

- Red-cell alloimmunization (≥ 2 antibodies) during longterm transfusion therapy

- Bilateral proliferative retinopathy with major visual impairment in at least one
eye

- Osteonecrosis of 2 or more joints

- Sickle cell nephropathy

- Stage I or II sickle lung disease

- Symptoms of pulmonary hypertension and mean pulmonary artery pressure > 25mmHg

- Age 16-60 years

- Karnofsky performance status of 70 or higher

- Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40%

- Adequate pulmonary function, defined as diffusion lung capacity of carbon monoxide ≥
50%

- Estimated GFR ≥ 30mL/min as calculated by the modified MDRD equation

- ALT ≤ 3x upper limit of normal

- No evidence of chronic active hepatitis or cirrhosis

- HIV-negative

- Patient is not pregnant

- History of compliance with medications and medical care

- Patient is able and willing to sign informed consent

- Patient has an HLA-identical matched related donor