Stem Cell Transplant in Patients With Severe Sickle Cell Disease

Stem cell transplantation recipients will be given Alemtuzumab, which is a non-myeloablative
pre-transplant conditioning regimen. This non-myeloablative therapy uses doses of
chemotherapy and radiation to weaken (but not destroy) the patients bone marrow and immune
system, while still allowing their body to accept the donor's stem cells. Alemtuzumab will be
given 7 days prior to stem cell infusion at 0.03 mg/kg IV, 6 days prior to stem cell infusion
at 0.1 mg/kg IV, and 5 thru 3 days prior to stem cell infusion at 0.3 mg/kg IV.

Inclusion Criteria:

- Patient selection

1. Age 18 - 40 years

2. Patients with Hb SS, Hb SC, Hb Sβ0 genotype

3. Presence of at least 1 of the following manifestations:

1. History of clinically significant neurologic event defined as stroke or any
neurological deficit lasting > 24 hours.

2. History of two or more episodes of acute chest syndrome (ACS) in the 2-year
period preceding enrollment despite the institution of supportive care
measures

3. Three or more pain crises per year in the 2-year period preceding referral
(required intravenous pain management in the outpatient or inpatient
hospital setting)

4. An echocardiographic finding of the tricuspid valve regurgitant jet (TRJ)
velocity ≥ 2.7 m/sec.

5. History of osteonecrosis or avascular necrosis of ≥ 2 joints

6. Administration of regular RBC transfusion therapy, defined as receiving 8 or
more transfusions per year for > 1 year to prevent vaso-occlusive clinical
complications (i.e. pain, stroke, and acute chest syndrome)

7. Evidence of sickle hepatopathy or iron overload in patients who received ≥ 8
packed RBC transfusions for ≥ 1 year or have received ≥ 20 cumulative packed
RBC transfusions. These patients will undergo MRI of the liver to estimate
liver iron content.

i. Patients with hepatic iron content of ≤ 7 mg Fe/ gm of liver will be included
ii. Patients with hepatic iron content of ≥ 7 mg Fe/ gm of liver will undergo
biopsy to look for absence of histological findings suggestive of cirrhosis,
fibrosis and active hepatitis h. Sickle nephropathy defined as Cr ≥ 1.5 times the
ULN or biopsy proven i.Reversible SCD complication not ameliorated by
hydroxyurea: i.Two or more vaso-occlusive crises requiring hospitalizations ii.
Any episode of ACS while on hydroxyurea

4. Adequate physical function as measured by all of the following:

1. Karnofsky performance score > or equal to 70

2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV
shortening fraction > 26% by cardiac echocardiogram or by MUGA scan.

3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of >85%,
DLCO > 50% (corrected for Hb) or mean pulmonary arterial pressure > 25 mm Hg

4. Hepatic function:

i. Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per
local laboratory; ii. ALT and AST < 5 times upper limit of normal. iii. Patients
with hyperbilirubinemia because of hyper hemolysis, or who experience a sudden,
profound change in the serum hemoglobin after a RBC transfusion are not excluded.

5. The HLA matched related donor must be willing to donate and must meet our
institutional guidelines to donate peripheral blood stem cells

6. Absence of donor specific HLA antibodies.

7. Absence of clinical or radiographic evidence of neurologic event within 6 months
prior to proceeding with transplantation.

1. Cerebral MRI/MRA within 30 days prior to initiation of transplant
conditioning.

2. If patient has a neurologic event such as stroke or transient ischemic
attack during recruitment process, patient will be deferred for 6 months
before reconsideration.

Donor selection

1. Siblings who are ≥18 years and capable and willing to donate PBSC

2. Sibling donors are HLA-matched. HLA-A, B, C, and DRB1 match based on high-resolution
typing

3. All sibling donors MUST meet institutional criteria for donation.

4. Donors with sickle cell trait (Hb AS) are permitted.

Exclusion Criteria:

Patient selection

1. Presence of red cell alloimmunization due to chronic transfusion therapy

2. Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment.

3. Seropositivity for HIV.

4. Previous stem cell transplantation.

5. Participation in a clinical trial in which the patient received an investigational
drug or device

6. A history of substance abuse as defined by version IV of the Diagnostic & Statistical
Manual of Mental Disorders (DSM IV).

7. Demonstrated lack of compliance with prior medical care as determined by referring
physician.

8. Pregnant or breast-feeding females.

9. Unwillingness to use approved contraception method from time of conditioning regimen
and 4 months after discontinuation of all immunosuppressive medications.

Donor selection

1. Donors with hemoglobinopathies: Hb SS, Hb SC, Hb Sβ0 and all other unstable
hemoglobins

2. Presence of anti-donor HLA antibodies in the recipient

3. Donors with ABO incompatibility are permitted

4. Donors who are HIV-1, HIV-2, HTLV-1, HTLV-2 seropositive or with active hepatitis B or
hepatitis C virus infection