HSCT For Patients With High Risk Hemoglobinopathies Using Reduced Intensity

Standard myeloablative regimens are toxic to non-hematopoietic tissue and are associated with
treatment related mortality and morbidity (TRM). Preparative regimens that are not
myeloablative are associated with a greatly decreased incidence of TRM. In addition to
providing a less toxic regimen, the reduced intensity chemotherapy preparative regimen also
remains immunosuppressive enough to allow donor engraftment. Recent report of
non-myeloablative regimens which resulted in engraftment of allogeneic stem cell in
hematological malignancies raises the possibility that this conditioning regimen might be
useful in achieving engraftment in non hematological disorder.

In an effort to achieve stable engraftment with any suitable donor stem cell source and to
minimize toxicity the investigators have developed a new reduced intensity conditioning
regimen for high risk hemoglobinopathies with the main aim of significantly suppressing the
recipient's immune system and facilitate engraftment.

Non-myeloablative or reduced-intensity immunosuppressive preparative regimens have achieved a
stable, mixed chimerism engraftment and successful allogeneic bone marrow transplants.

Inclusion Criteria:

- Patient Inclusion Criteria for Sickle Cell Disease

- Patients at least one year of age to less than or equal to 21 years of age with
(Sickle Cell Disease-SS or Sickle Cell-S-β-Thalassemia and with one or more of the
following disease complications:

- Development of stroke on chronic transfusion protocol.

- Allosensitization on chronic transfusion therapy

- Impaired neuropsychological function and abnormal MRI scan

- Abnormal Transcranial Doppler studies

- Acute chest syndrome (2 to 3 episodes of acute chest syndrome in last 3 to 4 years).

- Ferritin level < 1500 mg/ml

- Recurrent painful priapism; 3-4 episodes/year requiring intervention.

- Recurrent vaso-occlussive crisis of at least 3 to 4 episodes/year.

- Osteonecrosis of multiple bones with documented destructive changes.

- Signed informed consent

- Patients physically and psychologically capable of undergoing transplantation and a
period of strict isolation.

- Ferritin < 1500

- Liver Iron Concentration < 6mg/g

Patient Inclusion Criteria for β Thalassemia major Patients less than or equal to 21 years
of age with B- Thalassemia major on routine monthly transfusion protocol or with one or
more of the following complications;

1. Hepatomegaly.

2. Liver biopsy revealing evidence of portal fibrosis as A) Mild B) Moderate

3. Ferritin level≤ 1500ng/ml

4. Liver Iron Concentration (LIC) < 6mg/g

Exclusion Criteria:

- Exclusion Criteria for Both Sickle Cell and β Thalassemia Major Patient

- HIV positive result confirmed by Western Blot.

- Pregnancy (Pregnancy testing for females of child-bearing age will be performed and
those with a positive serum β-Human Chorionic Gonadotropin will be excluded) and
lactating females.

- Creatinine greater than two times the upper limit of normal for the laboratory,

- Pulmonary disease with FVC, FEV1 or DLCO parameters < 50% predicted (corrected for
hemoglobin) or stage 3 or 4 sickle lung disease.

- Cardiac insufficiency or coronary artery disease requiring treatment

- Active infection requiring systemic antibiotic therapy with antibacterial, antifungal
or antiviral agents

- Lansky performance score <70%- (Appendix B)

- Acute hepatitis/biopsy evidence of cirrhosis.

- Pulmonary Hypertension