In this study the investigators will prospectively investigate whether the addition of a 3-months long preconditioning with azathioprine to the alemtuzumab/TBI non-myeloablative conditioning results in improved disease-free survival and donor chimerism after allo-SCT in SCD patients. Furthermore, the investigators will evaluate whether azathioprine/hydroxyurea preconditioning leads to more patients being able to taper and discontinue sirolimus at 12 months post-transplantation.

Matched sibling donor (MSD) transplantation with non-myeloablative conditioning (1 mg/kg alemtuzumab and 300 cGy total body irradiation (TBI)) using peripheral blood derived stem cells has shown promising results in adult SCD patients. However, a large part of these patients did not reach complete donor chimerism (especially relatively low T-cell chimerism) with graft failure rates of approximately 13%. Furthermore a significant proportion of sickle cell patients need to continuously use the immunosuppressive medication sirolimus to prevent graft failure due to poor donor T-cell chimerism. Graft failure is more common in sickle cell patients than in patients who are transplanted for hematological malignancies. Due to the continuously active erythropoiesis, patients with hemoglobinopathies, such as thalassemia and SCD, have expanded bone marrow, which negatively affects engraftment. Another reason for graft failure in these patients is a continuously triggered immune system due to chronic hemolysis and inflammation in hemoglobinopathies. To improve engraftment and donor chimerism, a preconditioning with azathioprine (immunosuppressive) and hydroxyurea (suppressing bone marrow expansion) during three months has been added to the actual conditioning with alemtuzumab/TBI. Azathioprine/hydroxyurea preconditioning has been proven effective in allo-SCT in thalassemia.

In this study the investigators will prospectively investigate whether the addition of a 3-months long preconditioning with azathioprine to the alemtuzumab/TBI non-myeloablative conditioning results in improved disease-free survival and donor chimerism after allo-SCT in SCD patients. A secondary objective is to evaluate whether azathioprine/hydroxyurea preconditioning leads to more patients being able to taper and discontinue sirolimus at 12 months post-transplantation.

Protocol was amended: in the case of impending graft rejection, defined as declining T-cell chimerism in combination with new onset cytopenias, a second course of alemtuzumab 1mg/kg can be administered in order to avert overt graft failure.

Inclusion Criteria:

• SCD patients with an HLA-identical matched sibling donor eligible for allogeneic stem cell transplantation.
• Age 16 - 60 years
• Good performance status (ECOG 0 or 1; Karnofsky and Lansky 70-100)
• Patients and donors (MSD) must be able to sign consent forms for receiving and donating hematopoietic stem cells respectively. The sibling donor should be willing to donate.
• Patients must be geographically accessible and willing to participate in all stages of treatment.
• Eligible diagnoses: Patients with sickle cell disease such as sickle cell anemia (Hb SS), Hb/Sβ0-thalassemia, Hb/Sβ+-thalassemia, HbSC disease, HbSE disease, HbSD disease and Hemoglobin SO- Arab disease.

Exclusion Criteria:

• Poor performance status (ECOG>1).
• Poor cardiac function: left ventricular ejection fraction<35%.
• Poor pulmonary function: FEV1 and FVC<40% predicted.
• Poor liver function: direct bilirubin >3.1 mg/dl
• HIV-positive
• Women of childbearing potential who currently are pregnant (Beta-HCG+) or who are not practicing adequate contraception.
• Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow-up. However, patients with history of stroke and significant cognitive deficit, that would preclude giving informed consent or assent will not be excluded, if they have a family member or significant other with Power of Attorney to also consent of their behalf.

Sickle cell disease patients, 16 years and older, with an available matched sibling donor.