Nonmyeloablative Conditioning for Mismatched Hematopoietic Stem Cell Transplantation for Severe Sickle Cell Disease

Recipient Inclusion Criteria: * Age greater than or equal to 19 years. * Diagnosis of sickle cell disease (HB SS, SC, or SBeta-thal(0)); confirmed by hemoglobin electrophoresis, high-performance liquid chromatography, DNA testing when necessary or both. * At high risk for disease-related morbidity or mortality, defined by having at least one of the following manifestations (A-E): * A: Clinically significant neurologic event (stroke) or any neurological deficit lasting \> 24 hours. * B: 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 including hydroxyurea. * C: 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) despite the institution of supportive care measures including hydroxyurea. * D: 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, acute chest syndrome, and priapism). * E: Pulmonary hypertension (defined as tricuspid regurgitant jet velocity (TRV) ≥2.5 m/s at baseline (without vaso-occlusive crisis) * Any one of the below complications not ameliorated by hydroxyurea at the maximum tolerated dose for at least 6 months: * Vaso-occlusive crises with more than 1 hospital admission per year while on maximal tolerated dose of hydroxyurea * Acute chest syndrome occurring while on hydrox\*Eyurea * Age greater than or equal to 19 years. * Availability of one antigen mismatched unrelated or haploidentical related donor * Cerebral MRI/MRA within 30 days prior to initiation of transplant conditioning. If there is clinical or radiologic evidence of a recent neurologic event (such as stroke or transient ischemic attack) subjects will be deferred for at least 6 months with repeat cerebral MRI/MRA to ensure stabilization of the neurologic event prior to proceeding to transplantation. * Ability to comprehend and willing to sign an informed consent Recipient Exclusion Criteria: * Detectable antibody to ABO, Rh, or other red blood cell antigen of their donors * Presence of donor specific antibodies detected by donor specific antibody screen (if using product from a haploidentical donor). * Karnofsky/Lansky performance score \< 60 * Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen. * Poor cardiac function defined as left ventricular ejection fraction \< 40%. * Poor pulmonary function defined as FEV1 and FVC \< 40% predicted or diffusing capacity of the lung for carbon monoxide (DLCO) \< 40% (corrected for hemoglobin) * Poor liver function defined as direct bilirubin \> 2x upper limit of normal for age and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \> 5 times upper limit of normal. * Poor kidney function defined by creatinine clearance \< 70mL/min. * HIV-positive. * Unwillingness to use approved contraception method from time of biologic assignment until discontinuation of all immunosuppressive medications. * Demonstrated lack of compliance with prior medical care (determined by referring physician). * Pregnant or breastfeeding. * Diagnosis of any debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment and follow-up. Donor Selection: * Must be one antigen mismatched unrelated donor or first-degree relative who shares at least one HLA haplotype with the recipient. * Must not have SCD or another hemoglobinopathy. * In good health based on institutional standards. * Weight ≥ 20kg. * If donor is \< 18 years old must have ability to give informed assent based on institutional standards for pediatric donors. * Able to undergo peripheral blood stem cell mobilization with G-CSF * Hemoglobin S ≤ 50%. * HIV-1\&2 antibody, HTLV-I\&II antibody, HBV and HCV sero-negative. * Note: When more than one donor is available, the donor with the lowest number of HLA allele mismatches will be chosen, unless there is HLA cross-match incompatibility or a medical reason to select otherwise, in which case donor selection is the responsibility of the PI, in consultation with the immunogenetics laboratory. In cases where there is more than one donor with the least degree of mismatch, donors will be selected based on the most favorable combination of (i) HLA compatibility in cross-match testing, (ii) ABO compatibility, (iii) CMV status and (iv) non-inherited maternal antigens (NIMAs) mismatching. * HLA crossmatching (in order of priority) * Mutually compatible (no cross-matching antibodies) * Recipient non-cross-reactive with donor, donor cross-reactive with recipient * Mutually cross-reactive * ABO compatibility (in order of priority) * Compatible * Major incompatibility * Minor incompatibility * Major and minor incompatibility * CMV negative donor is preferred * NIMA mismatched donor is preferred