Sickle Cell Disease Transplant Using a Nonmyeloablative Approach for Patients With Anti-donor Red Cell Antibody

Inclusion Criteria: General: * Patients with SCD age 2-24.99 years who have a healthy HLA-identical sibling donor with major ABO incompatibility OR patients with RBC alloantibodies against other donor RBC antigens. * Patients must have an absolute neutrophil count of 1 x 109/L and a platelet count of 100 x 109/L. * Lansky/Karnofsky score of, at least, 70. Patients with genotypes hemoglobin SS and Sβ0 thalassemia must have at least one of the following: * History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥200 cm/sec by the non-imaging technique measured at a minimum of two separate occasions. * Progression of CNS vasculopathy on MRA determined to be secondary to SCD. * History of cerebral infarction on brain MRI (overt stroke, or silent stroke if ≥3 mm in one dimension, visible in two planes on fluid-attenuated inversion recovery T2-weighted images). * History of two or more episodes of Acute Chest Syndrome (ACS) in lifetime. * History of three or more SCD pain events requiring treatment with an opiate or IV pain medication in lifetime. * History of any hospitalization for a complication secondary to SCD (does NOT include empiric hospitalizations for fever only). * History of two or more episodes of priapism. * Administration of regular RBC transfusions (≥8 transfusions episodes in the previous 12 months). * At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration. Patients with all other sickle genotypes (e.g. hemoglobin SC, Sβ+ thalassemia, etc.) must have at least one of the following: * Clinically significant neurologic event (overt stroke). * History of two or more episodes of ACS in the 2-year period preceding enrollment. * History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the 1-year period preceding enrollment. * History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment. * History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care). * Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months) * At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration. Exclusion Criteria: * Life expectancy less than 6 month * Pregnant or breastfeeding patients. * Infectious Disease: Uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning. Patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning. Patients with confirmed seropositivity for HIV and patients with active or resolved Hepatitis B or C determined by serology and/or NAAT are excluded. * Liver: Direct (conjugated) bilirubin \> 1.5 mg/dL. Transaminases \>5x upper limit of normal for age. * Cardiac: Left ventricular shortening fraction \<25% or ejection fraction \<50% by ECHO. Uncontrolled cardiac arrhythmia. * Kidney: Estimated creatinine clearance less than 60 mL/min/1.73m2. * Pulmonary function: Diffusion capacity of carbon monoxide (DLCO) \<35% (adjusted for hemoglobin). Baseline oxygen saturation \<94% at rest or PaO2 \<70. Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. * Heme: Available, medically suitable, and equivalent HLA-matched sibling donor, who does not have major ABO incompatibility or express RBC antigens against which the patient is alloimmunized.