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 donorwith major ABO incompatibility OR patients with RBC alloantibodies against otherdonor 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 ≥200cm/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 mmin one dimension, visible in two planes on fluid-attenuated inversion recoveryT2-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 IVpain medication in lifetime.

• History of any hospitalization for a complication secondary to SCD (does NOT includeempiric 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 transfusionor 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 IVpain medication (inpatient or outpatient) in the 1-year period preceding enrollment.

• History of any hospitalization for SCD pain or ACS while receiving hydroxyureatreatment.

• History of two or more episodes of priapism (erection lasting ≥4 hours or requiringemergent medical care).

• Administration of regular RBC transfusions (≥8 transfusions in the previous 12months)

• At least two episodes of splenic sequestration requiring red blood cell transfusionor 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 (undergoingappropriate treatment and with progression of clinical symptoms) within 1 monthprior to conditioning. Patients with febrile illness or suspected minor infectionshould await clinical resolution prior to starting conditioning. Patients withconfirmed seropositivity for HIV and patients with active or resolved Hepatitis B orC determined by serology and/or NAAT are excluded.

• Liver: Direct (conjugated) bilirubin > 1.5 mg/dL. Transaminases >5x upper limit ofnormal for age.

• Cardiac: Left ventricular shortening fraction <25% or ejection fraction <50% byECHO. Uncontrolled cardiac arrhythmia.

• Kidney: Estimated creatinine clearance less than 60 mL/min/1.73m2.

• Pulmonary function: Diffusion capacity of carbon monoxide (DLCO) <35% (adjusted forhemoglobin). Baseline oxygen saturation <94% at rest or PaO2 <70. Known moderate orsevere persistent asthma within the past 2 years, or uncontrolled asthma of anyclassification.

• Heme: Available, medically suitable, and equivalent HLA-matched sibling donor, whodoes not have major ABO incompatibility or express RBC antigens against which thepatient is alloimmunized.