Siplizumab for Sickle Cell Disease Transplant (CD2 SCD)

Recipient Inclusion Criteria: Patients with sickle cell anemia (Hb SS, Sβ0 thalassemia or severe SC) who are 18 - 50 years of age inclusive AND who have 1 or more of the following: Clinically significant neurologic event (stroke) or any neurological deficit lasting at least 24 hours. Stroke will be defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI or cerebral arteriopathy requiring chronic transfusion therapy. History of two or more episodes of ACS in the 2-year period preceding enrollment despite supportive care measures (i.e. asthma therapy and/or hydroxyurea). History of three or more severe vaso-occlusive pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea). Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving 8 or more transfusions per year for 1 year or more to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and ACS) An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity > or equal to 2.7 m/sec or pulmonary hypertension diagnosed by right heart catheterization. Chronic kidney disease including patients on hemo-dialysis Recurrent tricorporal priapism defined as at least 2 episodes of an erection last ≥4 hours involving the corpus cavernosa and corpus spongiosa. Recipient cannot be pregnant or lactating. Adequate organ functions as defined as: Eastern Cooperative Group (ECOG) performance status of 2 or better Cardiac function: left ventricular ejection fraction (LVEF) of 40% or greater Pulmonary Function: Pulse oximetry with a baseline oxygen saturation of 85% or greater and corrected diffusing capacity of the Lungs for carbon monoxide (DLCO) of 35% or greater Hepatic Function: Serum conjugated (direct) bilirubin less than 3x upper limit of normal for age as per local laboratory, alanine aminotransferase (ALT) and aspartate transaminase (AST) less than 5 x upper limit of normal as per local laboratory. Patients whose hyperbilirubinemia is the result of hyperhaemolysis, or a sever drop in hemoglobin post blood transfusion are not excluded. Absence of liver cirrhosis, bridging fibrosis and active hepatitis as documented by liver biopsy for patients with evidence of iron overload by serum ferritin or MRI. The histological grading and scale described by Ishak and colleagues (1995) will be used. Patient must have a matched-or mismatched unrelated donor or mismatched related family donor. For HLA-matching we will assess 12 HLA-antigens (HLA-A, B, C, DRB1, DQB1 and DPB1). Fully matched unrelated transplanted are defined as matched at 12/12 HLA-alleles. We will include up to 7/8 (HLA-A, B, C, and DRB1) matched unrelated donors. One haplotype-mismatched related donors will be included. Recipient Exclusion Criteria: Pulmonary dysfunction defined as DLCO (corrected for hemoglobin and alveolar volume) < 35% of predicted OR baseline oxygen saturation of <85% or oxygen pressure in arterial blood (PaO2) <70. Severe cardiac dysfunction defined as ejection fraction <45% or subjects who have been receiving chronic transfusion therapy for > 1 year and have evidence of iron overload (serum ferritin levels >1000 ng/mL), a cardiac MRI is required. Cardiac T2* <10 ms results in exclusion. Liver iron content (LIC) ≥15 mg Fe/g dry weight on R2 MRI of liver, unless liver biopsy within 3 months prior to or at screening shows no evidence of bridging fibrosis or cirrhosis. Presence of bridging (portal to portal) fibrosis or cirrhosis in liver biopsy OR transaminases >5x normal upper limit (ULN) for age or direct bilirubin >3x normal upper limit (ULN). Clinical stroke within 6 months of anticipated transplant Karnofsky performance score < 50% HIV infection Uncontrolled viral, bacterial, fungal, or protozoal infection at the time of study enrollment. Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate HSCT in the opinion of the investigator. Patient unable to understand the nature and risks inherent in the HSCT process. History of non-compliance severe enough in the estimation of the treating team to preclude the patient from undergoing unrelated donor transplantation. Patient is pregnant or lactating. Inability to provide adequate transfusion support or increased risk immunohematological complications due presence of anti-RBC antibody against stem cell donor. Presence of donor-specific HLA antibodies Donor Eligibility and Selection Criteria Please note, donor selection will follow our institutional standard operating procedure (SOP). Key criteria are summarized below for convenience: Donor should be evaluated for eligibility to donate by an independent physician not directly caring for the patient on study protocol Donor is willing to sign informed consent allowing the use of the peripheral blood stem cell (PBSC) product for the hematopoietic stem cell transplant (HSCT) of the recipient Donor must meet HLA match criteria outlined in the inclusion criteria above Donor cannot be pregnant or lactating and must agree to contraception until after the donation procedure is complete Testing negative for HIV and viral hepatitis Free of Hb S (defined as Hb S less than 50%) and other hemoglobinopathies that are symptomatic or of clinical significance Targeted minimum stem cell dose of 5.0 x 10e6 CD34 cells/Kg (a marker of human hematopoietic stem cells) of recipient weight 8. Fulfills standard criteria for eligibility as a donor for hematopoietic stem cell transplant (HSCT)