Siplizumab for Sickle Cell Disease Transplant

Recipient Inclusion Criteria:

1. 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:

2. Clinically significant neurologic event (stroke) or any neurological deficitlasting at least 24 hours. Stroke will be defined as a clinically significantneurologic event that is accompanied by an infarct on cerebral MRI or cerebralarteriopathy requiring chronic transfusion therapy.

3. History of two or more episodes of ACS in the 2-year period precedingenrollment despite supportive care measures (i.e. asthma therapy and/orhydroxyurea).

4. History of three or more severe vaso-occlusive pain crises per year in the 2-year period preceding enrollment despite the institution of supportive caremeasures (i.e. a pain management plan and/or treatment with hydroxyurea).

5. Administration of regular red blood cell (RBC) transfusion therapy, defined asreceiving 8 or more transfusions per year for 1 year or more to preventvaso-occlusive clinical complications (i.e. pain, stroke, and ACS)

6. An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity > or equal to 2.7 m/sec or pulmonary hypertension diagnosed by right heartcatheterization.

7. Chronic kidney disease including patients on hemo-dialysis

8. Recurrent tricorporal priapism defined as at least 2 episodes of an erectionlast ≥4 hours involving the corpus cavernosa and corpus spongiosa.

9. Recipient cannot be pregnant or lactating.

10. Adequate organ functions as defined as:

11. Eastern Cooperative Group (ECOG) performance status of 2 or better

12. Cardiac function: left ventricular ejection fraction (LVEF) of 40% or greater

13. Pulmonary Function: Pulse oximetry with a baseline oxygen saturation of 85% orgreater and corrected diffusing capacity of the Lungs for carbon monoxide (DLCO) of 35% or greater

14. Hepatic Function: Serum conjugated (direct) bilirubin less than 3x upper limitof normal for age as per local laboratory, alanine aminotransferase (ALT) andaspartate transaminase (AST) less than 5 x upper limit of normal as per locallaboratory. Patients whose hyperbilirubinemia is the result of hyperhaemolysis,or a sever drop in hemoglobin post blood transfusion are not excluded.

15. Absence of liver cirrhosis, bridging fibrosis and active hepatitis asdocumented by liver biopsy for patients with evidence of iron overload by serumferritin or MRI. The histological grading and scale described by Ishak andcolleagues (1995) will be used.

16. Patient must have a matched-or mismatched unrelated donor or mismatched relatedfamily donor.

17. For HLA-matching we will assess 12 HLA-antigens (HLA-A, B, C, DRB1, DQB1 andDPB1).

18. Fully matched unrelated transplanted are defined as matched at 12/12HLA-alleles. We will include up to 7/8 (HLA-A, B, C, and DRB1) matchedunrelated donors.

19. One haplotype-mismatched related donors will be included.

Recipient Exclusion Criteria:

1. Pulmonary dysfunction defined as DLCO (corrected for hemoglobin and alveolar volume) < 35% of predicted OR baseline oxygen saturation of <85% or oxygen pressure inarterial blood (PaO2) <70.

2. Severe cardiac dysfunction defined as ejection fraction <45% or subjects who havebeen receiving chronic transfusion therapy for > 1 year and have evidence of ironoverload (serum ferritin levels >1000 ng/mL), a cardiac MRI is required. Cardiac T2* <10 ms results in exclusion.

3. Liver iron content (LIC) ≥15 mg Fe/g dry weight on R2 MRI of liver, unless liverbiopsy within 3 months prior to or at screening shows no evidence of bridgingfibrosis or cirrhosis. Presence of bridging (portal to portal) fibrosis or cirrhosisin liver biopsy OR transaminases >5x normal upper limit (ULN) for age or directbilirubin >3x normal upper limit (ULN).

4. Clinical stroke within 6 months of anticipated transplant

5. Karnofsky performance score < 50%

6. HIV infection

7. Uncontrolled viral, bacterial, fungal, or protozoal infection at the time of studyenrollment.

8. Patient with unspecified chronic toxicity serious enough to detrimentally affect thepatient's capacity to tolerate HSCT in the opinion of the investigator.

9. Patient unable to understand the nature and risks inherent in the HSCT process.

10. History of non-compliance severe enough in the estimation of the treating team topreclude the patient from undergoing unrelated donor transplantation.

11. Patient is pregnant or lactating.

12. Inability to provide adequate transfusion support or increased riskimmunohematological complications due presence of anti-RBC antibody against stemcell donor.

13. 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:

1. Donor should be evaluated for eligibility to donate by an independent physician notdirectly caring for the patient on study protocol

2. Donor is willing to sign informed consent allowing the use of the peripheral bloodstem cell (PBSC) product for the hematopoietic stem cell transplant (HSCT) of therecipient

3. Donor must meet HLA match criteria outlined in the inclusion criteria above

4. Donor cannot be pregnant or lactating and must agree to contraception until afterthe donation procedure is complete

5. Testing negative for HIV and viral hepatitis

6. Free of Hb S (defined as Hb S less than 50%) and other hemoglobinopathies that aresymptomatic or of clinical significance

7. Targeted minimum stem cell dose of 5.0 x 10e6 CD34 cells/Kg (a marker of humanhematopoietic stem cells) of recipient weight 8. Fulfills standard criteria foreligibility as a donor for hematopoietic stem cell transplant (HSCT)