Closely Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation with TCR alpha/beta+ T Cell and B Cell Depletion for Patients with Severe Sickle Cell Disease and Beta Thalassemia Major

Inclusion Criteria

• SUBJECT INCLUSION ELIGIBILITY:
• Patient age must be >= 2 years and =< 25 years at time of enrollment
• Patients of both genders and all ethnic backgrounds will be eligible
• A clinical decision has been made to transplant the subject and an acceptable donor product has been identified and will be obtained
• SEVERE SICKLE CELL DISEASE: Genotype: Sickle cell-SS disease (hemoglobin SS), sickle cell-hemoglobin C disease (hemoglobin SC), sickle cell-hemoglobin D disease (hemoglobin SD), hemoglobin S/O-Arab heterozygot (SOArab), or sickle beta 0 thalassemia (hemoglobin SBeta thalassemia)
• SEVERE SICKLE CELL DISEASE: Must have at least one of the following disease manifestations * Clinically symptomatic neurologic event (stroke) or any neurologic deficit lasting > 24 hours at any time prior to enrollment * History of two or more episodes of vaso-occlusive events (VOE) per year in the 2 years preceding enrolment. Patients must be refractory to hydroxyurea, defined as developing VOE despite receiving hydroxyurea for at least 6 months. Patients who are intolerant of hydroxyurea may also be enrolled. Vaso-occlusive events include: ** Acute chest syndrome, ** Pain episodes requiring intravenous pain management and/or hospitalization ** Priapism ** Splenic sequestration (defined as a 2 g/dL drop in hemoglobin in the setting of an acutely enlarging spleen. This will be determined as part of clinical care and prior to the research) * Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving >= 8 RBC transfusions in the year preceding enrollment to prevent sickle cell-related complications of any kind per treating hematologist’s judgment
• BETA THALASSEMIA MAJOR: Genotype: Confirmed beta thalassemia genotype by molecular genetic testing (May include hemoglobin beta heterozygous hemoglobin E plus null genotype [E/Beta0] and hemoglobin beta heterozygous insufficiency plus null genotype [Beta0/Beta+] genotypes)
• Serum creatinine < 1.5 x upper limit of normal for age and estimated creatinine clearance >= 60ml/min/1.73 m^2
• Transaminases =< 5 x upper limit of normal
• Serum conjugated bilirubin < 2 x upper limit of normal
• Shortening fraction >= 27% or left ventricular ejection fraction >= 50%
• Diffusing capacity of the lungs for carbon monoxide (DLCO) >= 40% predicted (corrected for hemoglobin) in patients old enough to comply with pulmonary function tests (PFTs) or no baseline oxygen requirement for younger patients
• Lansky or Karnofsky performance >= 60
• Transfusional iron overload: The following assessments apply to patients who have received or are currently receiving a chronic red blood cell transfusion regimen (>= 8 RBC transfusions per year) or for patients with sickle cell disease who have received > 10 lifetime episodic transfusions * Hepatic ** Liver iron concentration (LIC) =< 12 mg Fe/g dry weight as assessed by liver magnetic resonance imaging (MRI) within 6 months of study enrollment or ** Absence of cirrhosis and bridging fibrosis on a liver biopsy or on non-invasive imaging modalities (such as fibroscan) obtained within 6 months of study enrollment * Cardiac ** Patients with BTM and age >= 10 years must have cardiac T2* MRI performed and T2* must be >= 10 ms to be eligible ** For patients with BTM and age < 10 years, and all patients with SCD, Cardiac T2* assessment need will be based on prior LIC history and will be up to discretion of treating physician
• No active, untreated infections
• Negative for human immunodeficiency (HIV) by serology. No evidence of active hepatitis B and C infection by combination of serologic and nucleic acid testing. Subjects who had past infection but no evidence of active infection will be allowed in the study
• Patients with likely bacterial infections must be receiving appropriate antibacterial therapy and demonstrating therapy response
• Patients with likely fungal infections must have had at least 2 weeks of appropriate anti-fungal antibiotics and be asymptomatic
• Patients with symptoms consistent with active viral infection will be deferred until viral symptoms resolve. Patients with evidence of CMV, EBV or other known viremia must receive appropriate therapy to clear viremia prior to initiating study therapy
• Signed consent by parent/guardian for subjects under 18 years of age or patient if >= 18 years
• DONOR SELECTION AND ELIGIBILITY:
• Donor selection will comply with 21 Code of Federal Regulation (CFR) 1271* of the United States (U.S.) Food and Drug Administration’s Code of Federal Regulations
• Donor testing * Unrelated donor meets National Marrow Donor Program criteria for donation * The following infectious disease testing is standard of care for all donors: ** CMV Serology ** HIV 1/2 antibody and HIV nucleic acid testing (NAT) ** Hepatitis (HEP) B core total, HEP B surface antibody (AB), HEP C ** Syphilis ** Human T-lymphotropic virus (HTLV) I AND II
• Donor matching * High resolution human leukocyte antigens (HLA) typing of patient and unrelated donor at HLA-A, -B, -C, DRB1, and DQB1 loci * Unrelated donor must be an antigen and allele match at >= 8/10 HLA loci * In donor with 2 mismatches, only one mismatch involving HLA-A, -B, or -DRB1 will be allowed * Donor and collection center willing to undergo peripheral stem cell mobilization and collection by apheresis

Exclusion Criteria

• SUBJECT EXCLUSION ELIGIBILITY:
• Patients who do not meet disease, organ or infectious criteria
• Previous hematopoietic stem cell transplantation (HSCT)
• Patients with no suitable unrelated donor available. Patients with suitable fully matched related donor are also not eligible
• Pregnant females. All females of childbearing potential must have negative pregnancy test
• Participation in a clinical trial in which the patient receives an investigational drug must be discontinued prior to the time of initiation of transplant therapy. Specifically transplant chemotherapy should not begin until at least 3 half-lives after last use of the investigational drug
• Severe RBC alloimmunization, defined as inability to receive packed RBC transfusion therapy due to anti-RBC antibodies. Patients with high titer anti-donor HLA antibodies detected on screening may be enrolled if they are willing to undergo HLA antibody desensitization therapy