TCR Alpha Beta T-cell and CD19 B-cell Depleted Peripheral Blood Stem Cell Transplantation Using the CliniMACS System for Patients With Non-Malignant Hematologic Disorders From Matched or Mismatched, Related or Unrelated Donors
Condition: Non-Malignant Hematologic Disorders
MeSH terms: Hematologic Diseases
Intervention: Melphalan; Thiotepa; Clofarabine; Fludarabine; Anti-Thymocyte Globulin (Rabbit) (Thymoglobulin®); CliniMACS reagents
Intervention description: Melphalan 70 mg/m2/day x 2; Thiotepa 7.5 mg/kg/day x 2; Clofarabine 20-30 mg/m2/day x 5; Fludarabine 30 mg/m2/day x 5; antithymocyte globulin (ATG) (rabbit ATG 2.5 mg/kg/day x 3 or equine ATG 15 mg/kg/day x 3 (or 40 mg/kg/day x 1 equine ATG if rabbit ATG is not tolerated) during pre-transplant conditioning to deplete host T-cells that could hamper engraftment.; Products will then undergo TCR-αβ+ and CD-19 depletion using the CliniMACS.
Intervention MeSH terms: Fludarabine; Melphalan; Thiotepa; Clofarabine; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: For this trial, patients will be assigned to receive one of two conditioning regimens, based on their disease, disease severity, organ status and history of red blood cell alloimmunization.
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 1 Year
Maximum age: 69 Years
Healthy volunteers: No
Keywords: T-cell; B-cell; CliniMACS System; Melphalan; Thiotepa; Clofarabine; Fludarabine; 17-596

Summary:

      The purpose of this study is to find out if removing a specific type of white blood cell
      (called alpha beta T-cell) that help make up the transplant donor's stem cells can improve
      results of blood stem cell transplant for the participant's disease.
    

Eligibility criteria:

        Subject Inclusion Criteria:

          -  Lethal disorders of Hematopoiesis correctable by transplant for which Alpha βeta
             T-cell and CD-19 depleted allogeneic hematopoietic stem cell transplantation is
             indicated including:

          -  Sickle cell disease (HbSS, HbSC, HbSB0 thalassemia, HbSB+, HbSD, HbSE) with at least
             one of the following criteria (Walters et al):

               1. Cerebrovascular accident lasting longer than 24 hours

               2. Impaired neuropsychological function with abnormal brain MRI/MRA

               3. Recurrent hospitalizations (>2 episodes/year over several years) or exchange
                  transfusions for acute chest syndrome

               4. Recurrent priapism

               5. Stage I or II sickle chronic lung disease

               6. Sickle cell nephropathy (moderate to severe proteinuria or glomerular filtration
                  rate 30-50% of predicted normal value for age)

               7. Bilateral proliferative retinopathy with major visual impairment in at least one
                  eye

               8. Osteonecrosis of multiple joints

               9. Red cell alloimmunization during chronic transfusion therapy

          -  Thalassemia major with at least one of the following criteria:

               1. Age <16 years

               2. Available HLA-identical sibling

               3. Red blood cell transfusion dependency

               4. Lucarelli class 1 or 2 risk status (i.e. with only 0-2 of the following factors:
                  hepatomegaly, portal fibrosis, or poor response to chelation therapy)

               5. Recurrence of disease after previous stem cell transplant

          -  Bone Marrow Failure Syndromes:

               1. Aplastic anemia refractory to immunosuppressive therapy

               2. Diamond Blackfan Anemia refractory to conventional therapy

               3. Shwachman-Diamond Syndrome

               4. Severe Congenital Neutropenia

               5. Congenital Amegakaryocytic Thrombocytopenia

               6. Thrombocytopenia Absent Radii syndrome

               7. Other marrow failure disorders not otherwise specified

          -  Autoimmune cytopenias refractory to all conventional treatments

               1. Autoimmune hemolytic anemia

               2. Immune thrombocytopenia

               3. Evan's syndrome

               4. Pure red cell aplasia

          -  Histiocytic disorders:

               1. Hemophagocytic lymphohistiocytosis

               2. High risk, recurrent or refractory Langerhans cell histiocytosis

               3. Secondary HLH

        Subject Inclusion Criteria:

          -  Recipient's age birth to < 70 years old

          -  Patients must have adequate organ function measured by:

          -  Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 50% and must
             improve with exercise.

          -  Hepatic: < 3x ULN AST and ≤ 1.5 mg/dl total serum bilirubin, unless there is
             congenital benign hyperbilirubinemia or if the hyperbilirubinemia is directly caused
             by the disease in which the patient is receiving a transplant for. Patients with
             higher bilirubin levels due to causes other than active liver disease are also
             eligible with PI approval e.g. patients with PNH, Gilbert"s disease or other hemolytic
             disorders.

          -  Pulmonary: asymptomatic or if symptomatic, DLCO ≥ 50% of predicted (corrected for
             hemoglobin).

          -  Renal: serum creatinine ≤1.5x normal for age. If serum creatinine is outside the
             normal range, then CrCl > 70 mL/min/1.73m2 (calculated or estimated) or GFR
             (mL/min/1.72m2) >30% of predicted normal for age.

          -  Normal GFR in Children and Young Adults.

        Donor Inclusion Criteria:

          -  Each donor must meet criteria outlined by institutional guidelines and be medically
             eligible to donate according to NMDP (or equivalent donor search organization)
             criteria including testing for antibodies to Human TLymphotrophic Virus Types I & II
             (Anti-HTLV-I/II) and screening for West Nile Virus, Creutzfeldt-Jakob disease and
             Zika.

          -  Pediatric donors should weigh ≥ 25.0 kg, have adequate peripheral venous catheter
             access for leukapheresis or must agree to placement of a central catheter.

          -  Donor should be healthy and agree to receive G-CSF followed by donation of peripheral
             blood stem cells.

          -  Donors must agree to anesthesia and marrow donation (in cases of inadequate PBSC
             collection).

          -  Related or unrelated donors who are 7/8 or 8/8 HLA-antigen matched for haplotypes A,
             B, C, DRB1 OR Related donors who are 4-6/8 HLA-antigen matched.

        Subject Exclusion Criteria:

          -  Female patients who are pregnant or breast-feeding

          -  Active viral, bacterial or fungal infection

          -  Patient seropositive for HIV-I/II; HTLV-I/II

          -  Karnofsky (adult)/Lansky (pediatric) < 70%

          -  Inherited DNA repair deficiency: Fanconi Anemia and Dyskeratosis Congenita. These are
             presently undergoing transplantation based on a multi-center protocol

          -  Patients with Thalassemia major with Pesaro risk score >II

          -  Inherited metabolic disorders: Hurler Syndrome, Sly syndrome (MPSVIII),
             α-Mannosidosis, X- ALD, Osteopetrosis

        Donor Exclusion Criteria:

          -  Donors who are seropositive for HIV-I/II or HTLV-I/II and female patients who are
             pregnant or breastfeeding will not be eligible for this study.