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

This is an interventional treatment trial for Non-Malignant Hematologic Disorders focused on measuring T-cell, B-cell, CliniMACS System, Melphalan, Thiotepa, Clofarabine, Fludarabine, 17-596 Read More

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.