TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Non-Malignant Hematological Disorders in Children

Inclusion criteria

• Severe sickle cell disease (HbSS, HbSC, HbSB0, HbSB+, HbSD, HbSE) with at least one of the following criteria:

• Cerebrovascular accident lasting longer than 24 hours
• Impaired neuropsychological function with abnormal brain MRI/MRA
• Patients with frequent (≥ 3 per year for preceding 2 years) painful vaso-occlusive episodes
• Recurrent (≥ 3 in lifetime) acute chest syndrome events which have necessitated erythrocyte transfusion therapy
• Any combination of ≥ 3 acute chest syndrome episodes and vaso-occlusive pain episodes yearly for 3 years and have failed treatment with hydroxyurea (HU) (at least 6 months on maximum tolerated dose) or who are intolerant to HU therapy
• Thalassemia major with at least one of the following criteria:

• Transfusion dependency defined as receiving 8 or more transfusions per year
• Thalassemia diagnosis documented by clinical assessment, laboratory evidence with microcytic anemia and absence of HbA (< 10%) on electrophoresis and or confirmation by DNA analysis of alpha and beta gene loci
• Genotypically proven thalassemia major for children < 2 years of age even in the absence of transfusion dependency
• 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)
• Bone marrow failure syndromes and autoimmune cytopenias:

• Severe Aplastic Anemia refractory to immunosuppressive therapy
• Diamond Blackfan Anemia refractory to conventional therapy
• Inherited Bone Marrow Failure Syndromes such as Fanconi anemia and Shwachman-Diamond syndrome with progressive marrow failure (without cytogenetic evidence of MDS/AML)
• Severe Congenital Neutropenia
• Congenital Amegakaryocytic Thrombocytopenia
• Glanzmann Thrombasthenia
• Autoimmune Cytopenias refractory to conventional treatment (including Pure red cell aplasia, Evan's syndrome, Immune thrombocytopenia, autoimmune hemolytic anemia)
• Other marrow failure disorders not otherwise specified

Inclusion criteria

• Patient has a suitable genotypic identical match of 5/10. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1.
• Patients must have adequate organ function measured by:

• Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 40% or SF ≥ 26%
• Pulmonary: asymptomatic or if symptomatic DLCO ≥ 40% of predicted (corrected for hemoglobin) or pulse oximetry ≥ 92% on room air if the patient is unable to perform pulmonary function testing.
• Renal: Creatinine clearance (CrCl) or glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m2.
• Hepatic: Serum conjugated (direct) bilirubin < 2.0 x ULN for age as per local laboratory unless attributable to Gilbert's syndrome; AST and ALT < 5.0 x ULN for age as per local laboratory. Patients with hyperbilirubinemia as a consequence of hyperhemolysis, or a profound change in serum hemoglobin post blood transfusion, are not excluded.
• Karnofsky or Lansky (age-dependent) performance score ≥ 50
• Signed written informed consent

Exclusion criteria

• Participants who have an HLA-matched sibling who is able and willing to donate bone marrow. Patients with a HLA-matched unrelated donors are not excluded.
• Pregnant or breastfeeding females.
• Patient has HIV or uncontrolled fungal, bacterial or viral infections.
• Patient has received prior solid organ transplant.
• Patient has active GVHD (> grade II) or chronic extensive GVHD due to a previous allograft at the time of inclusion.
• For patients with hemoglobinopathy, liver biopsy is necessary if the patient has received chronic transfusions for over a year and has two ferritin levels of ≥ 1000 ng/ml. Patients with cirrhosis, extensive bridging hepatic fibrosis, or active hepatitis are excluded from enrollment.