Alpha/Beta T-cell Depleted Blood-forming Stem Cell Transplant From Related or Unrelated Donors for Blood Diseases in Children and Young Adults

This single institution, phase I clinical trial will determine the safety and feasibility of employing T-cell receptor (TCR) αβ+ and CD19+ (Cluster of Differentiation) depleted hematopoietic stem cell transplantation (HSCT) using peripheral blood stem cells (PBMC) from closely matched unrelated donors or haploidentical donors to treat non-malignant hematologic diseases in children and young adults. Allogeneic hematopoietic stem cell transplantation has become a curative option for children and adolescents with a variety of otherwise fatal conditions. To reduce the incidence and severity of graft-versus-host disease (GVHD) associated with allogeneic hematopoietic stem cell transplantation, donor grafts are depleted of T cells, either using CD34+ selection or CD3+/CD19+ depletion of grafts. However, these selection processes also deplete the graft of protective cell subsets, such as γδ T cells, natural killer (NK) cells, monocytes and dendritic cells, which play important roles in the immune response to infectious agents. Moreover, the presence of NK cells and γδ T cells in donor grafts is associated with more rapid immune reconstitution after HSCT transplantation. In order to retain these protective immune cell subsets, this trial will use a novel, highly selective graft engineering process using the Miltenyi CliniMACS system that selectively depletes αβ-T cells and B cells that are responsible for GVHD and Epstein Barr Virus (EBV)-related post-transplantation lymphoproliferative disorder, respectively. Prior to transplantation, patients will be treated with a conditioning regimen, specific for the original disorder.

The primary objective of this study is evaluation of the safety and feasibility of HSCT using TCRαβ+/CD19+ depleted hematopoietic stem cells to treat non-malignant hematologic diseases. This will be assessed by evaluating the incidence of graft failure, grade III-IV acute GVHD and chronic GVHD and TRM.

Secondary objectives include the evaluation of immune reconstitution and incidence of post-transplant infections, adverse events, serious adverse events, overall and disease-free survival and the efficiency of graft processing by the CliniMACS System.

Inclusion criteria

• No Human leukocyte antigen (HLA) identical sibling available AND
• NO HLA matched unrelated donor available OR urgent need of HSCT precludes time necessary to search for suitable HLA matched unrelated donor AND
• Haploidentical donor OR closely matched unrelated donor available and willing to undergo mobilization and apheresis
• If subject has genetically confirmed inherited bone marrow failure, related donor must be evaluated for this disorder and testing must be negative.
• If subject has sickle cell disease, donor must be unaffected or have only sickle cell trait
• Patient must be diagnosed with one of the following diseases or disorders:

• Hemoglobinopathies

• Sickle Cell Disease for patients ≤ 21 years of age for whom hydroxyurea has been trialed for at least six months, and failed
• Thalassemia Major for patients ≤ 21 years of age
• Acquired Bone Marrow Failure Syndromes

• Paroxysmal Nocturnal Hemoglobinuria with bone marrow failure
• Myelodysplastic Syndromes (lower risk)
• Severe acquired aplastic anemia
• Inherited Bone Marrow Failure Syndromes

• Fanconi Anemia
• Diamond Blackfan Anemia
• Dyskeratosis Congenita and related telomere disorders
• Congenital Thrombocytopenia Syndromes
• Severe Congenital Neutropenia
• Shwachman-Diamond Syndrome
• Inborn Errors of Immunity (IEI) or Primary Immune Regulatory Disorders (PIRD)

• Wiskott-Aldrich syndrome (WAS)
• Chronic granulomatous disease (CGD)
• Severe combined immunodeficiency (SCID)
• Primary hemophagocytic lymphohistiocytosis (HLH)
• Age ≤ 25 years (except patients with hemoglobinopathies)
• Life Expectancy ≥ 3 months
• Karnofsky (patients > 16 years)/Lansky (patients ≤ 16 years) index ≥ 60
• Organ Function Requirements

• Renal Function

• Creatinine clearance or radioisotope Glomerular Filtration Rate (GFR) greater than or equal to 60 ml/min/1.73m^2
• Liver Function

• Total bilirubin < 3 mg/dL
• Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase; synonymous with ALT (SCPT) ≤ 3 x Upper Limit of Normal (ULN) for age
• Cardiac Function

• Ejection fraction of > 40% by Multiple gated acquisition scan (MUGA) or echocardiogram
• Pulmonary Function

• No evidence of dyspnea at rest
• No supplemental oxygen requirement
• If measured, carbon monoxide diffusion capacity (DLCO) > 50%
• Willing to use effective birth control method if patient is of reproductive potential
• Informed consent obtained (patient or legal representative)

Exclusion criteria

• Pregnant
• HIV infection
• Uncontrolled, serious active infection at screening
• Significant serious intercurrent illnesses
• Enrollment in any other treatment study that would interfere with the endpoints of this study according to judgement of Principal Investigator (or PI designee).