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

TCRαβ+ and CD19+ Depleted Hematopoietic Stem Cell Transplant From Closely Matched Unrelated Donors or Haploidentical Related Donors for Hematologic Diseases in Children and Young Adults

This study is being done to see if the investigators can take peripheral blood stem cells from either an adult family member or a closely matched unrelated donor, and run them through a special lab instrument to remove alpha/beta T cells and B cells and then give them to the patient to treat disease. This is an experimental way of doing a hematopoietic stem cell transplant (HSCT). The investigators want to see if the new stem cells will grow without bad graft vs. host disease (GVHD). This treatment approach is experimental in the United States.

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).