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 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 which 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.


Eligibility Criteria:
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 may 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)

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
* Age ≤ 40 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).