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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Blood Disease

Intervention / Treatment
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* Biological: TCRαβ+/CD19+ depleted Hematopoietic stem cell (HSC) graft
* Device: CliniMACS® System


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>Participants will undergo a conditioning regimen, specific for the original disease, After that peripheral blood stem cell transplant from a haploidentical donor or closely matched unrelated donor, depleted of TCRαβ+ and CD19+ cells using the CliniMACS TCR α/β-biotin and CD19 Systems will be administered intravenously on Day 0 to all participants. | Biological: TCRαβ+/CD19+ depleted Hematopoietic stem cell (HSC) graft<br>* After undergoing a disease specific conditioning regimen (standard of care), participants will receive peripheral blood stem cell transplant from a haploidentical donor or closely matched unrelated donor, depleted of TCR αβ+ and CD19+ cells using the CliniMACS TCR α/β-biotin and CD19 Systems.<br>Device: CliniMACS® System<br>* The CliniMACS Cell Selection System is based on magnetic-activated cell sorting mechanism. The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of grade III-IV acute graft-versus-host disease (GVHD) | Acute GVHD will be assessed and graded according to the Keystone Consensus Criteria for staging and grading of acute graft-versus-host disease. | 100 days post transplantation | 
| Incidence of extensive chronic GVHD | Chronic GVHD will be assessed according to the current CIBMTR (Center for International Blood and Marrow Transplant Research) manual reflecting a grading system published by Sullivan KM (Sullivan 1981). | up to 2 years | 
| Incidence of graft failure | Graft failure - defined as failure to achieve ANC > 500 /µL at Day +28 or initial neutrophil engraftment followed by a decline in ANC < 500 /µL that is unresponsive to growth factor therapy (secondary graft failure). | up to 2 years after graft | 
| Incidence of Treatment related mortality(TRM) | TRM - defined as death from any cause other than disease progression. | Day +100 post-HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to neutrophil engraftment | The time to neutrophil engraftment is defined as the post-transplant day that is the first of 3 consecutive days with an absolute neutrophil count (ANC) of >500/µL as assessed by CBC. | up to 28 days following HSCT | 
| Time to platelet engraftment | The time to platelet engraftment is defined as the post-transplant day that is the first of 3 consecutive days with a platelet count ≥ 20,000/µL as assessed by complete blood count(CBC), without platelet support (transfusion) for 7 days. | up to 28 days following HSCT | 
| Percentage donor chimerism using Short tandem repeat (STR) | Short tandem repeat (STR) analysis will provide the percentage donor chimerism at specific time points post-transplant. | up to 12 months following HSCT | 
| Kinetics of lymphocyte reconstitution via immunophenotyping using flow cytometry | Lymphocyte reconstitution will be assessed at specific time points post-HSCT, expressed as the percentage of white blood cells comprised of T, B and NK cell subsets. | up to 12 months following HSCT | 
| CliniMACS system efficiency: Percentage of viable CD34+ cells recovered after the TCRαβ+ and CD19+ depletion procedure |  | up to 12 months following HSCT | 
| CliniMACS system efficiency: log depletion value for CD19+ cells after the TCRαβ+ and CD19+ depletion procedure |  | Day 0 | 
| CliniMACS system efficiency: log depletion value of TCRαβ+ cells after the TCRαβ+ and CD19+ depletion procedure |  | Day 0 | 
| CliniMACS system efficiency: number of viable blood cell subsets after the TCRαβ+ and CD19+ depletion procedure | Number of viable CD34+ blood stem cells, CD20+ B cells, CD3-CD56+ NK cells, TCRαβ+ T cells, and TCRγδ+ T cells in the HSC graft after the TCRαβ+ and CD19+ depletion procedure | Day 0 | 
| Correlation between GVHD incidence and donor killer-cell immunoglobulin-like receptor (KIR) haplotype content |  | up to 2 years | 
| Correlation between GVHD incidence and killer-cell immunoglobulin-like receptor (KIR)/KIR-ligand mismatch between donor and recipient. |  | up to 2 years | 
| Event free survival | An event is defined as death, graft failure or stable mixed chimerism with disease recurrence. | up to 1 years | 
| Overall survival (OS) |  | up to 2 years | 
| Incidence of symptomatic bacterial/fungal and viral reactivation requiring therapy | The incidence of infections (symptomatic bacterial/fungal and viral reactivation requiring therapy) will be used as an additional safety measure | up to 1 year | 
| Number of participants with adverse events related to infusion of the HSC graft |  | Day 0 | 
| Incidence of serious adverse events |  | up to 2 years |