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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
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.
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.
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.
Time frame: 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).
Time frame: 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).
Time frame: up to 2 years after graft
Incidence of Treatment Related Mortality (TRM)
TRM - defined as death from any cause other than disease progression.
Time frame: Day +100 post-HSCT
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: up to 12 months following HSCT
CliniMACS system efficiency: Percentage of viable CD34+ cells recovered after the TCRαβ+ and CD19+ depletion procedure
Time frame: up to 12 months following HSCT
CliniMACS system efficiency: log depletion value for CD19/CD20+ B cells after the TCRαβ+ and CD19+ depletion procedure
Time frame: Day 0
CliniMACS system efficiency: log depletion value of TCRαβ+ T cells after the TCRαβ+ and CD19+ depletion procedure
Time frame: 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
Time frame: Day 0
Correlation between GVHD incidence and donor killer-cell immunoglobulin-like receptor (KIR) haplotype content
Time frame: up to 2 years
Correlation between GVHD incidence and killer-cell immunoglobulin-like receptor (KIR)/KIR-ligand mismatch between donor and recipient.
Time frame: up to 2 years
Event free survival
An event is defined as death, graft failure or stable mixed chimerism with disease recurrence.
Time frame: up to 1 years
Overall survival (OS)
Time frame: 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
Time frame: up to 1 year
Number of participants with adverse events related to infusion of the HSC graft
Time frame: Day 0
Incidence of serious adverse events
Time frame: up to 2 years
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