Haploidentical HCT for Severe Aplastic Anemia
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
AgeUp to 21
SponsorSt. Jude Children's Research Hospital
About this trial
This study is a prospective, single center phase II clinical trial in which patients with Severe Aplastic Anemia (SAA) ) will receive a haploidentical transplantation. The purpose of this study is to learn more about newer methods of transplanting blood forming cells donated by a family member that is not fully matched to the patient. This includes studying the effects of the chemotherapy, radiation, the transplanted cell product and additional white blood cell (lymphocyte) infusions on the patient's body, disease and overall survival. The primary objective is to assess the rate of engraftment at 30 days and overall survival (OS) and event free survival (EFS) at 1 year post-hematopoietic cell transplantation (HCT).
Primary Objectives
* To estimate the rate of engraftment at 30 days after TCR αβ+ T-cell-depleted graft infusion in patients receiving a single dose of post graft infusion cyclophosphamide. * To estimate the overall survival and event free survival at 1-year post transplantation.
Secondary Objectives
* To calculate the incidence of acute and chronic GVHD after HCT. * To calculate the rate of secondary graft rejection at 1-year post transplantation * To calculate the cumulative incidence of viral reactivation (CMV, EBV and adenovirus). * To describe the immune reconstitution after TCR αβ+ T-cell-depleted graft infusion at 1 month, 3 months, 6 months, 9 months, and 1 year.
Exploratory Objectives
* To longitudinally assess the phenotype and epigenetic profile of T-cells in SAA patients receiving HCT for SAA. * To assess the phenotype and epigenetic profile of T-cells in DLI administered to SAA patients post HCT. * To longitudinally assess CD8 T cell differentiation status in SAA patients using an epigenetic atlas of human CD8 T cell differentiation. * To examine the effector functions and proliferative capacity of CD8 T cells isolated from SAA patients before and after DLI. * Quantify donor derived Treg cells at different time points in patients received HCT. * Determine Treg activation status at different stages after HCT. * Are specific features of the DLI product associated with particular immune repertoire profiles post-transplant? * How does the diversity and functional profile of the DLI product alter the response to pathogens in the recipient? * Do baseline features of the recipient's innate and adaptive immune cells correlate with post-transplant immune repertoires and response profiles?
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Age less than or equal to 21 years at time of enrollment.
Confirmed diagnosis of SAA or a single lineage cytopenia
i. Bone marrow cellularity < 25% or hypocellular marrow for age, AND
ii. One or more of the following (in peripheral blood): (i) Neutrophils < 0.5 x10^9/L (ii) Platelets < 20 x10^9/L, or platelet transfusion dependence (iii) Hemoglobin <8g/dL, or red blood cell transfusion dependence
Disqualifiers
Diagnosis of Fanconi anemia. Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing.
Known clinical or genetic diagnosis of dyskeratosis congenita
Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre- MDS) or MDS on marrow examination (e.g. Monosomy 7).
Diagnosis of myelodysplastic syndrome (MDS).
Trial design
Design model
Single group
Treatments tested in this trial
Anti-Thymocyte Globulin (Rabbit)
DrugGiven intravenously (IV)
Fludarabine
DrugGiven intravenously (IV)
Cyclophosphamide
DrugGiven intravenously (IV)
Mesna
DrugGiven intravenously (IV)
G-CSF
DrugFilgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by recombinant DNA technology. Dosage and Route of Administration: 5mcg/kg subcutaneous or intravenous daily until ANC \>2000 for 2 consecutive days, or as clinically indicated
Total Lymphoid Irradiation (TLI)
RadiationTLI will be given at 800 cGy total dose in 4 fractions.
CliniMACS
DeviceThe mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.
HPC, A Infusion
Biological/VaccineGiven intravenously Day 0-HPC, A Infusion (TCR αβ+/CD19+-depleted graft)
CD45RA-depleted DLI
Biological/VaccineCD45RA-depleted DLI will be given at least ONE week after engraftment
Treatment groups
21 Participants
are divided into 1 treatment groupGroup A: Haploidentical HCTExperimental treatment 9 interventions
Trial outcomes
Primary outcomes
1
Engraftment
Rate of patients engrafting at day 30 after TCR αβ+ T-cell-depleted graft infusion in patients receiving a single dose of post graft infusion cyclophosphamide.
Time frame
30 days2
Overall and event free survival
Rate of overall survival and event free survival at 1-year post transplantation.
Time frame
1 yearSecondary outcomes
1
Graft vs host disease
Incidence of acute and chronic GVHD after hematopoietic cell transplant
Time frame
1 year2
Graft rejection
Rate of secondary graft rejection at 1-year post transplantation
Time frame
1 year3
Viral reactivation
Cumulative incidence of viral reactivation post-transplant (CMV, EBV and adenovirus)
Time frame
1 year4
Immune reconstitution
We will record immune reconstitution parameters, including the order and magnitude of recovery of the different subtypes of leukocytes. Results will be summarized by descriptive statistics. The pattern of immune reconstitution will be evaluated using longitudinal approaches such as mixed effect models or generalized estimating equation (GEE) approach.
Time frame
1 yearSponsors and contacts
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Source ClinicalTrials.gov