CD45RA Depleted T-cell Infusion for Prevention of Infections After TCRab/CD19-depleted Allo-HSCT

Study Overview
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Brief Summary
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The purpose of this prospective randomized study is to determine whether infusions of T-memory cells prevent infections in children with leukemia after allogeneic alpha, beta T-cell receptor (TcRab)/CD19-depleted hematopoietic stem cell transplantation (HSCT).

Detailed Description
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Graft-versus-host disease (GVHD) remains the most important direct complication of hematopoietic stem cell transplantation. Methods used to prevent GVHD include diverse pharmacologic interventions and ex vivo methods of T-cell depletion, the latter being the most effective ones. Historically depletion of T-cells from the graft is associated with increased rate of graft failure, relapse of malignant disease and prolonged immune deficiency. Selective depletion of TCR-alpha/beta T-lymphocytes is a new method of hematopoietic stem cell graft manipulation, which is thought to conserve important cell populations, e.g. NK cells and gamma/delta T cells within the graft. Preliminary results suggest that TCR alpha/beta depletion ensures high engraftment rate, low early mortality and good control of GVHD. The problem of delayed immune reconstitution and life-threatening viral infections remains incompletely resolved. Depletion of naive (CD45RA-positive) T-cells was developed as a new method of graft manipulation to prevent GVHD. Research data indicate that alloreactivity is associated mainly with naive T-cell fraction. In vitro depletion of CD45RA lowers significantly the alloreactive response while retaining reactivity to pathogens. In previous pilot protocol the investigators confirmed that infusion after TCR-alpha/beta depleted transplantation of low doses of CD45RA-depleted mononuclear cells are safe and potentially protective against viral infections. The biologic readout for the protocol was a quantitative assessment of T-cell reactivity to common pathogens after infusion and owing to the trial results expansion of CMV-specific CD8 T-cells was discovered in most of the patients. In current randomized protocol the investigators are posing a question if donor lymphocytes infusion (DLI) of low doses of CD45RA-depleted mononuclear cells are effective in viral prophylaxis after TCR-alpha/beta depleted transplantation.

Official Title
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A Phase II Prospective Randomized Trial of Donor T-memory Cells (CD45RA Depleted) Infusion for Prevention of Infections After Allogeneic TcRαβ/CD19-depleted Hematopoietic Stem Cell Transplantation

Conditions
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Leukemia, Lymphoma, Myelodysplastic Syndromes, GvHD, Opportunistic Infections, Graft-versus-Host Disease

Intervention / Treatment
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* Biological: CD45RA-depleted peripheral blood mononuclear cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are considered candidates for allogeneic hematopoietic stem cell transplantation and have one of the following diagnoses: Acute lymphocytic leukemia (ALL) Acute myeloid leukemia Acute biphenotypic leukemia Acute bilinear leukemia Lymphoma Myelodysplastic syndrome Chronic myeloid leukemia Transplant processing: TCR ab/CD19-depletion Donors: HLA-match unrelated volunteers Partly and haploidentical relative Exclusion Criteria: ALL patients not in remission Patients with uncontrolled infections Clearance of creatinine < 70 ml/min Cardiac ejection fraction < 40% Patients who can perform pulmonary function tests will be excluded if they have a diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) of < 50% predicted; patients who are unable to perform pulmonary function tests will be excluded if the oxygen (O2) saturation is < 92% on room air Patients who have liver function test (LFTs) (including total bilirubin, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) >= twice the upper limit of normal Mental disease of both patient, patient's tutor (if patient is under age 18) and donor, that hinder understanding of main point of the study and keeping treatment plan, hygiene and sanitation

Ages Eligible for Study
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Maximum Age: 25 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: CD45RA-<br> | |
| Experimental: CD45RA+<br> | Biological: CD45RA-depleted peripheral blood mononuclear cells<br>* Infusion of escalating doses of CD45RA-depleted donor-derived allogeneic peripheral blood mononuclear cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cumulative incidence of the probability of CMV-reactivation after HSCT |  | 120 days after HSCT | 
| cumulative incidence of acute GVHD grade II-IV. |  | 150 days after HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cumulative incidence of of CMV-disease at 100,180 and 365 days after HSCT |  | 100, 180 and 365 days after HSCT | 
| overall survival at 365 days after HSCT |  | 365 days after HSCT | 
| Event-free survival at 365 days after HSCT |  | 365 days after HSCT | 
| cumulative incidence of relapse at 6 months and 365 days after HSCT |  | 6 months and 365 days | 
| cumulative incidence of transplant-related mortality at 6 months after HSCT |  | 6 months | 
| cumulative incidence of chronic GvHD |  | 1 year after HSCT | 
| cumulative incidence of neutrophil and platelets engraftment at 14 and 30 days after HSCT |  | 14 and 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD45RA-depletion, TCR-alpha/beta depletion, Hematopoietic Stem Cell Transplantation