Individualized Dose Study of ATG in Haploidentical Hematopoietic Stem Cell Transplantation

Study Overview
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Brief Summary
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The purpose of this study is to determine the response and toxicity rate of two different dosages (Individualized dosage VS. fixed dosage) of ATG as a prophylaxis for acute GVHD in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT).

Detailed Description
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Acute graft-versus-host disease (aGvHD) is an important complication of haplo-HSCT. The Seattle group initially introduced the use of ATG as a treatment for acute graft-versus-host disease (aGVHD) in allogeneic hematopoietic stem cell transplantation (haplo-PBSCT) recipients. Presently, in both myeloablative and reduced-intensity conditioning (RIC) haplo-PBSCT, ATG is part of postengraftment immunosuppressive regimens. The regimens for prophylaxis of GVHD based on 10mg/kg rabbit anti-human thymocyte immunoglobin (ATG, Thymoglobulin®, Genzyme Polyclonals S.A.S) effectively reduced the occurrence of grade II-IV aGvHD. However, the incidence of cytomegalovirus (CMV) and EB virus (EBV) reactivation were higher due to a slower immune reconstitution. The 100-day cumulative incidence of CMV and EBV viremia were both over 70% in our unmanipulated haplo-PBSCT program. The optimal dose of ATG balancing the efficacy of GVHD prophylaxis and the risk of virus reactivation in haplo-PBSCT remains unknown. Reports on the pharmacokinetics of Thymoglobulin in allo-HSCT revealed a high variability. Recent pharmacokinetic studies have shown that the half-life of total ATG after transplant is longer than the active ATG (which is available to bind to human lymphocytes and causes the desired immunological effects). And active ATG appears more associated with pharmacodynamics effects. The investigators found that virus reactivation and acute GVHD were highly affected by ATG exposure (area under the curve, AUC) in previous cohort study. The investigators have found an optimal range of active ATG exposure balancing the efficacy of GVHD prophylaxis and the risk of virus reactivation. The incidence of CMV reactivation and III-IV aGVHD reduced to 60%, 6% respectively. The results suggested that Individualized dosing of ATG has a potential advantage in balancing the efficacy of GVHD prophylaxis and the risk of virus reactivation in haplo-PBSCT. This may improve the survival and quality of life of patients undergoing haplo-PBSCT. A prospective randomized trial is required to compare the efficacy of Individualized dosage of ATG as a prophylaxis for acute GVHD in haplo-PBSCT.

Official Title
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Impact of Optimal Doses of Antithymocyte Globulin Conditioning on Graft-versus- Host Disease and Virus Reactivation in Haploidentical Hematopoietic Stem Cell Transplantation

Conditions
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Haploidentical Hematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Drug: Antithymocyte Globulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of hematological malignancies refer to the 2016 WHO classification. Aged 14 to 60 years. Karnofsky or Lansky performance status [27] ≥ 70%. Please refer to Appendix A. First transplantation. Adequate organ function Patient and/or legal guardian must sign informed consent for HSCT. Exclusion Criteria: Ex-vivo T-cell depleted grafts. Pregnancy or breast-feeding or unwilling to use proper contraception. Unable to assess whether the malignancy is in complete remission. History of hypersensitivity to any biological product. Sensibility to rabbit proteins or previous treatment with Thymoglobuline®. Subjects with uncontrollable systemic infection (viral, bacterial or fungal). Participation in other trial in which the dose of Thymoglobuline® is fixed other than individualized dose. Unable to sign the informed consent form.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 60 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: Individual dose of Thymoglobulin<br>Individual dose of Thymoglobulin (r-ATG) : Individual dose of ATG was Intravenous infused every day from day -5 to day -2 (total ATG dose was calculated based on pharmacokinetic index, within a range of 6 mg/kg to 10mg/kg) | Drug: Antithymocyte Globulin<br>* Individual dose of ATG was Intravenous infused every day from day -5 to day -2 (total ATG dose was calculated based on pharmacokinetic index, within a range of 6 mg/kg to 10mg/kg). Antithymocyte globulin (ATG) was added to conditioning regimens for 4 days (days -5 and -2). Prophylaxis against graft-versus-host disease (GVHD) was performed with cyclosporine A (CsA), mycophenolate mofetil (MMF) and short-term methotrexate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The cumulative incidences of CMV reactivation | The cumulative incidences of CMV reactivation in participants after transplantation, tested by realtime PCR | 180 days after transplantation | 
| The cumulative incidences of EBV reactivation | The cumulative incidences of EBV reactivation in participants after transplantation, tested by realtime PCR | 180 days after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment | Neutrophil engraftment was defined as the first day with a neutrophil count > 0.5 × 10^9/L on three consecutive days postnadir; platelet engraftment was defined as the first day with a platelet count > 20 × 10^9/L without transfusion for five consecutive days postnadir. | 28 days after transplantation | 
| The cumulative incidences of aGVHD (refer to MAGIC criteria) | Defined as the proportion of participants who developed acute GVHD | 100 days after transplantation | 
| The cumulative incidences of cGVHD (refer to NIH criteria) | cGvHD was diagnosed and graded according to the 2014 National Institutes of Health (NIH) consensus criteria: mild, moderate or severe respectively. | 2 years after transplantation | 
| Relapse | Defined as reappearance of leukemic blasts in peripheral blood or ≥5% blasts in BM or reappearance or new appearance of extramedullary leukemia. | 1 years after transplantation | 
| Nonrelapse mortality (NRM) | Defined as death due to causes other than malignancy relapse | 1 years after transplantation | 
| Disease-free survival (DFS) | Defined as survival with no evidence of relapse or progression. | 1 years after transplantation | 
| Overall survival (OS) | Defined as the time from transplantation to last follow-up or death due to any cause | 1 year after transplantation |