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 haploHSCT. 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 post engraftment immunosuppressive regimens. The regimens for prophylaxis of GVHD based on 10mg/kg rabbit anti-human thymocyte immunoglobin (ATG, Thymoglobin®, Genzyme Polyclonals S.A.S) effectively reduced the occurrence of grade II-IV aGvHD. Howevre, 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. In our previous cohort study, we found that virus reactivation and acute GVHD were highly affected by ATG exposure (area under the curve, AUC). We have found an optimal range of active ATG range is 110-148.5UE/ml.day the efficacy of GVHD prophylaxis and the risk of virus reactivation. The cumulative incidence of CMV reactivation and persistent CMV hyperemia at 180 days after transplantation in the optimal total AUC group was 60.57% and 31.52% respectively. Significantly lower than 77.08% and 56.25% in the non-optimal total AUC group. 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: Individual Antithymocyte globulin
* Drug: Antithymocyte globulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. All patients should have the indication of Haploidentical hematopoietic stem cell transplant. 2. All patients should sign an informed consent document indicating that they understand the purpose of and procedures required for the study and be willing to participate in the study. Exclusion Criteria: 1.Patients with any conditions not suitable for the trial (investigators' decision).

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Random Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Individual dose of ATG<br>Individual dose of 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 13mg/kg), and the active ATG concentration ranges from 110 to 148.5UE/ml. | Drug: Individual 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 13mg/kg). Prophylaxis against graft versus-host disease (GVHD) was performed with cyclosporine A (CsA), mycophenolate mofetil (MMF) and short-term methotrexate.<br>|
| Active Comparator: Fixed dose of ATG<br>A total amount of 10mg/kg ATG was divided into 4 days (from day -5 to day -2). The specific usage: 1.5mg/kg for day -5, 2.5mg/kg for day -4 and day -3, 3.5 mg/kg for day -2. | Drug: Antithymocyte globulin<br>* A 10mg/kg total dose of antithymocyte globulin (ATG) was added to conditioning regimens for 4 days (from day -5 to day -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 |
| --- | --- | --- |
| Cumulative incidences of CMV reactivation | The cumulative incidences of CMV reactivation in participants after transplantation, tested by CMV realtime PCR. | 6 months after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of CMV disease | The cumulative incidences of CMV disease in participants after transplantation, | 6 months after transplantation | 
| Cumulative incidences of aGVHD | The diagnosis and grading of aGVHD are based on the modified Glucksberg grading standard. | 365 days after transplantation | 
| Cumulative incidences of cGVHD | Chronic GVHD can be classified as limited or extensive according to the Seattle criteria, and also be classified as mild or moderate or severe according to the National Institutes of Health (NIH) criteria. | 365 days after transplantation | 
| Neutrophil engraftment | Neutrophil engraftment is defined as the first of 3 consecutive days with an absolute neutrophil count > 0.5 × 10^9/L. | 1 month after transplantation | 
| Platelet engraftment | Platelet engraftment is defined as the first of 7 consecutive days with an absolute platelet count > 20 × 10^9/L independent from transfusion | 1 month after transplantation | 
| Overall survival (OS) | Overall survival (OS) is defined as the time from randomization to death resulting from any cause. | 365 days after transplantation | 
| Disease-free survival (DFS) | Disease-free survival (DFS) is defined as the time from enrollment to relapse of primary disease or death from any cause, whichever occurred first. | 365 days after transplantation | 
| GRFS (GVHD free, relapse free survival) | GRFS is defined as the time from graft infusion to the onset of grades 3 to 4 aGVHD, moderate to severe cGVHD, or relapse/disease progression/death. | 365 days after transplantation | 
| Nonrelapse mortality (NRM) | Non-relapse mortality (NRM) is defined as the time from enrollment to death of any causes other than hematologic disease relapse. | 365 days after transplantation | 
| Infection rate | Infection rate is defined as the proportion of participants who developed all kinds of infection | 365 days after transplantation | 
| Cumulative incidences of EBV reactivation | The cumulative incidences of EBV reactivation in participants after transplantation, tested by EBV realtime PCR. | 6 months after transplantation | 
| Cumulative incidences of PTLD(posttransplant lymphoproliferative disorders) | The cumulative incidences of PTLD in participants after transplantation | 6 months after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATG, Haplo-HSCT