Targeted Dose Study of ATG in Haploidentical Hematopoietic Stem Cell Transplantation

Impact of Optimal Doses of Antithymocyte Globulin Conditioning on Graft Versus-host Disease and Virus Reactivation in Haploidentical Hematopoietic Stem Cell Transplantation

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).

Study Overview

• Status: Completed
• Conditions: Haploidentical Hematopoietic Stem Cell Transplantation
• Intervention / Treatment: Drug: Individual Antithymocyte globulin; Drug: Antithymocyte globulin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 204
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100853
      • Chinese PLA General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Individual dose of ATG; 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; 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.
Active Comparator: Fixed dose of ATG; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GVHD-free and relapse-free survival (GRFS)	GRFS is defined as a composite endpoint of death from any cause, disease relapse, grade III-IV acute GVHD, or moderate to severe chronic GVHD requiring systemic immunosuppression therapy.	12 months after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
Cumulative incidences of CMV reactivation	CMV reactivation was defined as DNA load ≥ 1×104 copies /mL or ≥ 1×103 copies/mL in two consecutive tests. The cumulative incidence of CMV reactivation by Day +180 post-transplantation was defined as the proportion of CMV reactivation occurring at any monitoring point during 6 months post-transplant.	6 months after transplantation

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital
• Collaborators: Peking University People's Hospital, Peking University Institute of Hematology; Department of Hematology, The First Affiliated Hospital of Zhengzhou University
• Investigators: Principal Investigator: Daihong Liu, Doctor, Chinese PLA General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Actual): February 16, 2024
• Study Completion (Actual): July 29, 2025

Study Registration Dates

• First Submitted: November 22, 2021
• First Submitted That Met QC Criteria: December 12, 2021
• First Posted (Actual): December 22, 2021

Study Record Updates

• Last Update Posted (Actual): January 21, 2026
• Last Update Submitted That Met QC Criteria: January 18, 2026
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: ATG; Haplo-HSCT
• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Proteins; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Immune Sera; Antilymphocyte Serum
• Other Study ID Numbers: S2020-484-02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No