Individualized Dose Study of ATG in Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical Hematopoietic Stem Cell Transplantation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05166967
• Other study ID #: S2020-484-02
• Status: Recruiting
• Phase: Phase 4
• Start date: January 1, 2022
• Est. completion date: June 1, 2024

Study information

• Verified date: September 2022
• Source: Chinese PLA General Hospital
• Contact: Liping Dou, Doctor
• Phone: 86-13681207138
• Email: lipingruirui[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 204
• Est. completion date: June 1, 2024
• Est. primary completion date: February 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years to 65 Years

Eligibility

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).

Related Conditions & MeSH terms

• Haploidentical Hematopoietic Stem Cell Transplantation

Intervention

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.
• 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.

Locations

Country	Name	City	State
China	Chinese PLA General Hospital	Beijing	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Chinese PLA General Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Incidence of CMV disease	The cumulative incidences of CMV disease in participants after transplantation,	6 months after transplantation
Secondary	Cumulative incidences of aGVHD	The diagnosis and grading of aGVHD are based on the modified Glucksberg grading standard.	365 days after transplantation
Secondary	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
Secondary	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
Secondary	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
Secondary	Overall survival (OS)	Overall survival (OS) is defined as the time from randomization to death resulting from any cause.	365 days after transplantation
Secondary	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
Secondary	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
Secondary	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
Secondary	Infection rate	Infection rate is defined as the proportion of participants who developed all kinds of infection	365 days after transplantation
Secondary	Cumulative incidences of EBV reactivation	The cumulative incidences of EBV reactivation in participants after transplantation, tested by EBV realtime PCR.	6 months after transplantation
Secondary	Cumulative incidences of PTLD(posttransplant lymphoproliferative disorders)	The cumulative incidences of PTLD in participants after transplantation	6 months after transplantation