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).
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
204
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.
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.
Chinese PLA General Hospital
Beijing, Beijing Municipality, China
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.
Time frame: 12 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.
Time frame: 6 months after transplantation
Incidence of CMV disease
The cumulative incidences of CMV disease in participants after transplantation,
Time frame: 6 months after transplantation
Cumulative incidences of EBV reactivation
The cumulative incidences of EBV reactivation in participants after transplantation, tested by EBV realtime PCR.
Time frame: 6 months after transplantation
Cumulative incidences of PTLD(posttransplant lymphoproliferative disorders)
The cumulative incidences of PTLD in participants after transplantation
Time frame: 6 months after transplantation
Cumulative incidences of aGVHD
The diagnosis and grading of aGVHD are based on the modified Glucksberg grading standard.
Time frame: 365 days after transplantation
Cumulative incidences of cGVHD
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
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.
Time frame: 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.
Time frame: 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
Time frame: 1 month after transplantation
Overall survival (OS)
Overall survival (OS) is defined as the time from randomization to death resulting from any cause.
Time frame: 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.
Time frame: 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.
Time frame: 365 days after transplantation
Infection rate
Infection rate is defined as the proportion of participants who developed all kinds of infection
Time frame: 365 days after transplantation