Individualized Dose Study of ATG in Haploidentical Hematopoietic Stem Cell Transplantation

Chinese PLA General Hospital63 enrolled

Overview

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 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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Haploidentical Hematopoietic Stem Cell Transplantation

Interventions

Antithymocyte GlobulinDRUG

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

Eligibility

Sex: ALLMin age: 14 YearsMax age: 60 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Confirmed diagnosis of hematological malignancies refer to the 2016 WHO classification. 2. Aged 14 to 60 years. 3. Karnofsky or Lansky performance status \[27\] ≥ 70%. Please refer to Appendix A. 4. First transplantation. 5. Adequate organ function 6. Patient and/or legal guardian must sign informed consent for HSCT. Exclusion Criteria: 1. Ex-vivo T-cell depleted grafts. 2. Pregnancy or breast-feeding or unwilling to use proper contraception. 3. Unable to assess whether the malignancy is in complete remission. 4. History of hypersensitivity to any biological product. 5. Sensibility to rabbit proteins or previous treatment with Thymoglobuline®. 6. Subjects with uncontrollable systemic infection (viral, bacterial or fungal). 7. Participation in other trial in which the dose of Thymoglobuline® is fixed other than individualized dose. 8. Unable to sign the informed consent form.

Locations (1)

Chinese PLA General Hospital

Beijing, Beijing Municipality, China

Outcomes

Primary Outcomes

The cumulative incidences of CMV reactivation

The cumulative incidences of CMV reactivation in participants after transplantation, tested by realtime PCR

Time frame: 180 days after transplantation

The cumulative incidences of EBV reactivation

The cumulative incidences of EBV reactivation in participants after transplantation, tested by realtime PCR

Time frame: 180 days after transplantation

Secondary Outcomes

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.

Time frame: 28 days after transplantation

The cumulative incidences of aGVHD (refer to MAGIC criteria)

Defined as the proportion of participants who developed acute GVHD

Time frame: 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.

Time frame: 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.

Time frame: 1 years after transplantation

Nonrelapse mortality (NRM)

Data from ClinicalTrials.gov

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