Clinical Study of rATG Individualized Administration in Haploidentical Hematopoietic Stem Cell Transplantation

Study Overview
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Brief Summary
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The purpose of this prospective, open-label, pairing design, single-center study is to evaluate the effect of individualized rATG dosing vs traditional weight-based rATG dosing regimen（10mg/kg）for patients with acute leukemia undergoing a myeloablative conditioning regimen and haploidentical hematopoietic stem cell transplantation (haplo-HSCT).

Detailed Description
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Allogeneic hematopoietic stem-cell transplantation (HSCT) is a potentially curative treatment option for acute leukemia. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has become the main choice for acute leukemia in China. Major difficulties of the procedure include graft-versus-host disease (GVHD), graft failure, and relapse. As an important role of haplo-HSCT, Rabbit anti-thymocyte globulin (rATG), a polyclonal rabbit-derived antibody that depletes lymphocytes, including T cells, was introduced to prevent GVHD and transplant rejection. The recommended dose of rATG in haplo-HSCT is 10 mg/kg. However, while the traditional weight-based rATG dosing regimen (10mg/kg) reduces the incidence of GVHD, it increases the risk of delayed immune reconstitution, viral reactivation, and relapse in patients. Our previous retrospective study showed that active ATG exposure (area under the curve, AUC)) post-transplantation is associated with immune reconstitution, GVHD, relapse, survival, and viral reactivation in HSCT of acute leukemia patients. Identifying the optimal dose of ATG to achieve the optimal exposure range of active ATG is a pressing clinical issue. The pharmacokinetics of ATG varies significantly in both pediatric and adult populations, especially the active ATG levels, and clarifying the relationship between the pharmacokinetics of ATG and the prognosis of patient outcomes can help in precise treatment. By constructing a population pharmacokinetic model of ATG, we can provide an individualized optimal dose of ATG based on factors prior to transplantation. ATG individualized administration may improve the survival and quality of life of patients undergoing haplo-HSCT. A prospective pairing design trial is required to evaluate the effect of individualized rATG dosing vs traditional weight-based rATG dosing regimen (10mg/kg) for patients with acute leukemia undergoing haplo-HSCT.

Official Title
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Clinical Study of rATG Individualized Administration for Prevention of GVHD and Maintenance of GVL in Haploidentical Hematopoietic Stem Cell Transplantation.

Conditions
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Hematopoietic Stem Cell Transplantation, Acute Leukemia

Intervention / Treatment
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* Drug: Individual ATG
* Drug: ATG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients were diagnosed with acute leukemia. All patients should have the indication of Haploidentical hematopoietic stem cell transplant and receive the myeloablative conditioning regimen. 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: Patients with any conditions not suitable for the trial (investigators' decision).

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 60 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Individual dose of ATG<br>The total individual ATG dose was calculated based on population pharmacokinetic modeling. ATG was intravenously infused every day from day -5 to day -2. | Drug: Individual 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 population pharmacokinetic modeling). Prophylaxis against graft-versus-host disease (GVHD) was performed with cyclosporine A, mycophenolate mofetil, and low-dose methotrexate.<br>|
| Active Comparator: ATG 10mg/kg<br>The total ATG dose was 10mg/kg. ATG was intravenously infused every day from day -5 to day -2. | Drug: ATG<br>* ATG 10mg/kg: The total ATG dose was 10mg/kg. ATG was intravenously infused every day from day -5 to day -2. Prophylaxis against graft-versus-host disease (GVHD) was performed with cyclosporine A, mycophenolate mofetil, and low-dose methotrexate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidences of aGVHD | The diagnosis and grading of aGVHD are based on the modified Glucksberg grading standard. | 100 days after transplantation | 
| CD4+ immune reconstitution | CD4+ T-cells >0·05 × 10⁹/L twice within 3 months after transplantation | 3 months after transplantation | 
| Leukemia-free survival (LFS) | Leukemia-free survival (LFS) is defined as the time from enrollment to relapse of primary disease or death from any cause, whichever occurred first. | 1 years after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 years after transplantation | 
| Cumulative incidences of EBV reactivation | The cumulative incidences of EBV reactivation after transplantation | 1 years after transplantation | 
| Cumulative incidence of CMV reactivation | The cumulative incidences of CMV reactivation after transplantation. | 1 years 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. | 1 years after transplantation | 
| GVHD-free and relapse-free survival (GRFS) | 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. | 1 years after transplantation | 
| Non-relapse mortality (NRM) | Non-relapse mortality (NRM) is defined as the time from enrollment to death of any causes other than hematologic disease relapse. | 1 years after transplantation | 
| Relapse-related mortality (RRM) | Relapse-related mortality (RRM) is defined as the time from enrollment to death of relapse. | 1 years after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antithymocyte Globulin, Population pharmacokinetic model, Haploidentical Hematopoietic Stem Cell Transplantation, Acute Leukemia