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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Individual dose of ATG | Experimental | The total individual ATG dose was calculated based on population pharmacokinetic modeling. ATG was intravenously infused every day from day -5 to day -2. |
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| ATG 10mg/kg | Active Comparator | The total ATG dose was 10mg/kg. ATG was intravenously infused every day from day -5 to day -2. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Individual ATG | Drug | 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. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
Patients with any conditions not suitable for the trial (investigators' decision).
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Xiaowen Tang, PhD | Contact | 67781525 | xwtang1020@163.com | |
| Depei Wu, PhD | Contact | 67781856 | drwudepei@163.com |
| Name | Affiliation | Role |
|---|---|---|
| Xiaowen Tang, PhD | The First Affiliated Hospital of Soochow University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The First Affiliated Hospital of Soochow University | Recruiting | Suzhou | Jiangsu | 215006 | China |
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| ATG | Drug | 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. |
|
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 |