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

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

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).

Study Overview

• Status: Recruiting
• Conditions: Acute Leukemia; Hematopoietic Stem Cell Transplantation
• Intervention / Treatment: Drug: Individual ATG; Drug: ATG

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Suzhou, Jiangsu, China, 215006
      • Recruiting
      • The First Affiliated Hospital of Soochow University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. All patients were diagnosed with acute leukemia.
2. All patients should have the indication of Haploidentical hematopoietic stem cell transplant and receive the myeloablative conditioning regimen.
3. 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Individual dose of ATG; 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; 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.
Active Comparator: ATG 10mg/kg; The total ATG dose was 10mg/kg. ATG was intravenously infused every day from day -5 to day -2.	Drug: ATG; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Soochow University

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2022
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): May 1, 2025

Study Registration Dates

• First Submitted: November 22, 2022
• First Submitted That Met QC Criteria: November 22, 2022
• First Posted (Actual): December 2, 2022

Study Record Updates

• Last Update Posted (Actual): February 15, 2023
• Last Update Submitted That Met QC Criteria: February 13, 2023
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Acute Leukemia; Antithymocyte Globulin; Population pharmacokinetic model; Haploidentical Hematopoietic Stem Cell Transplantation
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia
• Other Study ID Numbers: ATGIA2022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No