ATG Individualized Dosing Model in URD-PBSCT.

Application of Thymoglobulin (ATG) Individualized Dosing Model in Unrelated Allogeneic Hematopoietic Stem Cell Transplantation.

Anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation to prevent severe graft-versus-host disease (GVHD) and graft failure. However, overexposure to ATG may increase cytomegalovirus (CMV), Epstein-Barr virus (EBV) reactivation, non-relapse mortality, and disease recurrence. A targeted dosing strategy was established based on ATG concentration monitoring and conducted a phase 2 trial to evaluate the safety and efficacy of the dosing strategy in adult unmanipulated haplo-PBSCT, a encouraging result was attained. In this trial, The ATG-targeted dosing strategy was extended to adult unrelated donor allogeneic hematopoietic stem cell transplantation, ATG was administered for 4 days (-5 days to -2 days) during conditioning. The ATG doses on-3 days and- 2days were adjusted by our dosing strategy to achieve the optimal ATG exposure. The primary endpoint was CMV reactivation on +180 days.

Study Overview

• Status: Recruiting
• Conditions: Cytomegalovirus Infections; Stem Cell Transplant Complications; Infection Reactivation
• Intervention / Treatment: Drug: individualized ATG dosing strategy

Detailed Description

Allogeneic hematopoietic cell transplantation(allo-HCT) is a curative therapy for hematological disorders and the ATG is commonly used as prophylaxis for GVHD. Previous studies have indicated that there is an optimal dosage for ATG administration, if the dosage is too high, it may affect engraftment and increase the risk of infection and relapse, whereas an inadequate dosage may increase the risk of acute or chronic GVHD, there is still controversy about the optimal dose of ATG, its pharmacologic effects on clinical outcomes of HSCT are associated with donor source, human leukocyte antigen (HLA) disparity, conditioning intensity, and GVHD prophylaxis, so although has been investigated for decades, the optimal dosage of ATG in allogeneic hematopoietic stem cell transplantation remains undetermined.

ATG exerts pharmacologic effects in its active form upon binding to lymphocytes, and its exposure is presented as the area under the concentration-time curve (AUC). To obtain plasma active ATG concentrations, investigators developed an active ATG concentration detection method based on flow-cytometry with HUT-78 T-cells. In previous study, investigators quantified active ATG exposure in 106 haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) recipients, who received a conventional fixed dose of 10 mg/kg ATG during conditioning, the optimal concentration range of active ATG-AUC was determined through the application of machine learning methods, was found to be 100-148.5 × 10^3 UE·d/L. This concentration range was associated with a reduction in CMV/EBV reactivation, without an increase in acute GVHD or malignant disease relapse. Mathematical function was then exploited to determine the total targeted ATG dose on -3days to -2days based on concentrations of active ATG on -5daysto -4days. Based on this function, a dosing strategy was established that aimed to maintain the active ATG-AUC within the optimal range. To validate this individualized dosing strategy, investigators conducted a single-arm, phase 2 trial, demonstrating that this strategy could reduce CMV/EBV reactivation and improve survival without increasing the incidence of GVHD after haplo-PBSCT. Given the similarity between unrelated donor hematopoietic stem cell transplantation (URD-HSCT) and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in terms of conditioning regimens, GVHD prophylaxis, and supportive therapies, as well as the conventional fixed dose of 10mg/kg employed in both settings, investigators have designed and conducted a single-center, prospective, single-arm clinical trial. The aim of this trial is to translate the individualized ATG dosing strategy, which was originally developed based on ATG concentration monitoring in haplo-HSCT patients, to URD-HSCT, with the goal of further validating its effectiveness.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sheng Chen, master; Phone Number: 15101156205; Email: csto301@163.com

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Department of Hematology, First Medical Center of Chinese PLA General Hospital
    • Contact: jiang Cao; Phone Number: 010-66937166

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with malignant hematological tumors who have indications for allogeneic hematopoietic stem cell transplantation.
2. HLA-matched unrelated donor
3. Patient age ≥14 years old and ≤65 years old
4. ALT and AST ≤ 2.5 times the upper limit of normal values, bilirubin ≤ 2 times the upper limit of normal values
5. Creatinine ≤ high limit of normal value
6. No uncontrollable infection or serious mental illness
7. Physical strength score is 0-2 (ECOG)
8. Sign the informed consent form

Exclusion Criteria:

1. Unrelated donor who is not HLA matched
2. No indication for allogeneic hematopoietic stem cell transplantation
3. Patient age <14 years old or >65 years old
4. The donor or recipient are pregnant
5. Suffering from mental illness or other conditions and being unable to proceed as planned

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: targeted dosing ATG cohort; The targeted dosing ATG cohort received the same dose of medication at -5 days and -4 days as the traditional administration method (-5days, 1.5mg/kg; -4days 2.5mg/kg), Two individual doses were given on -3days and day -2days according to the dose adjustment strategy.

Drug: individualized ATG dosing strategy; Investigators quantified active ATG exposure in 106 haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) recipients, who received a conventional fixed dose of 10 mg/kg ATG during conditioning, the optimal concentration range of active ATG-AUC was determined through the application of machine learning methods, was found to be 100-148.5 × 10^3 UE·d/L. This concentration range was associated with a reduction in CMV/EBV reactivation, without an increase in acute GVHD or malignant disease relapse. Mathematical function was then exploited to determine the total targeted ATG dose on -3days to -2days based on concentrations of active ATG on -5daysto -4days. Based on this function, investigators established a dosing strategy that aimed to maintain the active ATG-AUC within the optimal range.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cumulative incidence of CMV reactivation	The primary endpoint was the cumulative incidence of CMV reactivation on +180 days after transplantation.	0Day-180Days

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital
• Investigators: Principal Investigator: diahong Liu, MD, First Medical center of Chinese PLA General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2020
• Primary Completion (Estimated): December 30, 2024
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: August 23, 2024
• First Submitted That Met QC Criteria: August 26, 2024
• First Posted (Actual): August 27, 2024

Study Record Updates

• Last Update Posted (Actual): December 3, 2024
• Last Update Submitted That Met QC Criteria: November 28, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Virus Diseases; DNA Virus Infections; Herpesviridae Infections; Latent Infection; Infections; Communicable Diseases; Cytomegalovirus Infections
• Other Study ID Numbers: S2023-794-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No