Individualized Dose Study of ATG in Haploidentical Hematopoietic Stem Cell Transplantation

Impact of Optimal Doses of Antithymocyte Globulin Conditioning on Graft-versus- Host Disease and Virus Reactivation in Haploidentical Hematopoietic Stem Cell Transplantation

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Haploidentical Hematopoietic Stem Cell Transplantation
• Intervention / Treatment: Drug: Antithymocyte Globulin

Detailed Description

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
• Enrollment (Anticipated): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100853
      • Chinese PLA General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

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: Individual dose of Thymoglobulin; Individual dose of Thymoglobulin (r-ATG) : 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)

Drug: Antithymocyte Globulin; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The cumulative incidences of EBV reactivation	The cumulative incidences of EBV reactivation in participants after transplantation, tested by realtime PCR	180 days after transplantation
The cumulative incidences of CMV reactivation	The cumulative incidences of CMV reactivation in participants after transplantation, tested by realtime PCR	180 days after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Defined as the time from transplantation to last follow-up or death due to any cause	1 year after transplantation
Nonrelapse mortality (NRM)	Defined as death due to causes other than malignancy relapse	1 years after transplantation
Disease-free survival (DFS)	Defined as survival with no evidence of relapse or progression.	1 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.	1 years after transplantation
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.	28 days after transplantation
The cumulative incidences of aGVHD (refer to MAGIC criteria)	Defined as the proportion of participants who developed acute GVHD	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.	2 years after transplantation

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital
• Investigators: Study Chair: Dai-Hong Liu, Dr., Chinese PLA General Hospital

Publications and helpful links

General Publications

• Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, Oneto R, Bruno B, Sacchi N, van Lint MT, Bosi A; Gruppo Italiano Trapianti Midollo Osseo (GITMO). Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant. 2006 May;12(5):560-5. doi: 10.1016/j.bbmt.2005.12.034.
• Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, Oneto R, Bruno B, Barbanti M, Sacchi N, Van Lint MT, Bosi A. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001 Nov 15;98(10):2942-7. doi: 10.1182/blood.v98.10.2942.
• Call SK, Kasow KA, Barfield R, Madden R, Leung W, Horwitz E, Woodard P, Panetta JC, Baker S, Handgretinger R, Rodman J, Hale GA. Total and active rabbit antithymocyte globulin (rATG;Thymoglobulin) pharmacokinetics in pediatric patients undergoing unrelated donor bone marrow transplantation. Biol Blood Marrow Transplant. 2009 Feb;15(2):274-8. doi: 10.1016/j.bbmt.2008.11.027.
• Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, Gallagher G, Kerr H, Kuruvilla J, Lee SJ, Moore J, Nevill T, Popradi G, Roy J, Schultz KR, Szwajcer D, Toze C, Foley R; Canadian Blood and Marrow Transplant Group. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016 Feb;17(2):164-173. doi: 10.1016/S1470-2045(15)00462-3. Epub 2015 Dec 24. Erratum In: Lancet Oncol. 2018 Nov;19(11):e581.
• Remberger M, Svahn BM, Mattsson J, Ringden O. Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation. Transplantation. 2004 Jul 15;78(1):122-7.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Actual): July 31, 2022
• Study Completion (Anticipated): January 14, 2024

Study Registration Dates

• First Submitted: February 24, 2021
• First Submitted That Met QC Criteria: February 28, 2021
• First Posted (Actual): March 3, 2021

Study Record Updates

• Last Update Posted (Actual): April 11, 2023
• Last Update Submitted That Met QC Criteria: April 7, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Antilymphocyte Serum
• Other Study ID Numbers: S2020-484-01

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